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Genetic Epilepsy v0.2759 SYNJ1 Zornitza Stark Phenotypes for gene: SYNJ1 were changed from Developmental and epileptic encephalopathy 53, MIM# 617389; Parkinson disease 20, early-onset, MIM# 615530 to Developmental and epileptic encephalopathy 53, MIM# 617389
Genetic Epilepsy v0.2665 KCNIP4 Ain Roesley gene: KCNIP4 was added
gene: KCNIP4 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KCNIP4 was set to Unknown
Publications for gene: KCNIP4 were set to 33826137
Phenotypes for gene: KCNIP4 were set to seizures; epilepsy
Review for gene: KCNIP4 was set to RED
gene: KCNIP4 was marked as current diagnostic
Added comment: single paper describing insertions of L1 retrotransposons in KCNIP4
samples were post-mortem of resected temporal cortex from individuals with idiopathic temporal lobe epilepsy

1x de novo insertion of L1 in KCNIP4 however ddPCR revealed that this did NOT alter KCNIP4 mRNA expression
Sources: Literature
Genetic Epilepsy v0.2218 SON Elena Savva Classified gene: SON as Green List (high evidence)
Genetic Epilepsy v0.2218 SON Elena Savva Gene: son has been classified as Green List (High Evidence).
Genetic Epilepsy v0.2217 SON Elena Savva Classified gene: SON as Green List (high evidence)
Genetic Epilepsy v0.2217 SON Elena Savva Gene: son has been classified as Green List (High Evidence).
Genetic Epilepsy v0.2217 SON Elena Savva Classified gene: SON as Green List (high evidence)
Genetic Epilepsy v0.2217 SON Elena Savva Gene: son has been classified as Green List (High Evidence).
Genetic Epilepsy v0.2216 SON Elena Savva Marked gene: SON as ready
Genetic Epilepsy v0.2216 SON Elena Savva Gene: son has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.2216 SON Elena Savva gene: SON was added
gene: SON was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: SON was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SON were set to PMID: 37488749; 27545680
Phenotypes for gene: SON were set to ZTTK syndrome MIM#617140
Review for gene: SON was set to GREEN
Added comment: Seizures (in some patients) noted in OMIM

PMID: 37488749 - review of 79 patients, seizures not described

PMID: 27545680 - 11 of 20 individuals developed seizures and/or epilepsy with an age of onset ranging from 1 to 6 years
Sources: Literature
Genetic Epilepsy v0.2149 EED Andrew Fennell gene: EED was added
gene: EED was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: EED was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EED were set to PMID: 34533271
Phenotypes for gene: EED were set to Cohen-Gibson syndrome, MIM# 617561
Review for gene: EED was set to RED
Added comment: PMID: 34533271 - single case report of child with absence epilepsy aged 5yrs and subsequent GTC seizures throughout childhood.

Note, Griffiths et al (2019) reported 1 patient with seizures but later attributed this to hyperinsulinaemic hypoglycaemia.
Sources: Literature
Genetic Epilepsy v0.2130 CHD1 Lilian Downie gene: CHD1 was added
gene: CHD1 was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: CHD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD1 were set to 28866611
Phenotypes for gene: CHD1 were set to Pilarowski-Bjornsson syndrome, MIM#617682
Review for gene: CHD1 was set to GREEN
Added comment: 3/6 seizures
Sources: Expert list
Genetic Epilepsy v0.2071 FAM50A Zornitza Stark changed review comment from: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).
Sources: Literature; to: Lee et al (2020 - PMID: 32703943) 6 affected individuals from 5 families.

Seizures in 3/6 from 2 families.
Genetic Epilepsy v0.1975 AMACR John Coleman gene: AMACR was added
gene: AMACR was added to Genetic Epilepsy. Sources: Literature,Expert Review
Mode of inheritance for gene: AMACR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMACR were set to (PMID:35428665; 21576695; 11060344; 21686617
Phenotypes for gene: AMACR were set to ALPHA-METHYLACYL-CoA RACEMASE DEFICIENCY - 614307
Penetrance for gene: AMACR were set to unknown
Review for gene: AMACR was set to GREEN
Added comment: Autosomal recessive affecting AMACR enzyme which is active in the mitochondrial & peroxisome. AMACR deficiency and Congenital Bile Acid Synthesis Defect 4 are distinctive phenotypes. Epilepsy a feature of AMACR deficiency on OMIM. AMACR deficiency reported in adults with later onset tonic clonic seizures in a 58 year old male, also had cerebellar features. Second case of female in her 70s with lacosamide responsive seizures and other neurological manifestations. Case series (Thompson et al 2009) - 44 year old male seizures onset at age 18, 52 year old female seizure onset 50s, and 57 y/o female tonic clonic seizures onset at age 13. Variable condition.
Sources: Literature, Expert Review
Genetic Epilepsy v0.1956 ALDH3A2 Zornitza Stark Phenotypes for gene: ALDH3A2 were changed from to Sjogren-Larsson syndrome, MIM# 270200
Genetic Epilepsy v0.1900 ZNF335 Zornitza Stark gene: ZNF335 was added
gene: ZNF335 was added to Genetic Epilepsy. Sources: Expert Review
Mode of inheritance for gene: ZNF335 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF335 were set to 23178126; 27540107; 29652087
Phenotypes for gene: ZNF335 were set to Microcephaly 10, primary, autosomal recessive (MIM#615095)
Review for gene: ZNF335 was set to GREEN
Added comment: At least 6 unrelated families reported in literature with different biallelic variants in ZNF335. Microcephaly is the primary feature, but also commonly in association with a variable epilepsy phenotype.

Stouffs et al. (PMID:29652087) report 2 unrelated cases: patient A, demonstrating refractory seizures leading to death at age 5 days, whereas patient B lacked any clinical seizures, but had frequent spasms that have yet to be recorded by EEG. The proband in Sato et al. (PMID:27540107) had rare focal seizures controlled by treatment. Although not noted by Yang et al. (PMID:231781260), affected individuals in that family had seizures described as paroxysmal myoclonic jerks (personal communication with Stouffs et al). The case by Rana et al. (PMID:31187448) presented multifocal drug-resistant epilepsy, and while details were limited in McSherry et al. (PMID:30500859), authors did also note seizures.
Sources: Expert Review
Genetic Epilepsy v0.1845 CNOT9 Karina Sandoval gene: CNOT9 was added
gene: CNOT9 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CNOT9 were set to PMID: 37092538
Phenotypes for gene: CNOT9 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: CNOT9 was set to GREEN
Added comment: 7 individuals with de novo variants. In silico predictions of functional relevance. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include.

Symptoms: Neuro dev disorder. ID, Epilepsy. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities.
Sources: Literature
Genetic Epilepsy v0.1627 NR4A2 Zornitza Stark Phenotypes for gene: NR4A2 were changed from Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, MIM# 619911
Genetic Epilepsy v0.1626 NR4A2 Zornitza Stark edited their review of gene: NR4A2: Changed phenotypes: Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, MIM# 619911
Genetic Epilepsy v0.1499 SYNJ1 Zornitza Stark Phenotypes for gene: SYNJ1 were changed from to Developmental and epileptic encephalopathy 53, MIM# 617389; Parkinson disease 20, early-onset, MIM# 615530
Genetic Epilepsy v0.1496 SYNJ1 Zornitza Stark reviewed gene: SYNJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32435303, 27435091, 23804563, 23804577, 27496670, 33841314; Phenotypes: Developmental and epileptic encephalopathy 53, MIM# 617389, Parkinson disease 20, early-onset, MIM# 615530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1317 OTUD5 Belinda Chong gene: OTUD5 was added
gene: OTUD5 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to PMID:33748114
Phenotypes for gene: OTUD5 were set to X-Linked Intellectual Disability and Congenital Malformation
Review for gene: OTUD5 was set to AMBER
Added comment: A hemizygous OTUD5 missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in a family in two brothers with epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly.
Sources: Literature
Genetic Epilepsy v0.1276 PHF6 Ain Roesley gene: PHF6 was added
gene: PHF6 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PHF6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PHF6 were set to 32399860
Phenotypes for gene: PHF6 were set to Borjeson-Forssman-Lehmann syndrome MIM#301900
Penetrance for gene: PHF6 were set to unknown
Review for gene: PHF6 was set to GREEN
Added comment: Epilepsy is part of the phenotypic spectrum for Borjeson-Forssman-Lehmann syndrome (OMIM). At least 18 mutations known to date.
Sources: Literature
Genetic Epilepsy v0.1112 ZEB2 Zornitza Stark Phenotypes for gene: ZEB2 were changed from to Mowat-Wilson syndrome, MIM# 235730; MONDO:0009341
Genetic Epilepsy v0.1110 ZEB2 Zornitza Stark reviewed gene: ZEB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mowat-Wilson syndrome, MIM# 235730, MONDO:0009341; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1110 SLC9A6 Zornitza Stark Phenotypes for gene: SLC9A6 were changed from to Mental retardation, X-linked syndromic, Christianson type, MIM# 300243; MONDO:0010278
Genetic Epilepsy v0.1107 SLC9A6 Zornitza Stark reviewed gene: SLC9A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 18342287, 19377476, 25044251, 33278113, 32569089, 31879735; Phenotypes: Mental retardation, X-linked syndromic, Christianson type, MIM# 300243, MONDO:0010278; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1003 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Added comment: 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: 31439720, 33390987
Genetic Epilepsy v0.987 YIF1B Zornitza Stark Phenotypes for gene: YIF1B were changed from Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement to Kaya-Barakat-Masson syndrome, MIM# 619125; Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Genetic Epilepsy v0.986 YIF1B Zornitza Stark reviewed gene: YIF1B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Kaya-Barakat-Masson syndrome, MIM# 619125, Central hypotonia, Failure to thrive, Microcephaly, Global developmental delay, Intellectual disability, Seizures, Spasticity, Abnormality of movement; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.772 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943
Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261)
Penetrance for gene: FAM50A were set to unknown
Review for gene: FAM50A was set to AMBER
Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference.

The authors provide clinical details on 6 affected individuals from 5 families.

Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6).

In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam).

In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40).

Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3).

Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones).

Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt.

Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish.

Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins.

Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism.

Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.).

Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families).
Sources: Literature
Genetic Epilepsy v0.745 ABCA2 Konstantinos Varvagiannis gene: ABCA2 was added
gene: ABCA2 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ABCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCA2 were set to 30237576; 29302074; 31047799
Phenotypes for gene: ABCA2 were set to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808
Penetrance for gene: ABCA2 were set to Complete
Review for gene: ABCA2 was set to GREEN
Added comment: Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808).

There are 3 relevant publications (01-07-2020) :
- Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations.
- Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures.
- Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype.

All subjects harbored biallelic pLoF variants.

N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency.

Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Literature
Genetic Epilepsy v0.470 SMS Zornitza Stark gene: SMS was added
gene: SMS was added to Genetic Epilepsy. Sources: Expert list
Mode of inheritance for gene: SMS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SMS were set to 30237987
Phenotypes for gene: SMS were set to Mental retardation X-linked Snyder-Robinson type, 309583
Review for gene: SMS was set to GREEN
gene: SMS was marked as current diagnostic
Added comment: Seizures reported in some affected individuals.
Sources: Expert list
Genetic Epilepsy v0.247 DNAJC6 Zornitza Stark Phenotypes for gene: DNAJC6 were changed from Parkinson disease 19b, early-onset, MIM#615528 to Parkinson disease 19b, early-onset, MIM#615528
Genetic Epilepsy v0.246 DNAJC6 Zornitza Stark Phenotypes for gene: DNAJC6 were changed from to Parkinson disease 19b, early-onset, MIM#615528
Genetic Epilepsy v0.243 DNAJC6 Zornitza Stark reviewed gene: DNAJC6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Parkinson disease 19b, early-onset, MIM#615528; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal