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Intellectual disability syndromic and non-syndromic v0.5939 SOX10 Zornitza Stark Phenotypes for gene: SOX10 were changed from to Peripheral demyelinating neuropathy Central demyelination, Waardenburg and Hirschsprung disease, OMIM #609136; Waardenburg syndrome, type 2E, with or without neurologic involvement (OMIM #611584)
Intellectual disability syndromic and non-syndromic v0.5881 SOX10 David Fairbairn reviewed gene: SOX10: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 10762540, 34667088, 38132479; Phenotypes: PCWH (Peripheral demyelinating neuropathy Central demyelination, Waardenburg and Hirschsprung disease) syndrome (OMIM #609136), Waardenburg syndrome, type 2E, with or without neurologic involvement (OMIM #611584); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.5821 SPR Zornitza Stark Marked gene: SPR as ready
Intellectual disability syndromic and non-syndromic v0.5821 SPR Zornitza Stark Gene: spr has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5821 SPR Zornitza Stark Phenotypes for gene: SPR were changed from to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716
Intellectual disability syndromic and non-syndromic v0.5820 SPR Zornitza Stark Publications for gene: SPR were set to
Intellectual disability syndromic and non-syndromic v0.5819 SPR Zornitza Stark Mode of inheritance for gene: SPR was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5818 SPR Zornitza Stark reviewed gene: SPR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5797 SPR Amy Chiang edited their review of gene: SPR: Added comment: SPR has been classified to have definitive association with dopa-responsive dystonia (reviewed by the Aminoacidopathy Expert Panel on 06/04/2021).

Clinical phenotypes are mainly neuromuscular with characteristic features of axial hypotonia, dystonia, delayed psychomotor development, oculogyric crises, diurnal fluctuation with improvement after sleep; though cognitive impairment ranging from mild to severe levels have been reported in patients with sepiapterin reductase deficiency (PMID: 16049044, 17188538) - 7 Maltese patients with the same homozygous spice variants in SPR (founder effect due to relative small Maltese population); note there was no significant improvement in cognitive ability with L-dopa treatment in these patients despite improvement in their motor abilities (PMID: 16049044) - ? other causes to cognitive impairment in these patients other than SPR associated sepiapterin reductase deficiency

There are 271 SPR variants registered in ClinVar to date with only 1 submission from a research lab reported 2 affected individuals with intellectual disability + family history (ClinVar # 625209) - no publication available to verify, ? from BRIDGE consortium study: SPEED project cohort
A start loss variant detected in 5 affected individuals with ID & epilepsy from a Persian consanguineous family - LOD score = 4.027 (PMID: 29302074); Changed publications: PMID: 29302074, 16049044, 17188538; Changed phenotypes: MONDO #0012994, OMIM #612716, axial hypotonia, dystonia with diurnal fluctuation, oculogyric crises, delayed psychomotor development, sepiapterin reductase deficiency
Intellectual disability syndromic and non-syndromic v0.5796 SPR Amy Chiang changed review comment from: SPR has been classified to have definitive association with dopa-responsive dystonia. This was reviewed by the Aminoacidopathy Expert Panel on 06/04/2021.
There are 271 SPR variants registered in ClinVar to date with only 1 submission from a research lab reported 2 affected individuals with intellectual disability + family history (ClinVar # 625209) - no publication available to verify, ? from BRIDGE consortium study: SPEED project cohort
A start loss variant detected in 5 affected individuals with ID & epilepsy from a Persian consanguineous family - LOD score = 4.027 (PMID: 29302074); to: SPR has been classified to have definitive association with dopa-responsive dystonia. This was reviewed by the Aminoacidopathy Expert Panel on 06/04/2021.
There are 271 SPR variants registered in ClinVar to date with only 1 submission from a research lab reported 2 affected individuals with intellectual disability + family history (ClinVar # 625209) - no publication available to verify, ? from BRIDGE consortium study: SPEED project cohort
A start loss variant detected in 5 affected individuals with ID & epilepsy from a Persian consanguineous family - LOD score = 4.027 (PMID: 29302074)
Intellectual disability syndromic and non-syndromic v0.5796 SPR Amy Chiang reviewed gene: SPR: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29302074; Phenotypes: dopa-responsive dystonia due to sepiapterin reductase deficiency, MONDO: 0012994, Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM: 612716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5746 DOCK4 Sangavi Sivagnanasundram changed review comment from: 7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities.

Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS).; to: 7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities. Two of the individuals are reportedly compound heterozygous.

Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS).
Intellectual disability syndromic and non-syndromic v0.5746 DOCK4 Sangavi Sivagnanasundram changed review comment from: Well-established gene-disease association

7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities.

Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS).; to: 7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities.

Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS).
Intellectual disability syndromic and non-syndromic v0.5628 PLA2G16 Lauren Rogers gene: PLA2G16 was added
gene: PLA2G16 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PLA2G16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLA2G16 were set to PMID: 37919452
Phenotypes for gene: PLA2G16 were set to Lipodystrophy (MONDO:0006573)
Added comment: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy.

Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4876 SMG9 Zornitza Stark Phenotypes for gene: SMG9 were changed from Heart and brain malformation syndrome, MIM# 616920 to Heart and brain malformation syndrome, MIM# 616920; Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Intellectual disability syndromic and non-syndromic v0.4874 SMG9 Zornitza Stark edited their review of gene: SMG9: Added comment: PMID 35087184: 5 individuals from 3 unrelated Finnish families reported with same homozygous missense variant (founder effect) and predominantly neurological phenotype. Uncertain if this is a distinct disorder or part of a spectrum with the previously reported cases.; Changed publications: 27018474, 31390136, 35087184; Changed phenotypes: Heart and brain malformation syndrome, MIM# 616920, Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, MIM# 619995
Intellectual disability syndromic and non-syndromic v0.4872 PSMC1 Hazel Phillimore gene: PSMC1 was added
gene: PSMC1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PSMC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC1 were set to PMID: 35861243
Phenotypes for gene: PSMC1 were set to spastic paraplegia; severe developmental delay; severe intellectual disability; hearing loss; micropenis; undescended testes; Syndromic disease MONDO:0002254, PSMC1-related
Review for gene: PSMC1 was set to RED
Added comment: Homozygosity mapping on one large consanguineous Bedouin kindred showed three affected children (out of the ten) to be homozygous for NM_002802.3:c.983T>C; p.(Ile328Thr).

Drosophila rescue experiments were carried out. Transgenic studies using drosophila with the silenced ortholog Rpt2 gene were rescued by the human wild-type PSMC1.

Three of the ten offspring of healthy consanguineous parents of Bedouin Israeli ancestry were affected with a similar phenotype of failure to thrive, developmental delay and severe intellectual disability, spastic tetraplegia with central hypotonia, chorea, as well as hearing loss. None of the three achieved verbal communication or ambulation (sitting / standing) at any age. They had mild dysmorphism of borderline dolichocephaly and microcephaly, prominent bushy eyebrows, flat midface, long nasal bridge and micrognathia. All three had micropenis with undescended testes. One of the affected (as a toddler) underwent thorough endocrinological analysis: testosterone and gonadotropin levels were low.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4662 PIGA Zornitza Stark edited their review of gene: PIGA: Added comment: PMID 34875027: variants in PIGA causing a neurodevelopment disorder and a juvenile form of hereditary hemochromatosis reported in > three unrelated patients. All patients had increased serum iron, ferritin and transferrin saturation levels, high ALP and low hepcidin. All patients had generalised seizures and intellectual disability. A subpopulation of patient blood cells showed a slight reduction of GPI-anchored proteins, suggesting that the mutations were hypomorphic and retained some residual activity. CRISPR/Cas12a-mediated knockdown of PIGA in Hep3B liver cells eliminated the cell surface expression of GPI-anchored proteins CD59 and hemojuvelin (HJV; 608374), as well as caused decreased expression of hepcidin (606464) compared to controls. These hypomorphic alleles could explain the milder neurologic phenotype, which allowed for sufficiently long survival for the iron overload phenotype to manifest.; Changed publications: 22305531, 24357517, 24706016, 26545172, 33333793, 32694024, 34875027; Changed phenotypes: Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM# 300868, MONDO:0010466, Neurodevelopmental disorder with epilepsy and haemochromatosis, MIM# 301072
Intellectual disability syndromic and non-syndromic v0.4500 SPRED2 Zornitza Stark Phenotypes for gene: SPRED2 were changed from Rasopathy; developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt to Noonan syndrome 14, MIM# 619745
Intellectual disability syndromic and non-syndromic v0.4499 SPRED2 Zornitza Stark reviewed gene: SPRED2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome 14, MIM# 619745; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty edited their review of gene: OGDHL: Added comment: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.; Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty commented on gene: OGDHL: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty changed review comment from: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature; to: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4322 OGDHL Melanie Marty gene: OGDHL was added
gene: OGDHL was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to PMID: 34800363
Phenotypes for gene: OGDHL were set to Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment
Added comment: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

Homozygous and compound heterozygous variants reported. Variant types reported include missense, PTCs and a synonymous variant that was shown to affect splicing.

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.4236 SPRED2 Zornitza Stark Marked gene: SPRED2 as ready
Intellectual disability syndromic and non-syndromic v0.4236 SPRED2 Zornitza Stark Gene: spred2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4236 SPRED2 Zornitza Stark Phenotypes for gene: SPRED2 were changed from developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt to Rasopathy; developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Intellectual disability syndromic and non-syndromic v0.4235 SPRED2 Zornitza Stark Classified gene: SPRED2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.4235 SPRED2 Zornitza Stark Gene: spred2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.4233 SPRED2 Dean Phelan gene: SPRED2 was added
gene: SPRED2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRED2 were set to PMID: 34626534
Phenotypes for gene: SPRED2 were set to developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Review for gene: SPRED2 was set to GREEN
Added comment: PMID: 34626534
Homozygosity for three different variants c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95) were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behaviour. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3384 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Added comment: PMID 33390987: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.; Changed rating: GREEN; Changed publications: 33390987; Changed phenotypes: Intellectual disability, seizures, autism; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.3368 RNU7-1 Paul De Fazio gene: RNU7-1 was added
gene: RNU7-1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like
Review for gene: RNU7-1 was set to GREEN
gene: RNU7-1 was marked as current diagnostic
Added comment: Review originally submitted by Ming Wong
- 16 affected individuals from 11 families
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3368 LSM11 Ee Ming Wong gene: LSM11 was added
gene: LSM11 was added to Intellectual disability syndromic and non-syndromic. 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
Intellectual disability syndromic and non-syndromic v0.3128 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 33057194
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.3102 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to Complete
Review for gene: PRKACB was set to AMBER
Added comment: ID was a feature in 2/4 individuals with PRKACB pathogenic variant reported to date.
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Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2994 SPRED1 Zornitza Stark Marked gene: SPRED1 as ready
Intellectual disability syndromic and non-syndromic v0.2994 SPRED1 Zornitza Stark Gene: spred1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.2994 SPRED1 Zornitza Stark Phenotypes for gene: SPRED1 were changed from to Legius syndrome, MIM# 611431
Intellectual disability syndromic and non-syndromic v0.2993 SPRED1 Zornitza Stark Publications for gene: SPRED1 were set to
Intellectual disability syndromic and non-syndromic v0.2992 SPRED1 Zornitza Stark Mode of inheritance for gene: SPRED1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2991 SPRED1 Zornitza Stark reviewed gene: SPRED1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17704776, 19366998, 21548021; Phenotypes: Legius syndrome, MIM# 611431; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.2849 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Mode of pathogenicity for gene: LMBRD2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2750 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to AMBER
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.2455 RSPRY1 Zornitza Stark Classified gene: RSPRY1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.2455 RSPRY1 Zornitza Stark Gene: rspry1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.2454 RSPRY1 Zornitza Stark gene: RSPRY1 was added
gene: RSPRY1 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: RSPRY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSPRY1 were set to 26365341
Phenotypes for gene: RSPRY1 were set to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585
Review for gene: RSPRY1 was set to AMBER
Added comment: Two unrelated individuals reported, some functional evidence.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.2420 TRIO Zornitza Stark changed review comment from: The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1.; to: The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly.
Intellectual disability syndromic and non-syndromic v0.2260 SRPX2 Zornitza Stark Phenotypes for gene: SRPX2 were changed from to Rolandic epilepsy, mental retardation, and speech dyspraxia, MIM# 300643
Intellectual disability syndromic and non-syndromic v0.2256 SRPX2 Zornitza Stark reviewed gene: SRPX2: Rating: RED; Mode of pathogenicity: None; Publications: 16497722, 23933820, 23871722; Phenotypes: Rolandic epilepsy, mental retardation, and speech dyspraxia, MIM# 300643; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.2256 SPRTN Zornitza Stark Marked gene: SPRTN as ready
Intellectual disability syndromic and non-syndromic v0.2256 SPRTN Zornitza Stark Gene: sprtn has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.2256 SPRTN Zornitza Stark Phenotypes for gene: SPRTN were changed from to Ruijs-Aalfs syndrome, MIM# 616200
Intellectual disability syndromic and non-syndromic v0.2255 SPRTN Zornitza Stark Publications for gene: SPRTN were set to
Intellectual disability syndromic and non-syndromic v0.2254 SPRTN Zornitza Stark Mode of inheritance for gene: SPRTN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.2253 SPRTN Zornitza Stark Classified gene: SPRTN as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.2253 SPRTN Zornitza Stark Gene: sprtn has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.2252 SPRTN Zornitza Stark reviewed gene: SPRTN: Rating: RED; Mode of pathogenicity: None; Publications: 25261934; Phenotypes: Ruijs-Aalfs syndrome, MIM# 616200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.1293 SNRPE Chirag Patel gene: SNRPE was added
gene: SNRPE was added to Intellectual disability, syndromic and non-syndromic_GHQ_VCGS. Sources: Literature
Mode of inheritance for gene: SNRPE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SNRPE were set to Hypotrichosis 11; OMIM #615059
Review for gene: SNRPE was set to AMBER
Added comment: 1 patient with de novo heterozygous missense SNRPE mutation, with non-syndromic primary microcephaly and intellectual disability. SNRPE encodes SmE and they showed that the microcephaly-linked SmE variant is unable to interact with the SMN complex and as a consequence fails to assemble into U snRNPs. This results in widespread mRNA splicing alterations in fibroblast cells derived from this patient. Similar alterations were observed in HEK293 cells upon SmE depletion that could be rescued by the expression of wild type but not mutant SmE. Depletion of SmE in zebrafish causes aberrant mRNA splicing alterations and reduced brain size, reminiscent of the patient microcephaly phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.1161 SELENON Zornitza Stark Phenotypes for gene: SELENON were changed from to Muscular dystrophy, rigid spine, 1, MIM# 602771; Myopathy, congenital, with fiber-type disproportion, MIM# 255310
Intellectual disability syndromic and non-syndromic v0.1158 SELENON Zornitza Stark reviewed gene: SELENON: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy, rigid spine, 1, MIM# 602771, Myopathy, congenital, with fiber-type disproportion, MIM# 255310; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.0 SPRTN Zornitza Stark gene: SPRTN was added
gene: SPRTN was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland
Mode of inheritance for gene: SPRTN was set to Unknown
Intellectual disability syndromic and non-syndromic v0.0 SPRED1 Zornitza Stark gene: SPRED1 was added
gene: SPRED1 was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland
Mode of inheritance for gene: SPRED1 was set to Unknown
Intellectual disability syndromic and non-syndromic v0.0 SPR Zornitza Stark gene: SPR was added
gene: SPR was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland
Mode of inheritance for gene: SPR was set to Unknown