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Regression v0.554 FDXR Zornitza Stark edited their review of gene: FDXR: Added comment: Multiple reports of individuals with extra-ocular features, including ID and regression; microcephaly.; Changed rating: GREEN; Changed publications: 30250212, 28965846, 29040572, 33348459, 37046037, 37481223; Changed phenotypes: Auditory neuropathy and optic atrophy, MIM# 617717, Neurodevelopmental disorder with mitochondrial abnormalities, optic atrophy, and developmental regression, MIM# 620887
Regression v0.552 PSMF1 Zornitza Stark gene: PSMF1 was added
gene: PSMF1 was added to Regression. Sources: Literature
Mode of inheritance for gene: PSMF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMF1 were set to https://www.medrxiv.org/content/10.1101/2024.06.19.24308302v1
Phenotypes for gene: PSMF1 were set to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PSMF1-related
Review for gene: PSMF1 was set to GREEN
Added comment: 22 individuals from 15 families reported with a range of neurological phenotypes ranging from early-onset Parkinson's disease; childhood conditions typified by ID and a range of movement disorders; through to perinatal lethal presentations with arthrogryposis multiplex.

Genotype-phenotype correlation: biallelic missense variants resulted in the milder phenotypes, while bi-allelic LoF variants in the more severe phenotypes. Supportive functional data.
Sources: Literature
Regression v0.548 ABCD1 Zornitza Stark reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15811009, 8651290, 7825602, 21700483; Phenotypes: adrenoleukodystrophy (MONDO:0018544); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Regression v0.548 NAA60 Zornitza Stark Phenotypes for gene: NAA60 were changed from Basal ganglia calcification, MONDO:0008947, NAA60-related to Basal ganglia calcification, idiopathic, 9, autosomal recessive, MIM# 620786
Regression v0.547 NAA60 Zornitza Stark edited their review of gene: NAA60: Changed phenotypes: Basal ganglia calcification, idiopathic, 9, autosomal recessive, MIM# 620786
Regression v0.546 CIAO1 Zornitza Stark gene: CIAO1 was added
gene: CIAO1 was added to Regression. Sources: Literature
Mode of inheritance for gene: CIAO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CIAO1 were set to 38411040; 38196629
Phenotypes for gene: CIAO1 were set to Neurodegenerative disease, MONDO:0005559, CIAO1-related
Review for gene: CIAO1 was set to GREEN
Added comment: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence. Muscle biopsy showed variation in fiber size and an increase in internalized nuclei, as well as scattered degenerating/regenerating fibers and a mild to minimal increase in endomysial fibrosis. Electron microscopy revealed morphologically abnormal mitochondria.

PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out.

All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1.
Sources: Literature
Regression v0.545 MMS19 Zornitza Stark gene: MMS19 was added
gene: MMS19 was added to Regression. Sources: Literature
Mode of inheritance for gene: MMS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMS19 were set to 38411040
Phenotypes for gene: MMS19 were set to Neurodegenerative disease, MONDO:0005559, MMS19-related
Review for gene: MMS19 was set to RED
Added comment: Single patient reported with postnatal microcephaly, bilateral cataracts, failure to thrive, progressive spastic tetraparesis, scoliosis, myoclonic epilepsy and precocious puberty. Cerebral MRI at age 4 years showed pontocerebellar atrophy and white matter abnormalities. Patient died age 13 after recurrent respiratory tract infections. A homozygous in-frame deletion p.(Glu213del) was identified. Cell line studies supported pathogenicity of the variant. A zebrafish knockout model showed Mms19 deficiency had detrimental effects on development.
Sources: Literature
Regression v0.544 HMBS Zornitza Stark Phenotypes for gene: HMBS were changed from to Encephalopathy, porphyria-related MIM#620704; Leukoencephalopathy, porphyria-related, MIM#620711
Regression v0.542 HMBS Zornitza Stark reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Encephalopathy, porphyria-related MIM#620704, Leukoencephalopathy, porphyria-related, MIM#620711; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.542 FTH1 Zornitza Stark Phenotypes for gene: FTH1 were changed from Neuroferritinopathy (MONDO:0011638) to Neurodegeneration with brain iron accumulation 9, MIM# 620669
Regression v0.541 FTH1 Zornitza Stark reviewed gene: FTH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with brain iron accumulation 9, MIM# 620669; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.540 BORCS8 Lauren Rogers changed review comment from: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature; to: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. 5/5 hypotonia, failure to thrive, global developmental delay, profound intellectual disability, muscle weakness and atrophy, dysmorphic features. 3/5 with microcephaly, 3/5 with seizures, 4/5 with spasticity, 3/5 with scoliosis, 4/4 with optic atrophy.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature
Regression v0.540 BORCS8 Lauren Rogers gene: BORCS8 was added
gene: BORCS8 was added to Regression. Sources: Literature
Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS8 were set to 38128568
Phenotypes for gene: BORCS8 were set to Neurodevelopmental disorder (MONDO#0700092), BORCS8-related
Review for gene: BORCS8 was set to GREEN
Added comment: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature
Regression v0.539 PRICKLE1 Zornitza Stark edited their review of gene: PRICKLE1: Added comment: LIMITED by ClinGen for AR PME, DISPUTED for AD epilepsy.; Changed rating: RED
Regression v0.537 PRICKLE1 Zornitza Stark Mode of inheritance for gene: PRICKLE1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Regression v0.535 PRICKLE1 Zornitza Stark reviewed gene: PRICKLE1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34597683, 30564977, 30345727, 29790814, 26727662, 31035234; Phenotypes: Epilepsy, progressive myoclonic 1B, MIM# 612437; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Regression v0.534 CAPRIN1 Zornitza Stark edited their review of gene: CAPRIN1: Changed rating: AMBER
Regression v0.534 CAPRIN1 Zornitza Stark gene: CAPRIN1 was added
gene: CAPRIN1 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAPRIN1 were set to 36136249
Phenotypes for gene: CAPRIN1 were set to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, MIM# 620636
Review for gene: CAPRIN1 was set to GREEN
Added comment: Two individuals reported with the same de novo c.1535C > T (p.Pro512Leu) variant and a progressive course with onset in childhood.

Another 12 individuals reported in previous publications with ID/SZ.
Sources: Expert Review
Regression v0.533 LNPK Lilian Downie gene: LNPK was added
gene: LNPK was added to Regression. Sources: Literature
Mode of inheritance for gene: LNPK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LNPK were set to PMID: 35599435, https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcad222/7243438?login=true
Phenotypes for gene: LNPK were set to Neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum MIM#618090
Review for gene: LNPK was set to GREEN
Added comment: Moderate to severe ID, majority of patients 10/15 have period of regression
Epilepsy (myoclonic frequently)
Structural brain anomalies 'ear of the lynx sign', callosal hypoplasia, mild brain including cerebellar atrophy.
Microcephaly, macrocephaly and normal head circumference described.
Sources: Literature
Regression v0.533 FTH1 Bryony Thompson Publications for gene: FTH1 were set to 36778397
Regression v0.532 FTH1 Bryony Thompson Classified gene: FTH1 as Green List (high evidence)
Regression v0.532 FTH1 Bryony Thompson Added comment: Comment on list classification: Article describing the gene-disease association with neuroferritinopathy now published in HGG advances
Regression v0.532 FTH1 Bryony Thompson Gene: fth1 has been classified as Green List (High Evidence).
Regression v0.531 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNH1-related; encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related to Neurodevelopmental disorder, MONDO:0700092, RNH1-related; {Encephalopathy, acute, infection-induced, susceptibiliyt to, 12}, MIM# 620461
Regression v0.529 NAA60 Zornitza Stark gene: NAA60 was added
gene: NAA60 was added to Regression. Sources: Other
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NAA60 were set to Basal ganglia calcification, MONDO:0008947, NAA60-related
Review for gene: NAA60 was set to GREEN
Added comment: ESHG 2023:
10 individuals from 7 families with biallelic variants in NAA60 (missense and framshift).
All with primary brain calcification - 4/10 childhood onset (DD, ID), 6/10 adult onset (cerebellar and pyramidal dysfunction, dystonia, parkinsonism, cognitive impairment, psychiatric manifestations).

NAA60 catalyses N-terminal acetylation of transmembrane proteins and localises to Golgi apparatus. In vitro assay of variants showed reduced capacity of Nt acetylation. Fibroblast studies showed significantly reduced levels of phosphate importer (SLC20A2). Loss of function variants in SLC20A2 (~50% of PFBC cases) lead to increased extracellular phosphate (which is thought to lead to calcium deposits in brain).
Sources: Other
Regression v0.527 ZIC1 Chirag Patel reviewed gene: ZIC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Regression v0.527 RNH1 Ain Roesley Phenotypes for gene: RNH1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNH1-related; encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related to Neurodevelopmental disorder, MONDO:0700092, RNH1-related; encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related
Regression v0.526 RNH1 Ain Roesley Phenotypes for gene: RNH1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNH1-related to Neurodevelopmental disorder, MONDO:0700092, RNH1-related; encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related
Regression v0.525 RNH1 Dean Phelan reviewed gene: RNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37191094; Phenotypes: encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.524 RNH1 Zornitza Stark reviewed gene: RNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.523 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Regression v0.523 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Regression. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Regression v0.522 SLC31A1 Zornitza Stark gene: SLC31A1 was added
gene: SLC31A1 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to 35913762; 36562171
Phenotypes for gene: SLC31A1 were set to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Review for gene: SLC31A1 was set to AMBER
Added comment: PMID:36562171
Homozygous c.236T>C; p.(Leu79Pro) identified in a newborn of consanguineous parents. Variant absent from gnomAD. Prenatal ultrasound showed a male fetus with short femoral bones, an apparently enlarged heart-to-thorax ratio, and a wide cisterna magna. The infant was born with pulmonary hypoplasia. At 2 weeks of age, multifocal brain hemorrhages were diagnosed and the infant developed seizures. The infant died at 1 month of age. The Mother had three healthy children while nine pregnancies had been extrauterine gravidities or ended in first or mid-trimester spontaneous abortions.

PMID: 35913762
SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert Review
Regression v0.521 FTH1 Zornitza Stark Marked gene: FTH1 as ready
Regression v0.521 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Regression v0.521 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)
Regression v0.521 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Regression v0.520 FTH1 Paul De Fazio gene: FTH1 was added
gene: FTH1 was added to Regression. Sources: Literature
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FTH1 were set to 36778397
Phenotypes for gene: FTH1 were set to Neuroferritinopathy (MONDO:0011638)
Mode of pathogenicity for gene: FTH1 was set to Other
Review for gene: FTH1 was set to AMBER
gene: FTH1 was marked as current diagnostic
Added comment: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Regression v0.520 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210 to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.520 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.519 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.519 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Regression v0.518 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Regression v0.517 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Regression. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Regression v0.515 KCTD7 Zornitza Stark Phenotypes for gene: KCTD7 were changed from to Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726)
Regression v0.513 KCTD7 Zornitza Stark reviewed gene: KCTD7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM#611726); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.513 BOLA3 Zornitza Stark gene: BOLA3 was added
gene: BOLA3 was added to Regression. Sources: Literature
Mode of inheritance for gene: BOLA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BOLA3 were set to 24334290; 29654549; 21944046; 22562699; 26741492; 24334290
Phenotypes for gene: BOLA3 were set to Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (MMDS2, OMIM #614299)
Review for gene: BOLA3 was set to GREEN
Added comment: At least 5 unrelated families reported. Clinical course is characterised by regression.
Sources: Literature
Regression v0.509 TCEAL1 Melanie Marty edited their review of gene: TCEAL1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related, hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features
Regression v0.509 TCEAL1 Melanie Marty edited their review of gene: TCEAL1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related, hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features.; Set current diagnostic: yes
Regression v0.509 EPRS Lucy Spencer gene: EPRS was added
gene: EPRS was added to Regression. Sources: Literature
Mode of inheritance for gene: EPRS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPRS were set to 36411955, 29576217
Phenotypes for gene: EPRS were set to Leukodystrophy, hypomyelinating, 15, MIM#617951
Review for gene: EPRS was set to GREEN
Added comment: 5 patients across 2 papers, with delayed development (3/5) and/or regression, ataxia, dystonia, hypomyelinating leukodystrophy or periventricular white matter abnormality, 2 with epilepsy, 3 with optic atrophy, 2 with deafness, 3 with microcephaly, 1 noted to have some facial dysmorphism.
Sources: Literature
Regression v0.509 TCEAL1 Melanie Marty changed review comment from: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.

Only 2 individuals with regression = amber at this stage.
Sources: Literature; to: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.

Only 2 individuals with regression = amber for this panel at this stage.
Sources: Literature
Regression v0.509 TCEAL1 Melanie Marty gene: TCEAL1 was added
gene: TCEAL1 was added to Regression. Sources: Literature
Mode of inheritance for gene: TCEAL1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TCEAL1 were set to PMID: 36368327
Phenotypes for gene: TCEAL1 were set to hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features.
Review for gene: TCEAL1 was set to AMBER
Added comment: 7 individuals (males and females) with de novo variants involving TCEAL1 with an X-linked
dominant neurodevelopmental syndrome. Individuals had hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features included strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies.

1 additional male individual with a maternally inherited missense variant (unaffected mother), which was considered a VUS. This individual had hypertonia and spasticity without syndromic features.

4 PTCs, 2 CNVs, 2 missense reported.

Only 2 individuals with regression = amber at this stage.
Sources: Literature
Regression v0.508 LETM1 Zornitza Stark gene: LETM1 was added
gene: LETM1 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214
Phenotypes for gene: LETM1 were set to Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM), MIM#620089
Review for gene: LETM1 was set to GREEN
Added comment: -18 affected individuals from 11 unrelated families harbouring ultra-rare bi-allelic missense and loss-of-function LETM1 variants
-Most of the affected individuals (14/18, 78%) had an infantile-onset disease manifestation,
and 4/18 (22%) presented first symptoms between the ages of 1.5 and 2 years
-Variant types included missense, frameshift, stop loss, in-frame deletion and splice defect
-From biochemical and morphological studies, bi-allelic LETM1 variants are associated with defective mitochondrial K efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components

Around half had regression.
Sources: Expert Review
Regression v0.507 ETHE1 Zornitza Stark Tag treatable tag was added to gene: ETHE1.
Regression v0.505 ARG1 Zornitza Stark reviewed gene: ARG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Argininaemia MIM#207800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.503 DBT Zornitza Stark reviewed gene: DBT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Maple syrup urine disease, type II (MIM#248600); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.501 ATP7A Zornitza Stark reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Menkes disease MIM#309400; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Regression v0.499 ARSA Zornitza Stark reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Metachromatic leukodystrophy, MIM# 250100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.496 UCHL1 Zornitza Stark Mode of inheritance for gene: UCHL1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Regression v0.495 UCHL1 Zornitza Stark edited their review of gene: UCHL1: Added comment: PMID 35986737: 34 individuals from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17).; Changed publications: 23359680, 3340629, 28007905, 32656641, 29735986, 28007905, 35986737; Changed phenotypes: Spastic paraplegia 79, autosomal recessive, MIM# 615491, MONDO:0014209, Neurodegenerative disease, MONDO:0005559, UCHL1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Regression v0.492 CC2D2A Zornitza Stark reviewed gene: CC2D2A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: COACH syndrome 2, MIM# 619111, Joubert syndrome 9, 612285, Meckel syndrome 6, 612284; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.489 ACO2 Zornitza Stark reviewed gene: ACO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22405087, 25351951, 30689204, 32519519, 25351951; Phenotypes: Infantile cerebellar-retinal degeneration, MIM#614559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.488 ACOX1 Alison Yeung gene: ACOX1 was added
gene: ACOX1 was added to Regression. Sources: Literature
Mode of inheritance for gene: ACOX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACOX1 were set to 32169171; 35715200
Phenotypes for gene: ACOX1 were set to Mitchell syndrome, MIM# 618960
Review for gene: ACOX1 was set to GREEN
Added comment: Mono-allelic variants (recurrent de novo missense, N237S) associated with Mitchell syndrome (MITCH): a progressive disorder characterised by episodic demyelination, sensorimotor polyneuropathy, and hearing loss. Bi-allelic variants cause a peroxisomal disorder characterised by neonatal hypotonia, seizures, apneic spells, delayed psychomotor development, and neurologic regression.
Sources: Literature
Regression v0.486 CHMP3 Chern Lim gene: CHMP3 was added
gene: CHMP3 was added to Regression. Sources: Literature
Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHMP3 were set to PMID: 35710109
Phenotypes for gene: CHMP3 were set to Hereditary spastic paraplegia (MONDO:0019064), CHMP3-related
Review for gene: CHMP3 was set to AMBER
gene: CHMP3 was marked as current diagnostic
Added comment: PMID: 35710109
- Single large family with consanguinity, homozygous missense variant in 5 affected individuals with intellectual and progressive motor disabilities, seizures and spastic quadriplegia.
- Functional studies showed reduced CHMP3 protein in patient's fibroblasts, lenti-rescue study showed improved cellular phenotypes associated with impaired autophagy.
Sources: Literature
Regression v0.484 DRD2 Zornitza Stark Mode of pathogenicity for gene: DRD2 was changed from to Other
Regression v0.481 DRD2 Zornitza Stark reviewed gene: DRD2: Rating: RED; Mode of pathogenicity: Other; Publications: 33200438; Phenotypes: Combined dystonia, MONDO:0020065, DRD2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.481 SHQ1 Zornitza Stark Phenotypes for gene: SHQ1 were changed from Dystonia; Neurodegeneration to Neurodevelopmental disorder with dystonia and seizures, MIM# 619922
Regression v0.480 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Changed phenotypes: Neurodevelopmental disorder with dystonia and seizures, MIM# 619922
Regression v0.479 IREB2 Zornitza Stark edited their review of gene: IREB2: Added comment: Additional individual reported PMID 35602653; Changed publications: 30915432, 31243445, 11175792, 35602653
Regression v0.476 GBA2 Zornitza Stark reviewed gene: GBA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23332916, 23332917, 29524657; Phenotypes: Spastic paraplegia 46, autosomal recessive, MIM# 614409, MONDO:0013737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.475 ATPAF2 Chirag Patel reviewed gene: ATPAF2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 14757859; Phenotypes: ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, OMIM# 604273; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.475 DRD2 Krithika Murali reviewed gene: DRD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Regression v0.474 FBP2 Zornitza Stark gene: FBP2 was added
gene: FBP2 was added to Regression. Sources: Expert list
Mode of inheritance for gene: FBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBP2 were set to 33977262
Phenotypes for gene: FBP2 were set to Leukodystrophy, childhood-onset, remitting, MIM# 619864
Review for gene: FBP2 was set to AMBER
Added comment: 8 individuals from 3 generations in a single family reported with a variant in this gene. The children presented with episode of regression and leukodystrophy in early childhood, from which they made a slow recovery. The adults had a broad range of neurobehavioural phenotypes but also had leukodystrophy on imaging. Some functional data presented (in vitro).
Sources: Expert list
Regression v0.472 DTYMK Zornitza Stark gene: DTYMK was added
gene: DTYMK was added to Regression. Sources: Expert Review
Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DTYMK were set to 34918187; 31271740
Phenotypes for gene: DTYMK were set to Neurodegeneration, childhood-onset, with progressive microcephaly (MIM# 619847)
Review for gene: DTYMK was set to GREEN
Added comment: Progressive neurodegenerative disorder, 3 families reported.
Sources: Expert Review
Regression v0.470 STX1A Ain Roesley gene: STX1A was added
gene: STX1A was added to Regression. Sources: Literature
Mode of inheritance for gene: STX1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: STX1A were set to neurodevelopmental disorder MONDO#0700092, STX1A-related
Review for gene: STX1A was set to AMBER
gene: STX1A was marked as current diagnostic
Added comment: Preprint: https://www.medrxiv.org/content/10.1101/2022.04.20.22274073v1
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature
Regression v0.465 PRKCG Zornitza Stark reviewed gene: PRKCG: Rating: RED; Mode of pathogenicity: None; Publications: 12644968, 14676051, 14694043, 16193476, 33739604, 34292398; Phenotypes: Spinocerebellar ataxia 14, MIM# 605361; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.464 SLC25A42 Zornitza Stark gene: SLC25A42 was added
gene: SLC25A42 was added to Regression. Sources: Expert Review
founder tags were added to gene: SLC25A42.
Mode of inheritance for gene: SLC25A42 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A42 were set to 26541337; 29327420; 29923093; 34258143
Phenotypes for gene: SLC25A42 were set to Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression , MIM#618416
Review for gene: SLC25A42 was set to GREEN
Added comment: Recurrent metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN) is an autosomal recessive metabolic disorder with a highly variable phenotype. Most affected individuals present in the first years of life with episodic lactic acidosis associated with illness or stress, resulting in transient or permanent neurologic dysfunction. Some patients may recover, whereas others show subsequent variable developmental regression of motor and cognitive skills. Other features may include dystonia, hypotonia with inability to sit or walk, seizures, and abnormal signals in the basal ganglia.

Sixteen individuals reported, 14 with the same founder variant, c.871A > G:p.Asn291Asp. Two additional variants reported in another two individuals.
Sources: Expert Review
Regression v0.462 NUP62 Krithika Murali reviewed gene: NUP62: Rating: AMBER; Mode of pathogenicity: None; Publications: 16786527; Phenotypes: Striatonigral degeneration, infantile - MIM#271930; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.458 ACER3 Zornitza Stark gene: ACER3 was added
gene: ACER3 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 32816236; 26792856; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, MIM:617762
Review for gene: ACER3 was set to GREEN
Added comment: Five unrelated families reported, including clinical presentations with regression following a period of normal development.
Sources: Expert Review
Regression v0.457 NUBPL Krithika Murali reviewed gene: NUBPL: Rating: GREEN; Mode of pathogenicity: None; Publications: 20818383, 32518176, 23553477, 31917109, 32518176, 31787496, 30897263, 22826544; Phenotypes: Mitochondrial complex I deficiency, nuclear type 21 - MIM#618242; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.457 TDP1 Zornitza Stark Phenotypes for gene: TDP1 were changed from to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 , MIM# 607250
Regression v0.453 TDP1 Zornitza Stark reviewed gene: TDP1: Rating: RED; Mode of pathogenicity: None; Publications: 31182267, 12244316; Phenotypes: Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 , MIM# 607250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.449 NOL3 Krithika Murali reviewed gene: NOL3: Rating: RED; Mode of pathogenicity: None; Publications: 22926851; Phenotypes: ?Myoclonus, familial, 1 - MIM#614937; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.446 NDUFV2 Krithika Murali reviewed gene: NDUFV2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811136, 34405929, 12754703, 26008862, 30770271, 19167255; Phenotypes: Mitochondrial complex I deficiency, nuclear type 7 - MIM#618229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.439 NDUFS6 Krithika Murali reviewed gene: NDUFS6: Rating: AMBER; Mode of pathogenicity: None; Publications: 15372108, 19259137, 30948790, 27290639, 28429146; Phenotypes: Mitochondrial complex I deficiency, nuclear type 9 - MIM#618232; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.433 NDUFS3 Krithika Murali reviewed gene: NDUFS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22499348, 30140060, 14729820, 33097395; Phenotypes: Mitochondrial complex I deficiency, nuclear type 8 - MIM#618230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.433 NDUFS2 Krithika Murali reviewed gene: NDUFS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28031252, 31411514, 22036843, 20819849, 11220739, 23266820, 31411514; Phenotypes: Mitochondrial complex I deficiency, nuclear type 6 - MIM#618228; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.433 NDUFS1 Krithika Murali reviewed gene: NDUFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33751534, 24952175, 20382551, 21203893, 20797884, 15824269, 25615419, 11349233, 22399432; Phenotypes: Mitochondrial complex I deficiency, nuclear type 5 - MIM#618226; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.429 VAMP1 Zornitza Stark reviewed gene: VAMP1: Rating: RED; Mode of pathogenicity: None; Publications: 22958904; Phenotypes: Spastic ataxia 1, autosomal dominant, MIM# 108600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.419 NDUFAF4 Krithika Murali changed review comment from: 2 unrelated families reported with patient-specific functional evidence provided for each. Regression noted in one reported patient. Other reported family had two siblings unwell from birth with a relatively fulminant course. Another large family reported with recurrent decompensation episodes.

PMID: 32949790 - report two siblings with facial dysmorphism and lactic acidosis diagnosed neonatally with subsequent fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Cerebral white matter anomalies reported in one patient and cardiomyopathy in the other. WES identified homozygous nonsense NDUFAF4 variants with absent NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I–containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network.

PMID: 28853723 - report one patient born at 38 weeks after IOL for IUGR. Presented age 7 months with developmental regression, growth failure and central hypotonia. Brain MRI revealed diffuse bilateral signal alterations in the basal ganglia and thalami and an EEG showed generalized slowing with multifocal spikes consistent with an epileptogenic focus. Homozygous missense NDUFAF4 variants identified. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and assembly defect

PMID 18179882 - report multiple affected individuals from one family. Most presented soon after birth with severe metabolic acidosis and high plasma lactate levels. Patients who survived longer were repeatedly admitted because of exacerbation of the acidosis during intercurrent infections. One long-term survivor had profound ID. Seizures occurred in 2 individuals during decompensation episodes. Brain MRI of one patient at 16 months of age revealed severe atrophy of both gray and white matter, with demyelination, most prominent at the anterior aspects of the brain, leaving a cortical ribbon. At the occipito-parietal region there were subventricular cysts, emphasizing the ventricular walls. The cerebellum, basal ganglia, pons, and medulla were severely atrophic; to: 3 unrelated families reported with patient-specific functional evidence provided for each. Regression noted in one reported patient. Other reported family had two siblings unwell from birth with a relatively fulminant course. Another large family reported with fulminant neonatal course / longer-term survivors having recurrent decompensation episodes.

PMID: 32949790 - report two siblings with facial dysmorphism and lactic acidosis diagnosed neonatally with subsequent fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Cerebral white matter anomalies reported in one patient and cardiomyopathy in the other. WES identified homozygous nonsense NDUFAF4 variants with absent NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I–containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network.

PMID: 28853723 - report one patient born at 38 weeks after IOL for IUGR. Presented age 7 months with developmental regression, growth failure and central hypotonia. Brain MRI revealed diffuse bilateral signal alterations in the basal ganglia and thalami and an EEG showed generalized slowing with multifocal spikes consistent with an epileptogenic focus. Homozygous missense NDUFAF4 variants identified. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and assembly defect

PMID 18179882 - report multiple affected individuals from one family. Most presented soon after birth with severe metabolic acidosis and high plasma lactate levels. Patients who survived longer were repeatedly admitted because of exacerbation of the acidosis during intercurrent infections. One long-term survivor had profound ID. Seizures occurred in 2 individuals during decompensation episodes. Brain MRI of one patient at 16 months of age revealed severe atrophy of both gray and white matter, with demyelination, most prominent at the anterior aspects of the brain, leaving a cortical ribbon. At the occipito-parietal region there were subventricular cysts, emphasizing the ventricular walls. The cerebellum, basal ganglia, pons, and medulla were severely atrophic
Regression v0.419 NDUFAF4 Krithika Murali reviewed gene: NDUFAF4: Rating: AMBER; Mode of pathogenicity: None; Publications: 32949790, 28853723, 18179882; Phenotypes: Mitochondrial complex I deficiency, nuclear type 15 - MIM#618237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.419 NDUFAF3 Krithika Murali reviewed gene: NDUFAF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27986404, 29344937, 19463981; Phenotypes: Mitochondrial complex I deficiency, nuclear type 18 - MIM#618240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.419 NDUFA2 Krithika Murali reviewed gene: NDUFA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28857146, 32154054, 18513682; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13 - MIM#618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.416 NDUFAF2 Zornitza Stark reviewed gene: NDUFAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33528536, 34364746, 16200211, 19384974, 20571988; Phenotypes: Mitochondrial complex I deficiency, nuclear type 10 - MIM#618233; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.412 NDUFAF1 Zornitza Stark reviewed gene: NDUFAF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 17557076, 21931170, 16218961, 24963768, 34975718; Phenotypes: Mitochondrial complex I deficiency, nuclear type 11 - MIM#618234; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.408 NDUFA9 Zornitza Stark reviewed gene: NDUFA9: Rating: AMBER; Mode of pathogenicity: None; Publications: 26425749, 28671271, 22114105; Phenotypes: Mitochondrial complex I deficiency, nuclear type 26 - MIM#618247; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.408 NDUFAF2 Krithika Murali reviewed gene: NDUFAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.408 NDUFAF1 Krithika Murali reviewed gene: NDUFAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.408 NDUFA9 Krithika Murali reviewed gene: NDUFA9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.407 IREB2 Zornitza Stark gene: IREB2 was added
gene: IREB2 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: IREB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IREB2 were set to 30915432; 31243445; 11175792
Phenotypes for gene: IREB2 were set to Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451
Review for gene: IREB2 was set to GREEN
Added comment: Two affected individuals from unrelated families with functional evidence including concordant phenotype in mice.
Sources: Expert Review
Regression v0.403 NDUFA10 Zornitza Stark reviewed gene: NDUFA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 21150889, 26741492, 28247337; Phenotypes: Mitochondrial complex I deficiency, nuclear type 22 - MIM#618243; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.403 NDUFA10 Krithika Murali reviewed gene: NDUFA10: Rating: GREEN; Mode of pathogenicity: None; Publications: 26741492, 21150889; Phenotypes: Mitochondrial complex I deficiency, nuclear type 22 - MIM#618243; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.398 NDUFA11 Zornitza Stark reviewed gene: NDUFA11: Rating: RED; Mode of pathogenicity: None; Publications: 18306244, 31074871; Phenotypes: Mitochondrial complex I deficiency, nuclear type 14, MIM#618236; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.397 SOD1 Naomi Baker gene: SOD1 was added
gene: SOD1 was added to Regression. Sources: Literature
Mode of inheritance for gene: SOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SOD1 were set to PMID: 31314961; 31332433; 34788402
Phenotypes for gene: SOD1 were set to Spastic tetraplegia and axial hypotonia, progressive, MIM#618598
Review for gene: SOD1 was set to GREEN
Added comment: Three individuals reported with biallelic LoF variants, with two apparently unrelated individuals having the same variant (c.335dupG).

Phenotypes include one individual with axial hypotonia and loss of gross and fine motor function beginning at 6 months of age, after which severe, progressive spastic tetraparesis developed and Babinski’s sign was present in both feet. MRI of brain detected mild frontoparietal atrophy.

The second individual had severe and marked by progressive loss of motor abilities from 9 months of age, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Dysmorphic features such as low set, posteriorly rotated ears, and overlapping toes

The third individual is an infant with severe global developmental delay, axial hypotonia and limb spasticity. No dysmorphic facial features were noted, but she had a high arched palate, bilateral 5th finger clinodactyly, partial toe syndactyly of the second and third toes, and a single hyperpigmented macule tongue fasciculations, axial hypotonia with limb spasticity (more pronounced in the lower limbs), ankle clonus, and brisk patellar deep tendon reflexes.
Sources: Literature
Regression v0.393 PIK3R5 Zornitza Stark reviewed gene: PIK3R5: Rating: RED; Mode of pathogenicity: None; Publications: 22065524; Phenotypes: Ataxia-oculomotor apraxia 3, OMIM #615217; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.393 ZIC4 Zornitza Stark Added comment: Comment when marking as ready: Two individuals with deletions of ZIC4 and ZIC1 reported with Dandy-Walker malformation.
Regression v0.391 ZIC4 Michelle Torres reviewed gene: ZIC4: Rating: RED; Mode of pathogenicity: None; Publications: 21204220, 15338008; Phenotypes: ; Mode of inheritance: Unknown
Regression v0.388 COX15 Zornitza Stark reviewed gene: COX15: Rating: GREEN; Mode of pathogenicity: None; Publications: 33746038, 32232962, 26959537, 21412973, 12474143, 15235026; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.384 CEP290 Zornitza Stark reviewed gene: CEP290: Rating: RED; Mode of pathogenicity: None; Publications: 18327255, 20690115, 16682973, 16682970, 17564967, 16909394, 17564974; Phenotypes: Bardet-Biedl syndrome 14, MIM# 615991, Joubert syndrome 5 610188, Leber congenital amaurosis 10, MIM# 611755, Meckel syndrome 4, MIM# 611134, Senior-Loken syndrome 6, MIM# 610189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.381 CSF1R Zornitza Stark reviewed gene: CSF1R: Rating: GREEN; Mode of pathogenicity: None; Publications: 30982609, 33749994, 34135456; Phenotypes: Brain abnormalities, neurodegeneration, and dysosteosclerosis, MIM# 618476, BANDDOS; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.381 ETHE1 Zornitza Stark Marked gene: ETHE1 as ready
Regression v0.381 ETHE1 Zornitza Stark Gene: ethe1 has been classified as Green List (High Evidence).
Regression v0.381 ETHE1 Zornitza Stark Classified gene: ETHE1 as Green List (high evidence)
Regression v0.381 ETHE1 Zornitza Stark Gene: ethe1 has been classified as Green List (High Evidence).
Regression v0.380 ETHE1 Zornitza Stark gene: ETHE1 was added
gene: ETHE1 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: ETHE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ETHE1 were set to 14732903; 28933811
Phenotypes for gene: ETHE1 were set to Ethylmalonic encephalopathy , MIM#602473
Review for gene: ETHE1 was set to GREEN
Added comment: Severe metabolic disorder characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhoea. Brain MRI shows necrotic lesions in deep gray matter structures.

Multiple families reported.
Sources: Expert Review
Regression v0.378 SHQ1 Zornitza Stark gene: SHQ1 was added
gene: SHQ1 was added to Regression. Sources: Literature
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645
Phenotypes for gene: SHQ1 were set to Dystonia; Neurodegeneration
Review for gene: SHQ1 was set to AMBER
Added comment: Three unrelated families reported. Family 1: isolated dystonia only; Family 2: dystonia, and neurodegeneration; Family 3: neurodegeneration. Rated Amber as phenotypes likely represent a continuum but currently unclear what proportion have neurodegeneration.
Sources: Literature
Regression v0.376 CSTB Zornitza Stark gene: CSTB was added
gene: CSTB was added to Regression. Sources: Expert Review
Mode of inheritance for gene: CSTB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSTB were set to 9012407; 9054946
Phenotypes for gene: CSTB were set to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), MIM# 254800
Review for gene: CSTB was set to GREEN
Added comment: Myoclonic epilepsy of Unverricht and Lundborg is an autosomal recessive disorder characterized by onset of neurodegeneration between 6 and 13 years of age. It is typically progressive in adolescence, with dramatic worsening of myoclonus and ataxia in the first 6 years after onset. The disease stabilises in early adulthood, and myoclonus and ataxia may even improve, and there is minimal to no cognitive decline.

Note the most common causative allele is a dodecamer repeat in the promoter region. Missense variants have been reported, most commonly compound het with the repeat, except for p.Gly4Arg which has been reported in the homozygous state also.
Sources: Expert Review
Regression v0.371 SLC1A3 Zornitza Stark reviewed gene: SLC1A3: Rating: RED; Mode of pathogenicity: None; Publications: 19139306, 16116111, 29208948, 27829685, 32741053; Phenotypes: Episodic ataxia, type 6, MIM# 612656; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.371 GCLC Zornitza Stark Phenotypes for gene: GCLC were changed from to Haemolytic anaemia due to gamma-glutamylcysteine synthetase deficiency, MIM# 230450
Regression v0.368 GCLC Zornitza Stark reviewed gene: GCLC: Rating: GREEN; Mode of pathogenicity: None; Publications: 28571779, 10515893; Phenotypes: Haemolytic anaemia due to gamma-glutamylcysteine synthetase deficiency, MIM# 230450; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.367 ABCB7 Zornitza Stark Phenotypes for gene: ABCB7 were changed from to Anaemia, sideroblastic, with ataxia, MIM# 301310
Regression v0.364 ABCB7 Zornitza Stark reviewed gene: ABCB7: Rating: RED; Mode of pathogenicity: None; Publications: 10196363, 11050011, 34354969; Phenotypes: Anaemia, sideroblastic, with ataxia, MIM# 301310; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Regression v0.363 SCA36 Bryony Thompson STR: SCA36 was added
STR: SCA36 was added to Regression. Sources: Expert list
Mode of inheritance for STR: SCA36 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA36 were set to 21683323
Phenotypes for STR: SCA36 were set to Spinocerebellar ataxia 36 MIM#614153
Review for STR: SCA36 was set to GREEN
STR: SCA36 was marked as clinically relevant
Added comment: NM_006392​.3:c.3+71GGCCTG[X]
Toxic RNA effect is suggested mechanism of disease
Normal: 3-14 repeats
Uncertain significance: 15-650 repeats
Pathogenic: ≥650 repeats
Sources: Expert list
Regression v0.362 NOP56 Bryony Thompson Added comment: Comment on list classification: STR expansion is the only reported cause of disease for this gene. An STR has been added to this panel under SCA36
Regression v0.362 NOP56 Bryony Thompson Gene: nop56 has been removed from the panel.
Regression v0.360 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Regression. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102; 34333668
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Oculopharyngodistal myopathy 3 MIM#619473; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[X]
Expanded repeat in NOTCH2NLC sequence is (GGC)9(GGA)2(GGC)2.
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 4-40, 1 control had 61 repeats and may have been a presymptomatic carrier.
Intermediate range: 41-60 identified in Parkinson's disease
Pathogenic repeat range: >=60-520
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Regression v0.359 Bryony Thompson removed STR:NIID from the panel
Regression v0.357 RNU7-1 Zornitza Stark edited their review of gene: RNU7-1: Changed phenotypes: Aicardi-Goutieres syndrome 9, MIM# 619487
Regression v0.357 LSM11 Zornitza Stark Phenotypes for gene: LSM11 were changed from type I interferonopathy Aicardi–Goutières syndrome to Aicardi-Goutieres syndrome 8, MIM# 619486
Regression v0.356 LSM11 Zornitza Stark reviewed gene: LSM11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 8, MIM# 619486; Mode of inheritance: None
Regression v0.356 VPS41 Zornitza Stark Phenotypes for gene: VPS41 were changed from Dystonia; intellectual disability to Spinocerebellar ataxia-29 (SCAR29), MIM#619389; Progressive neurodevelopmental disorder with ataxia, hypotonia, dystonia, intellectual disability and speech delay
Regression v0.355 VPS41 Zornitza Stark edited their review of gene: VPS41: Changed phenotypes: Spinocerebellar ataxia-29 (SCAR29), MIM#619389, Progressive neurodevelopmental disorder with ataxia, hypotonia, dystonia, intellectual disability and speech delay
Regression v0.355 TTC21B Zornitza Stark Phenotypes for gene: TTC21B were changed from to Nephronophthisis 12, MIM# 613820; Short-rib thoracic dysplasia 4 with or without polydactyly, MIM# 613819; Joubert syndrome
Regression v0.352 TTC21B Zornitza Stark reviewed gene: TTC21B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephronophthisis 12, MIM# 613820, Short-rib thoracic dysplasia 4 with or without polydactyly, MIM# 613819, Joubert syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.352 TMEM67 Zornitza Stark Phenotypes for gene: TMEM67 were changed from to Joubert syndrome 6, MIM# 610688; Meckel syndrome 3, MIM# 607361; Nephronophthisis 11, MIM# 613550; COACH syndrome 1, MIM# 216360
Regression v0.349 TMEM67 Zornitza Stark reviewed gene: TMEM67: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 6, MIM# 610688, Meckel syndrome 3, MIM# 607361, Nephronophthisis 11, MIM# 613550, COACH syndrome 1, MIM# 216360; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.346 C5orf42 Zornitza Stark reviewed gene: C5orf42: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 17, MIM# 614615, MONDO:0013824, Orofaciodigital syndrome VI, MIM# 277170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.344 TBP Bryony Thompson Added comment: Comment on list classification: Only STR reported as pathogenic in this gene. Added as an STR under SCA17
Regression v0.344 TBP Bryony Thompson Gene: tbp has been removed from the panel.
Regression v0.342 CTC1 Zornitza Stark gene: CTC1 was added
gene: CTC1 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: CTC1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CTC1 were set to Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199
Review for gene: CTC1 was set to GREEN
Added comment: Progressive cognitive decline.

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is an autosomal recessive pleomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anaemia and thrombocytopaenia. More than 30 unrelated patients reported.
Sources: Expert Review
Regression v0.340 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Regression. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[(66_517)]
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease. Normal repeat range: 7-60 Pathogenic repeat range: >=61-500 Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Regression v0.339 NOTCH2NL Bryony Thompson Added comment: Comment on list classification: STR is the only reported cause of disease in this gene. It has been added as an STR under NIID.
Regression v0.339 NOTCH2NL Bryony Thompson Gene: notch2nl has been removed from the panel.
Regression v0.334 SYT1 Zornitza Stark reviewed gene: SYT1: Rating: RED; Mode of pathogenicity: None; Publications: 30107533; Phenotypes: Baker-Gordon syndrome, MIM# 618218, MONDO:0033864; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.334 UBTF Zornitza Stark Phenotypes for gene: UBTF were changed from to Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701
Regression v0.331 UBTF Zornitza Stark reviewed gene: UBTF: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777933, 29300972; Phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672, MONDO:0044701; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.326 NDUFB3 Zornitza Stark reviewed gene: NDUFB3: Rating: RED; Mode of pathogenicity: None; Publications: 22277967, 22499348, 27091925; Phenotypes: Mitochondrial complex I deficiency, nuclear type 25, MIM#618246, MONDO:0032629; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.325 VPS41 Zornitza Stark gene: VPS41 was added
gene: VPS41 was added to Regression. Sources: Literature
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683; 33764426
Phenotypes for gene: VPS41 were set to Dystonia; intellectual disability
Review for gene: VPS41 was set to GREEN
Added comment: 10 individuals from 6 unrelated families reported with a progressive neurodevelopmental disorder. Affected individuals were born after uneventful pregnancies and presented in most cases early in life with developmental delay. Various degrees of ataxia, hypotonia, and dystonia developed in all affected individuals, preventing independent ambulation. Likewise, nystagmus was commonly described. In addition, all affected individuals displayed intellectual disability and speech delay, and one sib pair had treatment-resistant epilepsy.
Sources: Literature
Regression v0.323 POLR3K Zornitza Stark gene: POLR3K was added
gene: POLR3K was added to Regression. Sources: Expert Review
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Hypomyelinating leukodystrophy-21, MIM#619310
Review for gene: POLR3K was set to AMBER
Added comment: Two individuals from same ethnic background reported with a common homozygous missense variant in this gene, suggestive of founder effect. Some functional evidence, and note other gene family members are linked to similar phenotypes. Neurodegenerative phenotype: global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life.
Sources: Expert Review
Regression v0.320 AAAS Zornitza Stark changed review comment from: Intellectual disability is part of the phenotype of this multi-system syndromic condition.
Sources: Expert list; to: The association of adrenal and neurologic disease is similar to that in X-linked adrenoleukodystrophy, and neurological features are progressive.
Sources: Expert list
Regression v0.316 SGCE Zornitza Stark reviewed gene: SGCE: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia-11, myoclonic, MIM# 159900, MONDO:0008044; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Regression v0.313 PRKRA Zornitza Stark reviewed gene: PRKRA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia 16, MIM# 612067, MONDO:0012789; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.310 CIZ1 Zornitza Stark reviewed gene: CIZ1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia 23 MIM#614860; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.306 PNKD Zornitza Stark reviewed gene: PNKD: Rating: RED; Mode of pathogenicity: None; Publications: 15262732, 15496428, 15824259, 19124534, 21487022; Phenotypes: Paroxysmal nonkinesigenic dyskinesia 1, MIM# 118800, MONDO:0007326; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.302 GNAL Zornitza Stark reviewed gene: GNAL: Rating: RED; Mode of pathogenicity: None; Publications: 23222958, 33175450, 32180288; Phenotypes: Dystonia 25, MIM# 615073, MONDO:0014033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.302 THAP1 Zornitza Stark Marked gene: THAP1 as ready
Regression v0.302 THAP1 Zornitza Stark Gene: thap1 has been classified as Red List (Low Evidence).
Regression v0.302 THAP1 Zornitza Stark Phenotypes for gene: THAP1 were changed from to Dystonia 6, torsion, 602629; MONDO:0011264
Regression v0.301 THAP1 Zornitza Stark Publications for gene: THAP1 were set to
Regression v0.300 THAP1 Zornitza Stark Mode of inheritance for gene: THAP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.299 THAP1 Zornitza Stark Classified gene: THAP1 as Red List (low evidence)
Regression v0.299 THAP1 Zornitza Stark Gene: thap1 has been classified as Red List (Low Evidence).
Regression v0.298 THAP1 Zornitza Stark reviewed gene: THAP1: Rating: RED; Mode of pathogenicity: None; Publications: 21793105, 22377579; Phenotypes: Dystonia 6, torsion, 602629, MONDO:0011264; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.296 NDUFA12 Zornitza Stark edited their review of gene: NDUFA12: Added comment: Additional 7 individuals from 4 families reported: several had a progressive course, one specifically described as having complete regression.; Changed rating: GREEN; Changed publications: 21617257, 33715266
Regression v0.293 TPP1 Zornitza Stark reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9295267, 18684116, 23418007, 26224725, 31283065; Phenotypes: Ceroid lipofuscinosis, neuronal, 2, MIM# 204500, MONDO:0008769; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.290 MFSD8 Zornitza Stark reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564970, 19201763; Phenotypes: Ceroid lipofuscinosis, neuronal, 7, MIM# 610951, MONDO:0012588; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.288 MAN2B1 Zornitza Stark reviewed gene: MAN2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mannosidosis, alpha-, types I and II, MIM# 248500, MONDO:0009561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.285 HGSNAT Zornitza Stark reviewed gene: HGSNAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 19479962, 31228227, 20825431, 20583299; Phenotypes: Mucopolysaccharidosis type IIIC (Sanfilippo C), MIM# 252930, MONDO:0009657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.282 FUCA1 Zornitza Stark reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10094192; Phenotypes: Fucosidosis, MIM# 230000, MONDO:0009254; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.278 ATCAY Zornitza Stark reviewed gene: ATCAY: Rating: RED; Mode of pathogenicity: None; Publications: 29449188, 23226316, 26343454, 14556008; Phenotypes: Ataxia, cerebellar, Cayman type, MIM# 601238, MONDO:0011025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.275 TMEM231 Zornitza Stark reviewed gene: TMEM231: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 20, MIM# 614970, MONDO:0013994, Meckel syndrome 11, MIM# 615397, MONDO:0014164; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.272 TMEM216 Zornitza Stark reviewed gene: TMEM216: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 2, MIM# 608091, MONDO:0011963, Meckel syndrome 2, MIM# 603194, MONDO:0011296; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.269 TMEM138 Zornitza Stark reviewed gene: TMEM138: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 16, MIM# 614465, MONDO:0013764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.265 TCTN2 Zornitza Stark reviewed gene: TCTN2: Rating: RED; Mode of pathogenicity: None; Publications: 21462283, 21565611, 25118024, 21725307, 32139166, 25118024, 32655147, 33590725; Phenotypes: Joubert syndrome 24, MIM# 616654, MONDO:0014724, Meckel syndrome 8, MIM# 613885, MONDO:0013482; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.262 TCTN1 Zornitza Stark reviewed gene: TCTN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 13, MIM# 614173, MONDO:0013608; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.259 ANO3 Zornitza Stark edited their review of gene: ANO3: Changed rating: RED
Regression v0.259 ANO3 Zornitza Stark reviewed gene: ANO3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia 24, 615034, familial form of cranio-cervical dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.259 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Neurodevelopmental disorder; regression to Kohlschutter-Tonz syndrome-like, MIM# 619229; Neurodevelopmental disorder; regression
Regression v0.258 SATB1 Zornitza Stark changed review comment from: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. This phenotype was reported in 28 patients (patients 13 to 40, PMID 33513338), including 9 patients from 3 families. Most variants were de novo, though some were inherited, suggestive of incomplete penetrance and variable expressivity.; to: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. This phenotype was reported in 28 patients (patients 13 to 40, PMID 33513338), including 9 patients from 3 families. Most variants were de novo, though some were inherited, suggestive of incomplete penetrance and variable expressivity.

Note Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228 is a milder, allelic disorder.
Regression v0.258 SATB1 Zornitza Stark edited their review of gene: SATB1: Added comment: Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. This phenotype was reported in 28 patients (patients 13 to 40, PMID 33513338), including 9 patients from 3 families. Most variants were de novo, though some were inherited, suggestive of incomplete penetrance and variable expressivity.; Changed phenotypes: Kohlschutter-Tonz syndrome-like, MIM# 619229
Regression v0.258 SATB1 Zornitza Stark Phenotypes for gene: SATB1 were changed from Neurodevelopmental disorder; regression to Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Neurodevelopmental disorder; regression
Regression v0.257 SATB1 Zornitza Stark reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental delay with dysmorphic facies and dental anomalies, MIM# 619228; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.253 INPP5E Zornitza Stark reviewed gene: INPP5E: Rating: RED; Mode of pathogenicity: None; Publications: 19668216, 32139166, 29230161, 29052317, 27998989, 27401686, 19668215; Phenotypes: Joubert syndrome 1, MIM# 213300, MONDO:0008944, Mental retardation, truncal obesity, retinal dystrophy, and micropenis, MIM# 610156, MONDO:0012423; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.249 CSPP1 Zornitza Stark reviewed gene: CSPP1: Rating: RED; Mode of pathogenicity: None; Publications: 24360808, 24360803, 24360807, 25997910; Phenotypes: Joubert syndrome 21, MIM# 615636, MONDO:0014288; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.246 UCHL1 Zornitza Stark reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 3340629, 28007905, 32656641, 29735986, 28007905; Phenotypes: Spastic paraplegia 79, autosomal recessive, MIM# 615491, MONDO:0014209; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.245 AIMP1 Zornitza Stark gene: AIMP1 was added
gene: AIMP1 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: AIMP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AIMP1 were set to 21092922; 24958424; 33402283; 32531460; 30486714; 30477741
Phenotypes for gene: AIMP1 were set to Leukodystrophy, hypomyelinating, 3, MIM# 260600
Review for gene: AIMP1 was set to GREEN
Added comment: Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system. Abnormal nerve conduction demonstrated. More than 10 families reported.

Neurodegeneration is a feature.
Sources: Expert Review
Regression v0.243 CST3 Zornitza Stark reviewed gene: CST3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Regression v0.240 NHLRC1 Zornitza Stark reviewed gene: NHLRC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21505799, 12958597; Phenotypes: Epilepsy, progressive myoclonic 2B (Lafora) 254780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.236 CHMP1A Zornitza Stark reviewed gene: CHMP1A: Rating: RED; Mode of pathogenicity: None; Publications: 23023333; Phenotypes: Pontocerebellar hypoplasia, type 8, MIM# 614961; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.235 SLC39A14 Zornitza Stark gene: SLC39A14 was added
gene: SLC39A14 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: SLC39A14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A14 were set to 27231142; 29685658
Phenotypes for gene: SLC39A14 were set to Hypermanganesemia with dystonia 2, MIM# 617013
Review for gene: SLC39A14 was set to GREEN
Added comment: Hypermanganesemia with dystonia-2 (HMNDYT2) is an autosomal recessive neurodegenerative disorder characterized predominantly by loss of motor milestones in the first years of life. Affected individuals then develop rapidly progressive abnormal movements, including dystonia, spasticity, bulbar dysfunction, and variable features of parkinsonism, causing loss of ambulation. Cognition may be impaired, but is better preserved than motor function. The disorder results from abnormal accumulation of manganese (Mn), which is toxic to neurons. Chelation therapy, if started early, may provide clinical benefit. More than 5 unrelated families reported.
Sources: Expert Review
Regression v0.232 SATB1 Elena Savva gene: SATB1 was added
gene: SATB1 was added to Regression. Sources: Literature
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SATB1 were set to PMID: 33513338; 33057194
Phenotypes for gene: SATB1 were set to Neurodevelopmental disorders
Mode of pathogenicity for gene: SATB1 was set to Other
Review for gene: SATB1 was set to GREEN
Added comment: PMID: 33513338: 42 patients with SNVs. 28 de novo, 3 inherited from an affected parent.
Missense variants - more severe, profound ID
NMD PTCs - milder disease

Functional studies show missense variants have a STRONGER binding to downstream targets
Sources: Literature
Regression v0.232 RNU7-1 Zornitza Stark reviewed gene: RNU7-1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi–Goutières syndrome-like; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.230 LSM11 Ee Ming Wong gene: LSM11 was added
gene: LSM11 was added to Regression. Sources: Literature
Mode of inheritance for gene: LSM11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM11 were set to PMID: 33230297
Phenotypes for gene: LSM11 were set to type I interferonopathy Aicardi–Goutières syndrome
Review for gene: LSM11 was set to RED
gene: LSM11 was marked as current diagnostic
Added comment: - Two affected siblings from a consanguineous family carrying a homozygous variant in LSM11
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
- Knockdown of LSM11 in THP-1 cells results in an increase in misprocessed RDH mRNA and
interferon signaling

(added as Red as per discussion with Seb)
Sources: Literature
Regression v0.229 HSD17B10 Zornitza Stark gene: HSD17B10 was added
gene: HSD17B10 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: HSD17B10 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: HSD17B10 were set to HSD10 mitochondrial disease, MIM# 300438
Review for gene: HSD17B10 was set to GREEN
Added comment: HSD10 mitochondrial disease most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Multiple unrelated families reported.
Sources: Expert Review
Regression v0.227 BSCL2 Zornitza Stark gene: BSCL2 was added
gene: BSCL2 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: BSCL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BSCL2 were set to 23564749; 27452399
Phenotypes for gene: BSCL2 were set to Encephalopathy, progressive, with or without lipodystrophy 615924
Review for gene: BSCL2 was set to GREEN
Added comment: Progressive encephalopathy with or without lipodystrophy is a severe neurodegenerative disorder characterized by developmental regression of motor and cognitive skills in the first years of life, often leading to death in the first decade. Patients may show a mild or typical lipodystrophic appearance.

At least 5 unrelated families reported. The recurrent c.985C-T variant causes skipping of exon 7 (founder effect).
Sources: Expert Review
Regression v0.222 PDSS1 Zornitza Stark reviewed gene: PDSS1: Rating: RED; Mode of pathogenicity: None; Publications: 17332895, 22494076, 33285023; Phenotypes: Coenzyme Q10 deficiency, primary, 2 MIM#614651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.221 ST3GAL5 Zornitza Stark gene: ST3GAL5 was added
gene: ST3GAL5 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: ST3GAL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ST3GAL5 were set to 23436467; 22990144; 15502825; 27232954; 30691927; 30688114; 30576498
Phenotypes for gene: ST3GAL5 were set to Salt and pepper developmental regression syndrome 609056; GM3 synthase deficiency, MONDO:0018274; Lactosylceramide alpha-2,3-sialyltransferase deficiency (Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation)
Review for gene: ST3GAL5 was set to GREEN
Added comment: Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterised by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss. Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood. Although initially reported in the Amish (founder variant p.Arg288Ter), families from other ethnicities have also been reported.
Sources: Expert Review
Regression v0.219 CLCN6 Zornitza Stark gene: CLCN6 was added
gene: CLCN6 was added to Regression. Sources: Literature
Mode of inheritance for gene: CLCN6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLCN6 were set to 33217309
Phenotypes for gene: CLCN6 were set to Neurodegeneration with brain iron accumulation 5, MIM# 300894
Review for gene: CLCN6 was set to GREEN
Added comment: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans.
Sources: Literature
Regression v0.214 H3F3B Zornitza Stark edited their review of gene: H3F3B: Added comment: 13 unrelated individuals reported with missense variants in H3F3B. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression, seizures; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.210 H3F3A Zornitza Stark edited their review of gene: H3F3A: Added comment: 33 unrelated individuals reported with missense variants in H3F3A. Phenotype primarily comprised intellectual disability and minor congenital anomalies, regression in significant proportion. Seizures in 50%.; Changed rating: GREEN; Changed publications: 33268356; Changed phenotypes: Intellectual disability, regression, seizures; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.206 ALG6 Zornitza Stark reviewed gene: ALG6: Rating: RED; Mode of pathogenicity: None; Publications: 10914684, 27498540; Phenotypes: Congenital disorder of glycosylation, type Ic (MIM#603147); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.205 NHLRC2 Paul De Fazio gene: NHLRC2 was added
gene: NHLRC2 was added to Regression. Sources: Literature
Mode of inheritance for gene: NHLRC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NHLRC2 were set to 29423877; 32435055
Phenotypes for gene: NHLRC2 were set to Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) syndrome MIM#618278
Review for gene: NHLRC2 was set to GREEN
gene: NHLRC2 was marked as current diagnostic
Added comment: 3 families with compound het variants in total, all share one missense variant (p.Asp148Tyr)

PMID 29423877: 3 patients from 2 Finnish families compound het for the same missense variant (122 hets 0 homs) and the same frameshift variant (12 hets 0 homs), main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Expression studies in patient-derived fibroblasts supported the frameshift variant leading to NMD. Zebrafish knockdown affected the integrity of cells in the midbrain region.

PMID 32435055: patient with the same phenotype from a Ukrainian family chet for two missense variants, one shared with the Finnish families and one novel.
Sources: Literature
Regression v0.205 SLC30A10 Zornitza Stark Phenotypes for gene: SLC30A10 were changed from to Hypermanganesemia with dystonia 1, MIM# 613280
Regression v0.202 SLC30A10 Zornitza Stark reviewed gene: SLC30A10: Rating: GREEN; Mode of pathogenicity: None; Publications: 22341972, 22341971, 29193034; Phenotypes: Hypermanganesemia with dystonia 1, MIM# 613280; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.199 VAC14 Zornitza Stark reviewed gene: VAC14: Rating: GREEN; Mode of pathogenicity: None; Publications: 27292112, 31392254, 31591492, 31387860, 31876398; Phenotypes: Striatonigral degeneration, childhood-onset, MIM#617054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.198 NDUFA4 Zornitza Stark edited their review of gene: NDUFA4: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 21, MIM#619065, Leigh syndrome, Complex IV deficiency
Regression v0.197 APOPT1 Zornitza Stark gene: APOPT1 was added
gene: APOPT1 was added to Regression. Sources: Expert list
Mode of inheritance for gene: APOPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APOPT1 were set to 25175347
Phenotypes for gene: APOPT1 were set to Mitochondrial complex IV deficiency, nuclear type 17, MIM#619061
Review for gene: APOPT1 was set to GREEN
Added comment: 6 individuals from 5 unrelated families reported, presenting in late infancy or early childhood with evidence of complex IV deficiency. Phenotype varied widely. Five individuals had episodes of neurologic regression manifest as gait difficulties and spastic tetraparesis, sensorimotor polyneuropathy, and dysarthria that in some cases improved over time. The sixth individual never developed neurologic signs. Three had normal cognition and 3 had impaired cognition. Brain imaging showed a cavitating leukodystrophy, predominantly affecting the posterior cerebral white matter and corpus callosum, that stabilized or even improved over time.
Sources: Expert list
Regression v0.195 COX4I1 Zornitza Stark gene: COX4I1 was added
gene: COX4I1 was added to Regression. Sources: Expert list
Mode of inheritance for gene: COX4I1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX4I1 were set to 28766551; 22592081; 31290619
Phenotypes for gene: COX4I1 were set to Mitochondrial complex IV deficiency, nuclear type 16, MIM#619060
Review for gene: COX4I1 was set to AMBER
Added comment: Two unrelated families reported, regression was a feature in both.
Sources: Expert list
Regression v0.190 PET100 Zornitza Stark reviewed gene: PET100: Rating: RED; Mode of pathogenicity: None; Publications: 24462369, 25293719, 31406627; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 12, MIM# 619055; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.189 COX14 Zornitza Stark edited their review of gene: COX14: Changed phenotypes: Mitochondrial complex IV deficiency, nuclear type 10, MIM#619053
Regression v0.185 TACO1 Zornitza Stark reviewed gene: TACO1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19503089, 20727754, 25044680, 27319982; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 8, MIM# 619052; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.181 COX6B1 Zornitza Stark reviewed gene: COX6B1: Rating: AMBER; Mode of pathogenicity: None; Publications: 18499082, 24781756; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 7, MIM# 619051; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.180 SHANK3 Konstantinos Varvagiannis gene: SHANK3 was added
gene: SHANK3 was added to Regression. Sources: Literature
Mode of inheritance for gene: SHANK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SHANK3 were set to 32050889, 29719671
Phenotypes for gene: SHANK3 were set to # 606232. PHELAN-MCDERMID SYNDROME - PHMDS
Penetrance for gene: SHANK3 were set to Complete
Review for gene: SHANK3 was set to GREEN
Added comment: Regression has been reported in several individuals with Phelan-McDermid syndrome due to SHANK3 variants or deletions encompassing this gene.
Sources: Literature
Regression v0.176 SCO1 Zornitza Stark reviewed gene: SCO1: Rating: RED; Mode of pathogenicity: None; Publications: 11013136, 19295170, 31352446, 23878101; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 4, MIM# 619048; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.173 COX10 Zornitza Stark reviewed gene: COX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 10767350, 12928484, 15455402, 27290639; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 3, MIM# 619046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.172 ALG14 Zornitza Stark gene: ALG14 was added
gene: ALG14 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: ALG14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG14 were set to 30221345; 23404334; 28733338
Phenotypes for gene: ALG14 were set to Myopathy, epilepsy, and progressive cerebral atrophy, MIM# 619036
Review for gene: ALG14 was set to GREEN
Added comment: Three families reported in PMID 28733338 with a neurodegenerative phenotype in infancy.

Note there are 2 other families reported, one with myasthenic syndrome, no report of ID; second with predominantly ID phenotype, no repression. ALG14 is part of the UDP-GlcNAc transferase, which catalyzes a key step in endoplasmic reticulum N-linked glycosylation. These may all represent a spectrum of severity for a CDG.
Sources: Expert Review
Regression v0.171 HPDL Zornitza Stark commented on gene: HPDL: 17 individuals from 13 families, with a spectrum of neurologic impairment ranging from a severe congenital form without any neurological development (n = 2/17, 12%) to infantile-onset presentations (n = 10/17, 59%) with moderate to severe neurodevelopmental issues, partly with a pathology reminiscent of mitochondrial disease (Leigh-like syndrome), to juvenile-onset spastic paraplegia (n = 5/17, 29%).

Frequently observed clinical findings included chronic progression of neurological signs (n = 16/17, 94%), motor developmental delay (n = 12/17, 71%), intellectual impairment (n = 11/17, 65%), microcephaly (n = 9/16, 56%), and seizures/epilepsy (n = 9/17, 53%). Other relevant clinical findings were visual disturbances/strabismus (n = 9/17, 53%) and loss of developmental milestones (n = 6/17, 35%).

Acute central respiratory failure leading to life-threatening events requiring partly mechanically assisted ventilation occurred in half of individuals with infantile presentation (n = 5/10, 50%), respectively one third of all individuals (n = 5/17, 29%).

Demyelinating neuropathy was present in three individuals (n = 3/11, 27%), with reduced sensory nerve conduction velocity (NCV) in all and severely reduced motor NCV in one.
Regression v0.171 HPDL Zornitza Stark Phenotypes for gene: HPDL were changed from Progressive neurological disorder; Leigh-like syndrome to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Progressive neurological disorder; Leigh-like syndrome
Regression v0.170 HPDL Zornitza Stark reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), MIM#619026; Mode of inheritance: None
Regression v0.170 TREM2 Zornitza Stark Phenotypes for gene: TREM2 were changed from to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193
Regression v0.166 TREM2 Zornitza Stark reviewed gene: TREM2: Rating: RED; Mode of pathogenicity: None; Publications: 12080485, 15883308; Phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.166 FUS Zornitza Stark Phenotypes for gene: FUS were changed from to Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, MIM# 608030
Regression v0.163 FUS Zornitza Stark reviewed gene: FUS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, MIM# 608030; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.162 ISCA2 Zornitza Stark gene: ISCA2 was added
gene: ISCA2 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: ISCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA2 were set to 25539947; 29297947; 29122497; 29359243
Phenotypes for gene: ISCA2 were set to Multiple mitochondrial dysfunctions syndrome 4, MIM# 616370
Review for gene: ISCA2 was set to GREEN
Added comment: Over 10 unrelated families reported with bi-allelic variants in this gene and a neurodegenerative disorder that usually results in death in early childhood. Affected individuals have normal development for the first months of life, but thereafter show progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus. Patients regress to a vegetative state with lack of eye contact and speech, and poor feeding. Most patients have optic atrophy, and some may develop seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord.
Sources: Expert Review
Regression v0.157 TGM6 Zornitza Stark edited their review of gene: TGM6: Added comment: Recent publication refutes the association of this gene with SCA:
In a Chinese exome sequencing cohort, 8 families were identified with reported TGM6 variants sharing no features of SCA35. These variants were significantly more common in the East Asian gnomAD sub-population than in other ethnic groups (P < 0.0001). Gene constraint metrics showed that both missense and loss-of-function variants in TGM6 are likely to be tolerated and there is no regional constraint. Inflation analysis demonstrated that the cumulative frequency of TGM6 reported pathogenic variants is at least 111-fold inflated over disease prevalence of all autosomal dominant SCAs, indicating a high chance of misdiagnosis or low penetrance.; Changed publications: 30670339, 32426513
Regression v0.157 TGM6 Zornitza Stark reviewed gene: TGM6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 35, MIM# 613908; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.157 SQSTM1 Zornitza Stark Phenotypes for gene: SQSTM1 were changed from to Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, MIM# 617145
Regression v0.154 SQSTM1 Zornitza Stark reviewed gene: SQSTM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27545679; Phenotypes: Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, MIM# 617145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.154 SLC20A2 Zornitza Stark Phenotypes for gene: SLC20A2 were changed from to Basal ganglia calcification, idiopathic, 1, MIM# 213600
Regression v0.150 SLC20A2 Zornitza Stark reviewed gene: SLC20A2: Rating: RED; Mode of pathogenicity: None; Publications: 22327515, 23334463; Phenotypes: Basal ganglia calcification, idiopathic, 1, MIM# 213600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.149 HIBCH Zornitza Stark gene: HIBCH was added
gene: HIBCH was added to Regression. Sources: Expert list
Mode of inheritance for gene: HIBCH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIBCH were set to 26026795; 25251209; 24299452; 32677093
Phenotypes for gene: HIBCH were set to 3-hydroxyisobutryl-CoA hydrolase deficiency, MIM# 250620
Review for gene: HIBCH was set to GREEN
Added comment: Autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia. Multiple unrelated families reported.
Sources: Expert list
Regression v0.148 FDXR Zornitza Stark Phenotypes for gene: FDXR were changed from to Auditory neuropathy and optic atrophy, MIM# 617717
Regression v0.144 FDXR Zornitza Stark reviewed gene: FDXR: Rating: AMBER; Mode of pathogenicity: None; Publications: 30250212; Phenotypes: Auditory neuropathy and optic atrophy, MIM# 617717; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.143 TRAPPC6B Zornitza Stark gene: TRAPPC6B was added
gene: TRAPPC6B was added to Regression. Sources: Expert Review
Mode of inheritance for gene: TRAPPC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC6B were set to 28626029; 28397838; 31687267
Phenotypes for gene: TRAPPC6B were set to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862
Review for gene: TRAPPC6B was set to GREEN
Added comment: Five unrelated families reported with autosomal recessive neurodegenerative disorder characterised by global developmental delay, severe intellectual disability with poor or absent speech and autistic stereotypic behaviors, microcephaly, early-onset generalized seizures, and hypotonia.
Sources: Expert Review
Regression v0.142 TRAPPC12 Zornitza Stark Phenotypes for gene: TRAPPC12 were changed from to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669
Regression v0.139 TRAPPC12 Zornitza Stark reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837, 28777934; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.139 AARS2 Zornitza Stark Phenotypes for gene: AARS2 were changed from to Leukoencephalopathy, progressive, with ovarian failure MIM#615889
Regression v0.136 AARS2 Zornitza Stark edited their review of gene: AARS2: Changed phenotypes: Leukoencephalopathy, progressive, with ovarian failure MIM#615889
Regression v0.136 AARS2 Zornitza Stark reviewed gene: AARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30706699, 27839525, 21549344, 25058219, 24808023; Phenotypes: Leukoencephalopathy, progressive, with ovarian failure MIM#615889, MONDO:0013570; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.135 FOLR1 Zornitza Stark gene: FOLR1 was added
gene: FOLR1 was added to Regression. Sources: Expert list
Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOLR1 were set to 19732866; 30420205; 27743887
Phenotypes for gene: FOLR1 were set to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068
Review for gene: FOLR1 was set to GREEN
Added comment: Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function.
Sources: Expert list
Regression v0.130 TMEM237 Zornitza Stark reviewed gene: TMEM237: Rating: RED; Mode of pathogenicity: None; Publications: 22152675; Phenotypes: Joubert syndrome 14, MIM# 614424; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.129 SLC5A6 Zornitza Stark edited their review of gene: SLC5A6: Changed phenotypes: Developmental delay, epilepsy, neurodegeneration, Neurodegeneration, infantile-onset, biotin-responsive, MIM# 618973
Regression v0.127 HPDL Crystle Lee gene: HPDL was added
gene: HPDL was added to Regression. Sources: Expert Review
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086
Phenotypes for gene: HPDL were set to Progressive neurological disorder
Review for gene: HPDL was set to GREEN
Added comment: Biallelic variants reported in 13 families with a neurodegenerative disease ranging from neonatal encephalopathy to adolescent-onset spastic paraplegia
Sources: Expert Review
Regression v0.125 TBCE Elena Savva gene: TBCE was added
gene: TBCE was added to Regression. Sources: Literature
Mode of inheritance for gene: TBCE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCE were set to PMID: 27666369
Phenotypes for gene: TBCE were set to Encephalopathy, progressive, with amyotrophy and optic atrophy 617207
Review for gene: TBCE was set to GREEN
Added comment: PMID: 27666369 - 6 patients (4 families) with early-onset, progressive neurodegeneration encephalopathy with spinal muscular atrophy, supported by functional studies. Patients present within the first 18 months of life, phenotypes include hypotonia (3/6), dev delay (6/6), signs of regression (6/6, distal amyotrophy, ataxia, spasticity)
Missense variant p.I155N is recurring, very rare in gnomAD.
Sources: Literature
Regression v0.123 ADPRHL2 Zornitza Stark gene: ADPRHL2 was added
gene: ADPRHL2 was added to Regression. Sources: Expert list
Mode of inheritance for gene: ADPRHL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADPRHL2 were set to 30100084; 30401461
Phenotypes for gene: ADPRHL2 were set to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, MIM# 618170
Review for gene: ADPRHL2 was set to GREEN
Added comment: 14 families reported, onset is in the first years of life following normal early development. Patients have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy.
Sources: Expert list
Regression v0.121 IRF2BPL Elena Savva gene: IRF2BPL was added
gene: IRF2BPL was added to Regression. Sources: Literature
Mode of inheritance for gene: IRF2BPL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IRF2BPL were set to PMID: 30057031; 30166628
Phenotypes for gene: IRF2BPL were set to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures 618088
Review for gene: IRF2BPL was set to GREEN
Added comment: PMID: 30057031 - 7 patients with neurodevelopmental regression (5/7), progressive ataxia (5/7), seizures (7/7), spasticity (2/7), dystonia (3/7) and global devel delay (7/7). PTCs produced a more severe phenotype than missense. Onset was in childhood. Cerebellar changes also less frequently reported.

PMID: 30166628 - 11 patients with de novo PTCs with childhood neurological regression, epilepsy (7/11), hypotonia (5/11), dystonia (3/11), cerebellar atrophy (5/10). MRI showed CNS defects in 6/10 patients.
Sources: Literature
Regression v0.121 CACNA1E Elena Savva gene: CACNA1E was added
gene: CACNA1E was added to Regression. Sources: Literature
Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CACNA1E were set to PMID: 30343943
Phenotypes for gene: CACNA1E were set to Epileptic encephalopathy, early infantile, 69 618285
Mode of pathogenicity for gene: CACNA1E was set to Other
Review for gene: CACNA1E was set to GREEN
Added comment: PMID: 30343943 - 30 patients with de novo variants and early-onset developmental and epileptic encephalopathy. Patients had developmental regression (9/30), severe hypotonia (16/30), seizures (26/30), congenital joint contractures (13/30), macrocephaly (13/30). MRI shows white matter loss, cortical atrophy
Variants showed a GOF and LOF.
Sources: Literature
Regression v0.118 GATM Zornitza Stark reviewed gene: GATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 12468279, 20682460, 22386973; Phenotypes: Cerebral creatine deficiency syndrome 3, MIM# 612718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.116 ARL13B Zornitza Stark reviewed gene: ARL13B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 8, MIM# 612291; Mode of inheritance: None
Regression v0.116 ZIC4 Crystle Lee reviewed gene: ZIC4: Rating: RED; Mode of pathogenicity: None; Publications: 21204220, 15338008; Phenotypes: ; Mode of inheritance: Unknown
Regression v0.115 CRAT Zornitza Stark gene: CRAT was added
gene: CRAT was added to Regression. Sources: Literature
Mode of inheritance for gene: CRAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRAT were set to 29395073; 31448845
Phenotypes for gene: CRAT were set to Neurodegeneration with brain iron accumulation 8, MIM# 617917; Leigh syndrome
Review for gene: CRAT was set to AMBER
Added comment: Two unrelated families reported with bi-allelic variants, one with NBIA and one with Leigh syndrome phenotype.
Sources: Literature
Regression v0.114 NAXD Zornitza Stark Phenotypes for gene: NAXD were changed from to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Regression v0.111 NAXD Zornitza Stark reviewed gene: NAXD: Rating: GREEN; Mode of pathogenicity: None; Publications: 30576410; Phenotypes: Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.107 TSEN34 Zornitza Stark reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 18711368; Phenotypes: Pontocerebellar hypoplasia type 2C, MIM# 612390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.106 SLC44A1 Zornitza Stark gene: SLC44A1 was added
gene: SLC44A1 was added to Regression. Sources: Literature
Mode of inheritance for gene: SLC44A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC44A1 were set to 31855247
Phenotypes for gene: SLC44A1 were set to Childhood-onset neurodegeneration; progressive ataxia; tremor; cognitive decline; dysphagia; optic atrophy; dysarthria
Review for gene: SLC44A1 was set to GREEN
Added comment: Four affected individuals from three families with homozygous frameshift variants. Functional evidence points to impaired choline transporter function yet unchanged membrane phosphatidylcholine content. Choline treatments may be beneficial.
Sources: Literature
Regression v0.101 ZNF592 Zornitza Stark reviewed gene: ZNF592: Rating: RED; Mode of pathogenicity: None; Publications: 20531441, 26123727; Phenotypes: SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 5; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.100 AGTPBP1 Zornitza Stark gene: AGTPBP1 was added
gene: AGTPBP1 was added to Regression. Sources: NHS GMS
Mode of inheritance for gene: AGTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGTPBP1 were set to 30420557
Phenotypes for gene: AGTPBP1 were set to Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy; Neurodegeneration, childhood-onset, with cerebellar atrophy, 618276
Review for gene: AGTPBP1 was set to GREEN
Added comment: Thirteen individuals with bi-allelic variants in this gene, six of those had a progressive course.
Sources: NHS GMS
Regression v0.98 EIF2AK2 Zornitza Stark gene: EIF2AK2 was added
gene: EIF2AK2 was added to Regression. Sources: Literature
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness
Review for gene: EIF2AK2 was set to GREEN
Added comment: Eight individuals with de novo variants and complex neurodevelopmental phenotype.
Sources: Literature
Regression v0.91 NDUFA4 Zornitza Stark reviewed gene: NDUFA4: Rating: RED; Mode of pathogenicity: None; Publications: 30361421, 28988874, 23746447; Phenotypes: Leigh syndrome, Complex IV deficiency; Mode of inheritance: None
Regression v0.90 ISCA1 Zornitza Stark gene: ISCA1 was added
gene: ISCA1 was added to Regression. Sources: Expert list
Mode of inheritance for gene: ISCA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA1 were set to 28356563; 32092383; 31016283; 30113620; 30105122
Phenotypes for gene: ISCA1 were set to Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613
Review for gene: ISCA1 was set to GREEN
gene: ISCA1 was marked as current diagnostic
Added comment: Multiple unrelated families reported. Severe disorder characterised by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Rat model results in early lethality. Founder variant c.259G > A, p.(Glu87Lys) reported in Indian families.
Sources: Expert list
Regression v0.89 CAMTA1 Zornitza Stark Phenotypes for gene: CAMTA1 were changed from to Cerebellar ataxia, nonprogressive, with mental retardation (614756 AD)
Regression v0.85 CAMTA1 Zornitza Stark reviewed gene: CAMTA1: Rating: RED; Mode of pathogenicity: None; Publications: 32157189, 22693284; Phenotypes: Cerebellar ataxia, nonprogressive, with mental retardation (614756 AD); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.84 SPG11 Zornitza Stark gene: SPG11 was added
gene: SPG11 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: SPG11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPG11 were set to 21381113; 22554690; 19224311; 18067136; 27820618
Phenotypes for gene: SPG11 were set to Spastic paraplegia 11, autosomal recessive, MIM#604360; Charcot-Marie-Tooth disease, axonal, type 2X, MIM#616668; Amyotrophic lateral sclerosis 5, juvenile, MIM#602099
Review for gene: SPG11 was set to GREEN
gene: SPG11 was marked as current diagnostic
Added comment: Complex neurological phenotypes with onset in first and second decade, characterised by gradual deterioration.
Sources: Expert Review
Regression v0.79 SYT14 Zornitza Stark reviewed gene: SYT14: Rating: RED; Mode of pathogenicity: None; Publications: 21835308; Phenotypes: Spinocerebellar ataxia, autosomal recessive 11, MIM# 614229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.79 MTPAP Zornitza Stark Phenotypes for gene: MTPAP were changed from to Perinatal lethal encephalopathy; Spastic ataxia 4, autosomal recessive, MIM#613672
Regression v0.75 MTPAP Zornitza Stark reviewed gene: MTPAP: Rating: AMBER; Mode of pathogenicity: None; Publications: 31779033; Phenotypes: Perinatal lethal encephalopathy, Spastic ataxia 4, autosomal recessive, MIM#613672; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.74 RPIA Sebastian Lunke gene: RPIA was added
gene: RPIA was added to Regression. Sources: Expert Review
Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPIA were set to 14988808; 10589548; 20499043; 28801340; 30088433
Phenotypes for gene: RPIA were set to RPIA (ribose 5-phosphate isomerase A)
Review for gene: RPIA was set to AMBER
Added comment: Two of three patients described regressed in early childhood after earlier developmental delay

From GEL: Three patients described in total, one of these with functional data: Patient 1 with comp het missense and frameshift as well as functional data, early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy Patient 2 with missense, delayed early development, seizures and regression at the age of 7 with MRI white matter abnormalities Patient 3 with comp het missense and canonical splice, clinical biochem corroboration ribitol and arabitol in urine demonstrated significant elevations (>20x), neonatal onset leukoencephalopathy and developmental delay
Sources: Expert Review
Regression v0.70 UBR4 Zornitza Stark reviewed gene: UBR4: Rating: RED; Mode of pathogenicity: None; Publications: 29062094, 23982692, 28600779; Phenotypes: Episodic ataxia, progressive neurological deterioration; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.70 SERPINI1 Zornitza Stark Phenotypes for gene: SERPINI1 were changed from to Encephalopathy, familial, with neuroserpin inclusion bodies MIM#604218
Regression v0.67 SERPINI1 Zornitza Stark reviewed gene: SERPINI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28631894, 25401298, 12103288; Phenotypes: Encephalopathy, familial, with neuroserpin inclusion bodies MIM#604218; Mode of inheritance: None
Regression v0.64 NDUFA12 Zornitza Stark reviewed gene: NDUFA12: Rating: RED; Mode of pathogenicity: None; Publications: 21617257; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23 618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.64 COA5 Zornitza Stark Phenotypes for gene: COA5 were changed from Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3, MIM# 616500 to Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3, MIM# 616500
Regression v0.63 COA5 Zornitza Stark Phenotypes for gene: COA5 were changed from to Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3, MIM# 616500
Regression v0.60 COA5 Zornitza Stark reviewed gene: COA5: Rating: RED; Mode of pathogenicity: None; Publications: 21457908; Phenotypes: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3, MIM# 616500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.58 NOTCH2NL Sue White gene: NOTCH2NL was added
gene: NOTCH2NL was added to Regression_VCGS. Sources: Literature
Mode of inheritance for gene: NOTCH2NL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH2NL were set to 31332381
Phenotypes for gene: NOTCH2NL were set to OMIM 603472 NEURONAL INTRANUCLEAR INCLUSION DISEASE; NIID
Penetrance for gene: NOTCH2NL were set to Incomplete
Mode of pathogenicity for gene: NOTCH2NL was set to Other
Review for gene: NOTCH2NL was set to GREEN
Added comment: adult onset neurodegenerative condition caused by STR expansion 5' of NOTCH2NL
Sources: Literature
Regression v0.56 NUP214 Zornitza Stark Phenotypes for gene: NUP214 were changed from epileptic encephalopathy; developmental regression; microcephaly to Encephalopathy, acute, infection-induced, susceptibility to, 9, MIM# 618426; epileptic encephalopathy; developmental regression; microcephaly
Regression v0.54 NUP214 Sue White gene: NUP214 was added
gene: NUP214 was added to Regression_VCGS. Sources: Literature
Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP214 were set to 31178128
Phenotypes for gene: NUP214 were set to epileptic encephalopathy; developmental regression; microcephaly
Review for gene: NUP214 was set to GREEN
gene: NUP214 was marked as current diagnostic
Added comment: Sources: Literature
Regression v0.52 H3F3B Zornitza Stark commented on gene: H3F3B: Elizabeth J Bhoj, H3F3A/B Consortium, Hakon H. Hakonarson.: Mutations In H3f3a And H3f3b Encoding Histone 3.3: Report Of 26 Patients With Neurodevelopmental And Congenital Manifestations. American Society of Human Genetics, Orlando, FL October 2017 Notes: Platform Presentation.
Regression v0.49 PDE6D Zornitza Stark Added comment: Comment when marking as ready: Two families; link with regression not established.
Regression v0.43 ZNF423 Zornitza Stark Mode of inheritance for gene: ZNF423 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Regression v0.41 ZNF423 Zornitza Stark reviewed gene: ZNF423: Rating: RED; Mode of pathogenicity: None; Publications: 22863007; Phenotypes: Joubert syndrome 19, OMIM# 614844; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Regression v0.40 RNF13 Zornitza Stark gene: RNF13 was added
gene: RNF13 was added to Regression_VCGS. Sources: Literature
Mode of inheritance for gene: RNF13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF13 were set to 30595371
Phenotypes for gene: RNF13 were set to Epileptic encephalopathy, early infantile, 73, MIM# 618379
Mode of pathogenicity for gene: RNF13 was set to Other
Review for gene: RNF13 was set to GREEN
Added comment: Three unrelated individuals with de novo gain-of-function variants in this gene reported; severe neurodegenerative disorder, seizures are a prominent part of the phenotype.
Sources: Literature
Regression v0.38 CAD Zornitza Stark gene: CAD was added
gene: CAD was added to Regression_VCGS. Sources: Expert list
Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAD were set to 28007989; 25678555
Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50, MIM# 616457
Review for gene: CAD was set to GREEN
Added comment: Five individuals from four unrelated families reported, seizures are a prominent part of the phenotype of this progressive neurometabolic condition.
Sources: Expert list
Regression v0.31 ATP2B3 Zornitza Stark reviewed gene: ATP2B3: Rating: AMBER; Mode of pathogenicity: None; Publications: 22912398, 27653636, 27632770; Phenotypes: Spinocerebellar ataxia, X-linked 1, MIM#302500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Regression v0.27 CACNB4 Zornitza Stark reviewed gene: CACNB4: Rating: AMBER; Mode of pathogenicity: None; Publications: 10762541, 9628818, 27003325; Phenotypes: Episodic ataxia, type 5, MIM#613855; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.22 CCDC88C Zornitza Stark reviewed gene: CCDC88C: Rating: AMBER; Mode of pathogenicity: None; Publications: 25062847, 30398676; Phenotypes: Spinocerebellar ataxia 40, MIM#616053; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.20 EEF2 Zornitza Stark reviewed gene: EEF2: Rating: RED; Mode of pathogenicity: None; Publications: 15732118, 23001565; Phenotypes: Spinocerebellar ataxia 26; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Regression v0.17 MARS2 Zornitza Stark Deleted their review
Regression v0.14 CP Zornitza Stark reviewed gene: CP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aceruloplasminaemia, MIM#604290; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.10 COX14 Zornitza Stark reviewed gene: COX14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22243966; Phenotypes: Mitochondrial complex IV deficiency, MIM#220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.10 CA8 Zornitza Stark Phenotypes for gene: CA8 were changed from to Cerebellar ataxia and mental retardation with or without quadrupedal locomotion 3, MIM#613227
Regression v0.5 IFIH1 Zornitza Stark gene: IFIH1 was added
gene: IFIH1 was added to Regression_VCGS. Sources: Expert Review
Mode of inheritance for gene: IFIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFIH1 were set to 24686847
Phenotypes for gene: IFIH1 were set to Aicardi-Goutieres syndrome 7, MIM#615846
Mode of pathogenicity for gene: IFIH1 was set to Other
Review for gene: IFIH1 was set to GREEN
Added comment: Gain-of-function variants in this gene cause AGS, some affected individuals experience episodic neurological regression
Sources: Expert Review
Regression v0.3 TBCD Zornitza Stark gene: TBCD was added
gene: TBCD was added to Regression_VCGS. Sources: Expert Review
Mode of inheritance for gene: TBCD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCD were set to 27666370; 27666374
Phenotypes for gene: TBCD were set to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, MIM#617193
Review for gene: TBCD was set to GREEN
Added comment: 15 children from 9 unrelated families with bi-allelic variants in this gene and a progressive neurodegenerative encephalopathy.
Sources: Expert Review
Regression v0.0 THAP1 Zornitza Stark gene: THAP1 was added
gene: THAP1 was added to Regression_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: THAP1 was set to Unknown
Regression v0.0 TH Zornitza Stark gene: TH was added
gene: TH was added to Regression_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TH was set to Unknown
Regression v0.0 MTHFR Zornitza Stark gene: MTHFR was added
gene: MTHFR was added to Regression_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MTHFR was set to Unknown