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Early onset or syndromic epilepsy v2.352 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Tag Q2_21_rating tag was added to gene: CERS1.
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh edited their review of gene: CERS1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least two missense variants reported in two unrelated cases, together with supportive functional evidence.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Classified gene: CERS1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Gene: cers1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.350 CERS1 Sarah Leigh Phenotypes for gene: CERS1 were changed from ?Epilepsy, progressive myoclonic, 8, 616230 to ?Epilepsy, progressive myoclonic, 8 OMIM:616230; progressive myoclonic epilepsy type 8 MONDO:0014545
Early onset or syndromic epilepsy v2.349 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621
Early onset or syndromic epilepsy v2.348 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621
Early onset or syndromic epilepsy v2.347 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074
Early onset or syndromic epilepsy v2.346 NSF Sarah Leigh Classified gene: NSF as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.346 NSF Sarah Leigh Gene: nsf has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.345 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Tag Q2_21_rating tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh edited their review of gene: PMPCB: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Neurodegeneration in Early Childhood. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Classified gene: PMPCB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Gene: pmpcb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.344 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Early onset or syndromic epilepsy v2.343 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50 - MIM 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Tag Q2_21_rating tag was added to gene: TMEM222.
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh edited their review of gene: TMEM222: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (TMEM222 not listed on OMIM 11/05/2021). At least ten variants reported in at least nine unrelated families. Seizures were evident in six individuals from six families.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Classified gene: TMEM222 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Gene: tmem222 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.341 TMEM222 Sarah Leigh Publications for gene: TMEM222 were set to 33824500
Early onset or syndromic epilepsy v2.340 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to AMBER
Added comment: Seizures have been reported in 7 individuals (from 6 families). Consider inclusion with amber/green rating. From the ID panel :

Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17. Rare features incl. body tremors, decreased lower extremity muscle mass or disorder of motor neurons.

TMEM222 variants were identified following exome sequencing. Previous investigations incl. metabolic studies, FMR1, chromosomes by standard karyotype or CMA, SMA, CMT1A were reported to be normal (available for some individuals).

TMEM222 variants missense and pLoF ones mostly found in homozygosity (7/9 families were consanguineous, compound heterozygosity reported in a single case from the 9 families). Sanger sequencing was used for confirmation of variants, parental carrier state as well as testing of sibs (unaffected sibs tested in 4 families).

Few individuals had additional genetic findings in other genes, though classified as VUS (3 families).

The gene encodes transmembrane protein 222 (208 residues) which however has unknown function. The protein comprises 3 transmembrane domains and a domain of unknown function. TMEMs are a group of transmembrane proteins spanning membranes with - most commonly - unclear function.

The authors measured expression by qPCR mRNA analysis, demonstrating highest fetal and adult brain expression (incl. parietal and occipital cortex). Expression levels from GTEx data also support a role in neurodevelopment.

Immunocytochemistry revealed highest levels in mature human iPSC-derived glutaminergic cortical neurons and moderate in immature ones. Additional studies supported that the gene is highly expressed in dendrites and might play a role in postsynaptic vesicles (colocalization with postsynaptic and early endosomal markers).

A previous study by Riazuddin et al (2017 - PMID: 27457812) had identified TMEM222 as a candidate gene for ID. This family (PKMR213) however appears to be included as family 2 in the aforementioned publication (same pedigree, variant and phenotype in both articles).

In OMIM there is currently no associated phenotype.

The gene is listed among the primary ID genes in SysID.

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Early onset or syndromic epilepsy v2.340 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability; Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854
Early onset or syndromic epilepsy v2.339 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.339 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.338 UFSP2 Sarah Leigh Tag Q2_21_rating was removed from gene: UFSP2.
Tag founder-effect tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.338 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 33473208; 28892125; 26428751; 32755715
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Classified gene: UFSP2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Added comment: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.336 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: No OMIM reference for the pediatric neurodevelopmental anomalies and epilepsy feautres. Monoallelic variants have previously been associated with skeletal dysplasias (PMIDs 28892125;26428751;32755715), but there does not appear to be any phenotypic overlap between these and the phenotype seen for the biallelic rs142500730.
Early onset or syndromic epilepsy v2.336 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability to Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability
Early onset or syndromic epilepsy v2.335 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.335 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 33473208
Early onset or syndromic epilepsy v2.334 HERC2 Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 (MIM 615516) to Mental retardation, autosomal recessive 38, OMIM:615516
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova changed review comment from: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.; to: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline if this gene is upgraded to Green on this panel in the future.
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Classified gene: NCDN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Added comment: Comment on list classification: Rating Amber with monoallelic MOI, awaiting further cases with seizures (2/3 de novo cases with epilepsy - PMID: 33711248). Currently 'Red' evidence level for biallelic form.
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Gene: ncdn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.332 NCDN Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Early onset or syndromic epilepsy v2.332 NCDN Arina Puzriakova Mode of inheritance for gene: NCDN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.331 NCDN Arina Puzriakova gene: NCDN was added
gene: NCDN was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NCDN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to AMBER
Added comment: NCDN is not yet associated with any phenotype in OMIM (last edited on 08/08/2012) but in Gene2Phenotype monoallelic disease has a 'probable' confidence rating while biallelic variants have a 'possible' disease confidence rating.

- PMID: 33711248 (2021) - Six affected individuals (3 sibs with homozygous missense, and 3 unrelated patients with different de novo missense variants) with variable degrees of DD, ID, and seizures. All 3 sibs had generalised seizures (fever induced in 2), while 2/3 individuals with heterozygous variants developed epileptic spasms presenting several times per day prior to treatment. Supportive functional data included.
Sources: Literature
Early onset or syndromic epilepsy v2.330 UFSP2 Tracy Lester gene: UFSP2 was added
gene: UFSP2 was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability
Penetrance for gene: UFSP2 were set to Complete
Mode of pathogenicity for gene: UFSP2 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: UFSP2 was set to GREEN
Added comment: This is a founder variant that has been reported homozygously in several individuals with an epileptic encephalopathy like phenotype. Three additional cases have been identified in the GEL 100K database by the MSK GeCIP. Recessive LOF variants in this gene cause a skeletal dysplasia phenotype. Functional studies support a gain of function for this variant.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.330 PIGC Arina Puzriakova Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16, 617816 to Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816
Early onset or syndromic epilepsy v2.329 PIGC Arina Puzriakova Publications for gene: PIGC were set to
Early onset or syndromic epilepsy v2.328 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.328 KCNA2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both dominant negative variants that result in LOF effect (RCV000170511, rs786205231) and GOF variants (rs786205231, rs786205232) have been associated with Developmental and epileptic encephalopathy 32 OMIM:616366
Early onset or syndromic epilepsy v2.328 KCNA2 Sarah Leigh Mode of pathogenicity for gene: KCNA2 was changed from None to None
Early onset or syndromic epilepsy v2.327 KCNA2 Sarah Leigh Phenotypes for gene: KCNA2 were changed from Epileptic encephalopathy, early infantile, 32; EPILEPTIC ENCEPHALOPATHY to Developmental and epileptic encephalopathy 32 OMIM:616366; developmental and epileptic encephalopathy, 32 MONDO:0014607
Early onset or syndromic epilepsy v2.326 KCNA2 Sarah Leigh Publications for gene: KCNA2 were set to Syrbe et al (2015) Nat Genet 47(4): 393-9
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.

Associated with relevant phenotype in OMIM (MIM# 618374) but not yet listed in Gene2Phenotype.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Classified gene: NEUROD2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.

Associated with relevant phenotype in OMIM (MIM# 618374) but not yet listed in Gene2Phenotype.
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Gene: neurod2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.324 NEUROD2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: NEUROD2.
Early onset or syndromic epilepsy v2.324 NEUROD2 Arina Puzriakova edited their review of gene: NEUROD2: Added comment: - Conference poster (Genomics of Rare Disease 2021) - 'Neuronal Differentiation Factor 2 (NEUROD2) Pathogenic Variant as a Molecular Aetiology of Infantile Spasm ' by Sakpichaisakul et al, QSNICH, Thailand -
In a 15 month-old female with infantile spasm, trio exome sequencing revealed a de novo variant in NEUROD2 (c.388G>C, p.E130Q). She was born of non-consanguineous healthy parents with no family history of epilepsy. Poor eye contact and no social smile were noted in the first few months, followed by the first infantile spasm at 5 months of age. This was initially controlled by combined vigabatrin and prednisolone therapy - however relapsing seizures were detected at 15 months. Sequential treatment with vigabatrin following prednisolone resulted in cessation of seizures, and subsequently regaining of neurodevelopmental milestones (sitting without support, grabbing objects without pincer grasp and speaking one single word); Changed rating: GREEN
Early onset or syndromic epilepsy v2.324 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042; seizures to Congenital disorder of glycosylation, type Iu, OMIM:615042
Early onset or syndromic epilepsy v2.323 DPM2 Arina Puzriakova commented on gene: DPM2
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Classified gene: KCNH1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Added comment: Comment on list classification: Sufficient number of unrelated cases (>3) of epilepsy in patients with variants in the KCNH1 gene. Inclusion on this panel would be of particular benefit to individuals without typical gingival and/or nail anomalies and only mild developmental delays - who may not be tested under other panels (e.g. Limb disorders, ID) and thus may otherwise be missed in analysis.
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Gene: kcnh1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.322 KCNH1 Arina Puzriakova gene: KCNH1 was added
gene: KCNH1 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: KCNH1.
Mode of inheritance for gene: KCNH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNH1 were set to 18203178; 20009591; 20683999; 21626675; 23994350; 25420144; 33811134
Phenotypes for gene: KCNH1 were set to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Review for gene: KCNH1 was set to GREEN
Added comment: Well-established cause of Temple-Baraitser syndrome (MIM #611816) and Zimmermann-Laband syndrome (MIM #135500) characterised by ID with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia. Overall, sufficient number of cases with epilepsy to rate Green on this panel (PMIDs: 18203178; 20009591; 20683999; 21626675; 23994350; 25420144)

- PMID: 33811134 (2021) - 7 patients with de novo KCNH1 variants presenting mild/moderate to severe DD/ID, but without any distinctive features of TBS/ZLS such as gingival hyperplasia and nail anomalies. Four patients had epilepsy starting in infancy, with generalised tonic–clonic (4/4), myoclonic (2/4), focal motor (2/4) and tonic (1/4) seizures. One patient experienced status epilepticus. Epilepsy was pharmacoresponsive in all individuals. This study provides evidence of KCNH-related encephalopathy even without the presence of other extra-neurological symptoms that are typically associated with pathogenic variants in this gene.
Sources: Literature
Early onset or syndromic epilepsy v2.321 IRF2BPL Sarah Leigh Publications for gene: IRF2BPL were set to 30057031; 28135719; 25363768
Early onset or syndromic epilepsy v2.320 IRF2BPL Sarah Leigh Phenotypes for gene: IRF2BPL were changed from Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures 618088 to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures OMIM:618088; neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures MONDO:0060759
Early onset or syndromic epilepsy v2.319 FBXL4 Sarah Leigh Added comment: Comment on phenotypes: Seizures
Early onset or syndromic epilepsy v2.319 FBXL4 Sarah Leigh Phenotypes for gene: FBXL4 were changed from Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), 615471; Seizures to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) OMIM:615471; mitochondrial DNA depletion syndrome 13 MONDO:0014198
Early onset or syndromic epilepsy v2.318 KCNQ2 Arina Puzriakova Publications for gene: KCNQ2 were set to Dedek et al (2003) Epilepsy Res 54: 21-27
Early onset or syndromic epilepsy v2.317 KCNQ2 Arina Puzriakova Phenotypes for gene: KCNQ2 were changed from BENIGN NEONATAL EPILEPSY TYPE 1 (EBN1); EPILEPTIC ENCEPHALOPATHY EARLY INFANTILE TYPE 7 (EIEE7); Epileptic encephalopathy, early infantile, 7; Myokymia; Seizures, benign neonatal, 1 to Developmental and epileptic encephalopathy 7, OMIM:613720; Seizures, benign neonatal, 1, OMIM:121200
Early onset or syndromic epilepsy v2.316 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from Peroxisomal fatty acyl-CoA reductase 1 disorder 616154 to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Early onset or syndromic epilepsy v2.315 MED27 Arina Puzriakova Classified gene: MED27 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.315 MED27 Arina Puzriakova Gene: med27 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.314 MED27 Arina Puzriakova gene: MED27 was added
gene: MED27 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: MED27.
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Review for gene: MED27 was set to GREEN
Added comment: MED27 is currently not associated with any phenotype in OMIM (last edited on 08/03/2012), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'MED27-related neurodevelopmental disorder'

- PMID: 33443317 (2021) - 16 individuals from 11 families with a neurodevelopmental syndrome characterised by mild to profound GDD/ID (14/14), axial hypotonia (14/15), distal spasticity and dystonic movements (13/15), cerebellar hypoplasia (12/14), cataracts (10/15), epilepsy (9/15), and microcephaly (4/14). Age of seizure onset ranged from 20 days to 5 years and seizure types were varied. Epilepsy was drug-resistant in 3/9 patients. Exome sequencing revealed biallelic variants in the MED27 gene, including 3 recurrent variants found in 2 or more families with different background.

Overall sufficient (>3) unrelated cases with epilepsy in patients with MED27 variants for inclusion on this panel as diagnostic-grade (Green).
Sources: Literature
Early onset or syndromic epilepsy v2.313 ALDH5A1 Sarah Leigh Publications for gene: ALDH5A1 were set to
Early onset or syndromic epilepsy v2.312 ALDH5A1 Sarah Leigh Phenotypes for gene: ALDH5A1 were changed from Succinic semialdehyde dehydrogenase deficiency 271980 to Succinic semialdehyde dehydrogenase deficiency OMIM:271980; succinic semialdehyde dehydrogenase deficiency MONDO:0010083
Early onset or syndromic epilepsy v2.311 ADPRHL2 Sarah Leigh Publications for gene: ADPRHL2 were set to 30100084
Early onset or syndromic epilepsy v2.310 ADPRHL2 Sarah Leigh Phenotypes for gene: ADPRHL2 were changed from Intellectual disability, cerebellar atrophy, ataxia and epilepsy to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170; neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures MONDO:0100095
Early onset or syndromic epilepsy v2.309 NEUROD2 Arina Puzriakova Publications for gene: NEUROD2 were set to 30323019; 16504944
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova edited their review of gene: NEUROD2: Changed publications: 16504944, 30323019, 33438828
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova reviewed gene: NEUROD2: Rating: ; Mode of pathogenicity: None; Publications: 30323019, 16504944; Phenotypes: Developmental and epileptic encephalopathy 72, OMIM:618374; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.308 NEUROD2 Arina Puzriakova Phenotypes for gene: NEUROD2 were changed from Epileptic encephalopathy, early infantile, 72, MIM# 618374 to Developmental and epileptic encephalopathy 72, OMIM:618374
Early onset or syndromic epilepsy v2.307 SLC7A6OS Sarah Leigh Added comment: Comment on phenotypes: Based on the phenotypic spectrum reported in PMID 33085104, this gene may be suitable for additional panels.
Early onset or syndromic epilepsy v2.307 SLC7A6OS Sarah Leigh Phenotypes for gene: SLC7A6OS were changed from Progressive myoclonus epilepsy to Epilepsy, progressive myoclonic, 12 OMIM:619191
Early onset or syndromic epilepsy v2.306 SLC7A6OS Sarah Leigh changed review comment from: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one variant reported in two familes, shown to share common ancestors by haplotype analysis (PMID 33085104).; to: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one variant reported in two families, shown to share common ancestors by haplotype analysis (PMID 33085104).
Early onset or syndromic epilepsy v2.306 PIGU Arina Puzriakova Phenotypes for gene: PIGU were changed from Glycosylphosphatidylinositol biosynthesis defect 2, 618590; myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis, OMIM:618590
Early onset or syndromic epilepsy v2.305 SETD1B Arina Puzriakova Phenotypes for gene: SETD1B were changed from Epilepsy with myoclonic absences; intellectual disability to Intellectual developmental disorder with seizures and language delay, OMIM:619000; Intellectual developmental disorder with seizures and language delay, MONDO:0033559
Early onset or syndromic epilepsy v2.304 SETD1B Arina Puzriakova Publications for gene: SETD1B were set to 20648245; 27106595; 25428890; 22369279; 29322246; 31440728; 31685013
Early onset or syndromic epilepsy v2.303 PROSC Arina Puzriakova Tag curated_removed tag was added to gene: PROSC.
Early onset or syndromic epilepsy v2.303 CDK19 Julia Baptista reviewed gene: CDK19: Rating: GREEN; Mode of pathogenicity: None; Publications: 33495529, 33568421, 32330417; Phenotypes: developmental delay, hypotonia, seizures, autism/autistic traits; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Tag Q2_21_rating tag was added to gene: SCAMP5.
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh edited their review of gene: SCAMP5: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (18/02/2021). At single heterozygous variant (NM_001178111.1: c.538G>T, p.Gly180Trp) has been reported to be associated with intellectual disability; seizures; autism in at least six unrelated cases (PMID 33390987; 31439720).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.303 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.302 SCAMP5 Sarah Leigh Added comment: Comment on phenotypes: OMIM does not have a phenotype associated with variants in this gene (18/02/21).
Early onset or syndromic epilepsy v2.302 SCAMP5 Sarah Leigh Phenotypes for gene: SCAMP5 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Early onset or syndromic epilepsy v2.301 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363
Early onset or syndromic epilepsy v2.300 SLC7A6OS Sarah Leigh Classified gene: SLC7A6OS as Red List (low evidence)
Early onset or syndromic epilepsy v2.300 SLC7A6OS Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one variant reported in two familes, shown to share common ancestors by haplotype analysis (PMID 33085104).
Early onset or syndromic epilepsy v2.300 SLC7A6OS Sarah Leigh Gene: slc7a6os has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.299 SLC7A6OS Sarah Leigh Publications for gene: SLC7A6OS were set to 33085104
Early onset or syndromic epilepsy v2.298 SLC7A6OS Sarah Leigh Tag founder-effect tag was added to gene: SLC7A6OS.
Early onset or syndromic epilepsy v2.298 SLC7A6OS Zornitza Stark gene: SLC7A6OS was added
gene: SLC7A6OS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SLC7A6OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC7A6OS were set to 33085104
Phenotypes for gene: SLC7A6OS were set to Progressive myoclonus epilepsy
Review for gene: SLC7A6OS was set to RED
Added comment: Two unrelated families reported with same homozygous splice site variant, shared haplotype (founder effect). Limited functional data.
Sources: Literature
Early onset or syndromic epilepsy v2.298 CCDC186 Sarah Leigh Tag watchlist tag was added to gene: CCDC186.
Early onset or syndromic epilepsy v2.298 CCDC186 Sarah Leigh Classified gene: CCDC186 as Red List (low evidence)
Early onset or syndromic epilepsy v2.298 CCDC186 Sarah Leigh Added comment: Comment on list classification: Not associated with a relevant phenotype in OMIM or Gen2Phen. At least 2 terminating variants reported in cases with failure to thrive and developmental delay, epileptic encephalopathy was rerported in one case (PMID33259146).
Early onset or syndromic epilepsy v2.298 CCDC186 Sarah Leigh Gene: ccdc186 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.297 CCDC186 Sarah Leigh Publications for gene: CCDC186 were set to 33259146
Early onset or syndromic epilepsy v2.296 LMBRD2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both of the references for this entry suggest a gain-of-function action for LMBRD2 variants.
Early onset or syndromic epilepsy v2.296 LMBRD2 Sarah Leigh Mode of pathogenicity for gene: LMBRD2 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early onset or syndromic epilepsy v2.295 ADAM22 Sarah Leigh changed review comment from: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a boarderline case.; to: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a borderline case.
Early onset or syndromic epilepsy v2.295 ADAM22 Sarah Leigh Classified gene: ADAM22 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.295 ADAM22 Sarah Leigh Added comment: Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a boarderline case.
Early onset or syndromic epilepsy v2.295 ADAM22 Sarah Leigh Gene: adam22 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.294 SATB1 Arina Puzriakova Classified gene: SATB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.294 SATB1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next major review.
Early onset or syndromic epilepsy v2.294 SATB1 Arina Puzriakova Gene: satb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.293 SATB1 Arina Puzriakova gene: SATB1 was added
gene: SATB1 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: SATB1.
Mode of inheritance for gene: SATB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SATB1 were set to 33513338
Phenotypes for gene: SATB1 were set to Neurodevelopmental disorder
Review for gene: SATB1 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited: 30/09/2020) but has a 'confirmed' disease confidence rating for 'SATB1-related developmental disorder (monoallelic)' in Gene2Phenotype.

- Den Hoed et al. 2021 (PMID: 33513338) - Total of 42 individuals from 35 families with SATB1 variants (including previously reported cases) - 30 patients harboured 15 unique SATB1 missense variants, including three recurrent variants; 10 had premature protein truncating variants; and and 2 individuals carried a (partial) gene deletion. 28 variants occurred de novo, 3 were inherited from an affected parent, 5 resulted from suspected parental mosaicism (2 inherited from an unaffected parent indicating reduced penetrance), and unknown inheritance in remaining 4 variants.

Phenotypes include neurodevelopmental delay (35/36, 97%), intellectual disability (28/31, 90%), muscle tone abnormalities (abnormal tone 28/37, 76%; hypotonia 28/37, 76%; spasticity 10/36, 28%), epilepsy (22/36, 61%), facial dysmorphisms (24/36, 67%), and dental abnormalities (24/34, 71%). Variable seizure phenotypes described but multiple refractory early-onset cases.

Missense variants were associated with a more severe phenotype - for instance, 57% of individuals with a missense variant had severe/profound ID whereas this level of ID was not observed for any individuals with truncating variants.
Sources: Literature
Early onset or syndromic epilepsy v2.292 HPDL Arina Puzriakova Phenotypes for gene: HPDL were changed from spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613
Early onset or syndromic epilepsy v2.291 HPDL Arina Puzriakova Publications for gene: HPDL were set to PMID: 32707086; 33188300
Early onset or syndromic epilepsy v2.290 HPDL Arina Puzriakova Classified gene: HPDL as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.290 HPDL Arina Puzriakova Added comment: Comment on list classification: New gene added by Evan Reid (University of Cambridge). There is enough evidence for this gene to be rated Green at the next major review.
Early onset or syndromic epilepsy v2.290 HPDL Arina Puzriakova Gene: hpdl has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.289 HPDL Arina Puzriakova Tag Q2_21_rating tag was added to gene: HPDL.
Early onset or syndromic epilepsy v2.289 HPDL Arina Puzriakova reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707086, 33188300; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.289 FUK Sarah Leigh Phenotypes for gene: FUK were changed from Seizures; Generalized hypotonia; Feeding difficulties; Intellectual disability; Global developmental delay; Abnormality of vision; Congenital disorder of glycosylation with defective fucosylation 2, 618324 to Congenital disorder of glycosylation with defective fucosylation 2 OMIM:618324; congenital disorder of glycosylation with defective fucosylation 2 MONDO:0020777
Early onset or syndromic epilepsy v2.288 HPDL Evan Reid gene: HPDL was added
gene: HPDL was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to PMID: 32707086; 33188300
Phenotypes for gene: HPDL were set to spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual; motor disability
Penetrance for gene: HPDL were set to Complete
Review for gene: HPDL was set to GREEN
Added comment: Newly identified gene that can give a phenotype ranging from infantile epileptic encephalopathy to juvenile onset progressive spastic paraplegia.
Sources: Literature
Early onset or syndromic epilepsy v2.288 PMPCB Ivone Leong Tag for-review was removed from gene: PMPCB.
Early onset or syndromic epilepsy v2.288 ADAM22 Sarah Leigh Tag for-review tag was added to gene: ADAM22.
Early onset or syndromic epilepsy v2.288 ADAM22 Sarah Leigh reviewed gene: ADAM22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.288 ADAM22 Sarah Leigh Phenotypes for gene: ADAM22 were changed from ?Epileptic encephalopathy, early infantile, 61 OMIM:617933 to ?Epileptic encephalopathy, early infantile, 61 OMIM:617933; developmental and epileptic encephalopathy, 61 MONDO:0033370
Early onset or syndromic epilepsy v2.287 ADAM22 Sarah Leigh Tag watchlist tag was added to gene: ADAM22.
Early onset or syndromic epilepsy v2.287 GALNT2 Sarah Leigh changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review, depending on the policy of inclusion of metabolic genes on this panel.; to: Comment on list classification:
For-review tag has been added to highlight that there is enough evidence for this gene to be rated GREEN at the next major review, depending on the policy of inclusion of metabolic genes on this panel.
Early onset or syndromic epilepsy v2.287 GALNT2 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.287 GALNT2 Sarah Leigh commented on gene: GALNT2: For-review tag has been added to highlight whether this gene should be green on this panel due to the uncoupling of metabolic genes from Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.287 ALG14 Sarah Leigh commented on gene: ALG14: For-review tag has been added to highlight whether this gene should be green on this panel due to the uncoupling of metabolic genes from Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.287 TET3 Sarah Leigh changed review comment from: Taking account the review of Helen Lord and Konstantinos Varvagiannis, there is not enough convincing evidence for this gene to be rated GREEN on the Genetic epilepsy syndromes panel. The "for-review" tag has been replaced with the "watchlist" tag to highlight that further cases with seizures are needed for this gene to be rated Green on this panel.; to: Taking account the review of Helen Lord and Konstantinos Varvagiannis, there is not enough convincing evidence for this gene to be rated GREEN on the Genetic epilepsy syndromes panel. The "for-review" tag has been removed. The "watchlist" tag will remain to highlight that further cases with seizures are needed for this gene to be rated Green on this panel.
Early onset or syndromic epilepsy v2.287 TET3 Sarah Leigh Tag for-review was removed from gene: TET3.
Early onset or syndromic epilepsy v2.287 TET3 Sarah Leigh changed review comment from: There is enough evidence for this gene to be rated GREEN at the next major review.; to: Taking account the review of Helen Lord and Konstantinos Varvagiannis, there is not enough convincing evidence for this gene to be rated GREEN on the Genetic epilepsy syndromes panel. The "for-review" tag has been replaced with the "watchlist" tag to highlight that further cases with seizures are needed for this gene to be rated Green on this panel.
Early onset or syndromic epilepsy v2.287 TET3 Sarah Leigh Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007; 31928709
Early onset or syndromic epilepsy v2.286 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Beck-Fahrner syndrome 618798 to Beck-Fahrner syndrome OMIM:618798
Early onset or syndromic epilepsy v2.285 SNX27 Sarah Leigh Tag for-review was removed from gene: SNX27.
Tag watchlist tag was added to gene: SNX27.
Early onset or syndromic epilepsy v2.285 SNX27 Sarah Leigh edited their review of gene: SNX27: Added comment: Taking account of Helen Lord's review that there is insufficient evidence that seizures are associated with variants in SNX27, the "for review" tag has been replaced with the "watchlist" tag. The rating of this gene will remain amber on the Genetic epilepsy syndromes panel.; Changed rating: AMBER
Early onset or syndromic epilepsy v2.285 SLC5A6 Sarah Leigh changed review comment from: For review tag has been added, to allow for GMS discussion in relation to the metabolic role of this gene.; to: For review tag has been added, to allow for GMS discussion in relation to the metabolic role of this gene. There are insufficient cases with seizures to be green on the Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.285 SEMA6B Sarah Leigh Phenotypes for gene: SEMA6B were changed from Epilepsy, progressive myoclonic, 11, 618876 to Epilepsy, progressive myoclonic, 11 OMIM:618876
Early onset or syndromic epilepsy v2.284 PIGK Sarah Leigh Phenotypes for gene: PIGK were changed from Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879 to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures OMIM:618879
Early onset or syndromic epilepsy v2.283 GALNT2 Sarah Leigh Phenotypes for gene: GALNT2 were changed from Congenital disorder of glycosylation, type IIt 618885 to Congenital disorder of glycosylation, type IIt OMIM:618885
Early onset or syndromic epilepsy v2.282 GAD1 Sarah Leigh Publications for gene: GAD1 were set to 15571623; 26503795; 24896178; 26350204; https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Early onset or syndromic epilepsy v2.281 CCDC186 Zornitza Stark gene: CCDC186 was added
gene: CCDC186 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CCDC186 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC186 were set to 33259146
Phenotypes for gene: CCDC186 were set to Epileptic encephalopathy
Review for gene: CCDC186 was set to RED
Added comment: One individual reported with bi-allelic truncating variant and EE.
Sources: Literature
Early onset or syndromic epilepsy v2.281 TET3 Helen Lord reviewed gene: TET3: Rating: AMBER; Mode of pathogenicity: None; Publications: 31928709; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 SNX27 Helen Lord reviewed gene: SNX27: Rating: AMBER; Mode of pathogenicity: None; Publications: 31721175; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 SLC5A6 Helen Lord reviewed gene: SLC5A6: Rating: RED; Mode of pathogenicity: None; Publications: 31754459, 27904971; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 SEMA6B Helen Lord reviewed gene: SEMA6B: Rating: AMBER; Mode of pathogenicity: None; Publications: 32169168; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.281 RALGAPA1 Helen Lord reviewed gene: RALGAPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32004447; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 PIGK Helen Lord reviewed gene: PIGK: Rating: GREEN; Mode of pathogenicity: None; Publications: 32220290; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 LMBRD2 Helen Lord reviewed gene: LMBRD2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32820033; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.281 GALNT2 Helen Lord reviewed gene: GALNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32293671, 27508872; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 GAD1 Helen Lord reviewed gene: GAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 320705143, 32282878; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.281 KATNB1 Arina Puzriakova Phenotypes for gene: KATNB1 were changed from Lissencephaly 6, with microcephaly, 616212; seizures to Lissencephaly 6, with microcephaly, OMIM:616212, MONDO:0014534
Early onset or syndromic epilepsy v2.280 DHX16 Helen Lord reviewed gene: DHX16: Rating: AMBER; Mode of pathogenicity: None; Publications: 31256877; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.280 ADAM22 Sarah Leigh Phenotypes for gene: ADAM22 were changed from ?Epileptic encephalopathy, early infantile, 61, 617933 to ?Epileptic encephalopathy, early infantile, 61 OMIM:617933
Early onset or syndromic epilepsy v2.279 TMX2 Arina Puzriakova Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures; Primary microcephaly, cortical malformation and epileptic encephalopathy to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, OMIM:618730; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, MONDO:0032887
Early onset or syndromic epilepsy v2.278 ANKRD11 Sarah Leigh reviewed gene: ANKRD11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.278 SCN9A Sarah Leigh edited their review of gene: SCN9A: Added comment: This gene should remain Red on this panel.; Changed rating: RED
Early onset or syndromic epilepsy v2.278 CACNB4 Sarah Leigh Phenotypes for gene: CACNB4 were changed from {Epilepsy, idiopathic generalized, susceptibility to, 9}, 607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, 607682; Episodic ataxia, type 5, 613855; Intellectual disability to {Epilepsy, idiopathic generalized, susceptibility to, 9} OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6} OMIM:607682; Episodic ataxia, type 5 OMIM:613855; Intellectual disability
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh Tag for-review tag was added to gene: CPA6.
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh commented on gene: CPA6: After consultation Helen Lord, recommend change of MOI to BIALLELIC, autosomal or pseudosomal
Early onset or syndromic epilepsy v2.277 CPA6 Sarah Leigh edited their review of gene: CPA6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.277 CPA6 Helen Lord reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.277 ALG14 Sarah Leigh edited their review of gene: ALG14: Changed rating: GREEN
Early onset or syndromic epilepsy v2.277 ADAM22 Sarah Leigh Publications for gene: ADAM22 were set to 27066583; 30237576; 15876356
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Classified gene: SCN9A as Red List (low evidence)
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Added comment: Comment on list classification: Evidence presented by PMID 33216760 disputes the association between SCN9A and epilepsy, inparticular the serendipitous identification of the SCN9A p.(Asn641Tyr) variant within the Wisconsin Amish community with no epilepsy in their phenotypes. The authors report this lack of gene disease association was also evident in the UK Biobank.
Early onset or syndromic epilepsy v2.276 SCN9A Sarah Leigh Gene: scn9a has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.275 SCN9A Sarah Leigh Publications for gene: SCN9A were set to 19763161; 29500686; 30834459; 23895530
Early onset or syndromic epilepsy v2.274 CEP85L Helen Lord reviewed gene: CEP85L: Rating: GREEN; Mode of pathogenicity: None; Publications: 32097630; Phenotypes: Lissencephaly 10; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.274 CDK19 Helen Lord changed review comment from: Chung et al 2020 - 3 iunrealrted indicuduals with de novo missense variants in CDK19 - presented with hypotonia, global developmental delay, epileptic encephalopathy and dysmorphic features. Two patients had the Thr196Ala variant and the other Tyr32His - predicted to be likely pathogenic. Fuinctional work suggests dominant loss of function variants.; to: Chung et al 2020 - 3 unrelated indiviuduals with de novo missense variants in CDK19 - presented with hypotonia, global developmental delay, epileptic encephalopathy and dysmorphic features. Two patients had the Thr196Ala variant and the other Tyr32His - predicted to be likely pathogenic. Fuinctional work suggests dominant loss of function variants.
Early onset or syndromic epilepsy v2.274 CDK19 Helen Lord reviewed gene: CDK19: Rating: AMBER; Mode of pathogenicity: None; Publications: 32330417; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.274 CACNB4 Helen Lord reviewed gene: CACNB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 32176688; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.274 SCN9A Helen Lord reviewed gene: SCN9A: Rating: RED; Mode of pathogenicity: None; Publications: 33216760; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.274 ANKRD11 Helen Lord reviewed gene: ANKRD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33476899; Phenotypes: KBG syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.274 ALG14 Helen Lord reviewed gene: ALG14: Rating: GREEN; Mode of pathogenicity: None; Publications: 28733338, 30221345; Phenotypes: epilepsy, behavioural problems, severe developmental delay, mild dysmorphic features, severe neurodegeneration with myopathic and myasthenic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.274 ADAM22 Helen Lord reviewed gene: ADAM22: Rating: AMBER; Mode of pathogenicity: None; Publications: 31432233, 33397806; Phenotypes: Developmental and epileptic encephalopathy 61; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.274 ABCA2 Helen Lord reviewed gene: ABCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29302074, 31047799, 30237576; Phenotypes: intellectual delay, poor growth, ataxia, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Classified gene: UBR7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but sufficient number of unrelated cases with relevant phenotype to promote this gene to Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.274 UBR7 Arina Puzriakova Gene: ubr7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.273 UBR7 Arina Puzriakova gene: UBR7 was added
gene: UBR7 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: UBR7.
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Review for gene: UBR7 was set to GREEN
Added comment: - PMID: 33340455 (2021) - At least 6 SNVs and 1 intragenic deletion reported in 7 individuals from 6 families with a comparable neurodevelopmental disorder. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile).
Sources: Literature
Early onset or syndromic epilepsy v2.272 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954
Early onset or syndromic epilepsy v2.271 PMPCB Sarah Leigh Tag for-review tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.271 FLNA Sarah Leigh Phenotypes for gene: FLNA were changed from Heterotopia, periventricular 300049 to Heterotopia, periventricular OMIM:300049
Early onset or syndromic epilepsy v2.270 ASNS Sarah Leigh Classified gene: ASNS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.270 ASNS Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.270 ASNS Sarah Leigh Gene: asns has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.269 ASNS Sarah Leigh reviewed gene: ASNS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.269 ASNS Sarah Leigh Publications for gene: ASNS were set to
Early onset or syndromic epilepsy v2.268 ASNS Sarah Leigh Phenotypes for gene: ASNS were changed from Asparagine synthetase deficiency, MIM# 615574 to Asparagine synthetase deficiency OMIM:615574
Early onset or syndromic epilepsy v2.267 ASNS Sarah Leigh Tag for-review tag was added to gene: ASNS.
Early onset or syndromic epilepsy v2.267 APC2 Sarah Leigh Phenotypes for gene: APC2 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system to Cortical dysplasia, complex, with other brain malformations 10 OMIM:618677
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh edited their review of gene: APC2: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 9 variants in 8 unrealated cases of Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay (PMID 31585108).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Tag for-review tag was added to gene: APC2.
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Classified gene: APC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.266 APC2 Sarah Leigh Gene: apc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Classified gene: PPIL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with relevant phenotype, supported by functional data.
Early onset or syndromic epilepsy v2.265 PPIL1 Arina Puzriakova Gene: ppil1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.264 PPIL1 Arina Puzriakova gene: PPIL1 was added
gene: PPIL1 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: PPIL1.
Mode of inheritance for gene: PPIL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIL1 were set to 33220177
Phenotypes for gene: PPIL1 were set to PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
Review for gene: PPIL1 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on: 10/07/2001) but has a 'probable' gene rating for 'PPIL1-related Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly' in Gene2Phenotype.

- PMID: 33220177 (2021) - At least 12 variants identified in 17 individuals from 9 unrelated families. All displayed pontocerebellar hypoplasia and progressive congenital microcephaly. Infantile-onset seizures were reported in 7/9 families - medically controlled in only 1 individual.
Further common phenotypes included hypotonia, intellectual disability with delayed language and motor development, and cortical changes on brain MRI, most notably simplified gyri pattern. Pathogenicity is supported by mouse model.
Sources: Literature
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Classified gene: FGF13 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) - sufficient number of unrelated cases with relevant phenotype (early-onset epilepsy represents the main feature of the disorder), supported by functional data.
Early onset or syndromic epilepsy v2.263 FGF13 Arina Puzriakova Gene: fgf13 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.262 FGF13 Arina Puzriakova Mode of pathogenicity for gene: FGF13 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Early onset or syndromic epilepsy v2.261 FGF13 Arina Puzriakova edited their review of gene: FGF13: Changed mode of pathogenicity: Other
Early onset or syndromic epilepsy v2.261 FGF13 Arina Puzriakova gene: FGF13 was added
gene: FGF13 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: FGF13.
Mode of inheritance for gene: FGF13 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: FGF13 were set to 33245860
Phenotypes for gene: FGF13 were set to Developmental and epileptic encephalopathy; Intellectual disability; Infantile-onset seizures
Mode of pathogenicity for gene: FGF13 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: FGF13 was set to GREEN
Added comment: - PMID: 33245860 (2021) - Three variants (c.31C>T, c.41G>C, c.32G>C) identified by WES/WGS in seven individuals from five unrelated families who presented with severe infantile-onset seizures and severe-to-profound ID. Supportive functional data indicating variants impair long-term inactivation of voltage-gated sodium channels while retaining pro-excitatory properties of A isoform - consistent with the epileptic potential of FGF13 variants
Sources: Literature
Early onset or syndromic epilepsy v2.260 TRAPPC12 Arina Puzriakova Publications for gene: TRAPPC12 were set to 28777934
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Classified gene: TRAPPC12 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Added comment: Comment on list classification: With addition of the recently reported case, there are now at least 3 unrelated patients with epilepsy and biallelic variants in this gene (PMIDs: 28777934 and 32369837).

This now reaches threshold for inclusion as diagnostic-grade, and therefore TRAPPC12 can be promoted to Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.259 TRAPPC12 Arina Puzriakova Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC12.
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 32369837; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.258 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, 617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Classified gene: GLS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Biallelic variants identified in two families with three individuals affected by neonatal lethal epileptic encephalopathy and respiratory insufficiency (PMID: 30575854). The variants were predicted to result in loss of function, supported by elevated glutamine in all cases.

Rating Amber, awaiting further cases/clinical evidence prior to inclusion as diagnostic-grade.
Early onset or syndromic epilepsy v2.257 GLS Arina Puzriakova Gene: gls has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.256 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328 to Developmental and epileptic encephalopathy 71, OMIM:618328; Developmental and epileptic encephalopathy, 71, MONDO:0032678
Early onset or syndromic epilepsy v2.255 SCAMP5 Zornitza Stark edited their review of gene: SCAMP5: Changed mode of pathogenicity: Other
Early onset or syndromic epilepsy v2.255 SCAMP5 Zornitza Stark reviewed gene: SCAMP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 31439720, 33390987; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.255 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957; 25326637
Early onset or syndromic epilepsy v2.254 TUBB2A Arina Puzriakova Phenotypes for gene: TUBB2A were changed from Cortical dysplasia, complex, with other brain malformations 5, 615763; infantile-onset epilepsy to Cortical dysplasia, complex, with other brain malformations 5, OMIM:615763; Complex cortical dysplasia with other brain malformations 5, MONDO:0014337
Early onset or syndromic epilepsy v2.253 GRN Ivone Leong Classified gene: GRN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.253 GRN Ivone Leong Gene: grn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.252 GRN Ivone Leong gene: GRN was added
gene: GRN was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 31855245; 28404863; 30922528
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; neuronal ceroid lipofuscinosis 1, MONDO:0013866
Review for gene: GRN was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Biallic variants in GRN cause Ceroid lipofuscinosis, neuronal, 11, which is characterised by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. There is enough evidence to support a gene-disease association. This gene has been promoted to Amber and should be considered for Green status at the next review.

This gene is also on the Retinal disorders panel (Version 2.71), with the following review:
"Multiple individuals reported with bi-allelic variants and CLN phenotype. Please also note literature regarding retinal abnormalities in those with mono-allelic variants.
Zornitza Stark (Australian Genomics), 11 Oct 2020"
Sources: Literature
Early onset or syndromic epilepsy v2.251 CELF2 Zornitza Stark gene: CELF2 was added
gene: CELF2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 33131106
Phenotypes for gene: CELF2 were set to Developmental and epileptic encephalopathy
Review for gene: CELF2 was set to GREEN
Added comment: Five unrelated individuals reported. Four with de novo variants, and one inherited from a mosaic mother. Notably, all identified variants, except for c.272‐1G>C, were clustered within 20 amino acid residues of the C‐terminus, which might be a nuclear localization signal.
Sources: Literature
Early onset or syndromic epilepsy v2.251 RALGAPB Zornitza Stark gene: RALGAPB was added
gene: RALGAPB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RALGAPB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RALGAPB were set to 32853829
Phenotypes for gene: RALGAPB were set to Neurodevelopmental disorders, autism
Review for gene: RALGAPB was set to AMBER
Added comment: PMID: 32853829 - 2 patients with de novo missense variants, 1 patient with a de novo PTC with autism spectrum disorder from a large cohort.
Reviews previous publications and identifies 10 de novo variants (5 PTCs, 5 missense, epilepsy only present in 2/10 and ID in 1/10.

Variants in this gene cause a neurodevelopmental disorder, but autism seems to be the most prominent feature.
Sources: Literature
Early onset or syndromic epilepsy v2.251 TBCD Arina Puzriakova Phenotypes for gene: TBCD were changed from Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, 617193; seizures; West syndrome to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum, OMIM:617193; Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, MONDO:0044646
Early onset or syndromic epilepsy v2.250 CPA6 Zornitza Stark reviewed gene: CPA6: Rating: AMBER; Mode of pathogenicity: None; Publications: 25875328, 21922598, 23105115; Phenotypes: Epilepsy, familial temporal lobe, 5 MIM#614417, Febrile seizures, familial, 11 MIM#614418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.250 SMC1A Arina Puzriakova Phenotypes for gene: SMC1A were changed from Cornelia de Lange syndrome 2, 300590; seizures; EPILEPTIC ENCEPHALOPATHY; Rett-like phenotype to Cornelia de Lange syndrome 2, OMIM:300590; Cornelia de Lange syndrome 2, MONDO:0010370; Developmental and epileptic encephalopathy 85, with or without midline brain defects, OMIM:301044; Developmental and epileptic encephalopathy, 85, with or without midline brain defects, MONDO:0026771
Early onset or syndromic epilepsy v2.249 KCNMA1 Arina Puzriakova Phenotypes for gene: KCNMA1 were changed from ?Cerebellar atrophy, developmental delay, and seizures, 617643; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 to Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Cerebellar atrophy, developmental delay, and seizures, MONDO:0060551; Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, OMIM:609446; Generalized epilepsy-paroxysmal dyskinesia syndrome, MONDO:0012276; Liang-Wang syndrome, OMIM:618729; Liang-Wang syndrome, MONDO:0032886; {Epilepsy, idiopathic generalized, susceptibility to, 16}, OMIM:618596; Epilepsy, idiopathic generalized, susceptibility to, 16, MONDO:0032827
Early onset or syndromic epilepsy v2.248 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 26195193; 27567911; 29545233; 27567911
Early onset or syndromic epilepsy v2.247 H3F3B Arina Puzriakova Publications for gene: H3F3B were set to
Early onset or syndromic epilepsy v2.246 H3F3B Arina Puzriakova Phenotypes for gene: H3F3B were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Early onset or syndromic epilepsy v2.245 H3F3B Arina Puzriakova Mode of inheritance for gene: H3F3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Classified gene: H3F3B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) in view of evidence in recent publication (PMID: 33268356)
Early onset or syndromic epilepsy v2.244 H3F3B Arina Puzriakova Gene: h3f3b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.243 H3F3B Arina Puzriakova Tag for-review tag was added to gene: H3F3B.
Early onset or syndromic epilepsy v2.243 H3F3B Arina Puzriakova reviewed gene: H3F3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Intellectual disability, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.243 H3F3A Arina Puzriakova Phenotypes for gene: H3F3A were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Early onset or syndromic epilepsy v2.242 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
Early onset or syndromic epilepsy v2.241 H3F3A Arina Puzriakova Mode of inheritance for gene: H3F3A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber, but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) in view of evidence in recent publication (PMID: 33268356)
Early onset or syndromic epilepsy v2.240 H3F3A Arina Puzriakova Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.239 H3F3A Arina Puzriakova Tag for-review tag was added to gene: H3F3A.
Early onset or syndromic epilepsy v2.239 H3F3A Arina Puzriakova reviewed gene: H3F3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33268356; Phenotypes: Developmental delay, Intellectual disability, Neurodegeneration, Epilepsy, Facial dysmorphism, Congenital anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.239 CSNK1G1 Arina Puzriakova Mode of inheritance for gene: CSNK1G1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.238 EXT2 Zornitza Stark edited their review of gene: EXT2: Changed publications: 26246518, 30288735, 30997052, 30075207; Changed phenotypes: Seizures, scoliosis, and macrocephaly syndrome, MIM# 616682
Early onset or syndromic epilepsy v2.238 AARS Arina Puzriakova Phenotypes for gene: AARS were changed from Epileptic encephalopathy, early infantile, 29 616339 to Developmental and epileptic encephalopathy 29, OMIM:616339; Developmental and epileptic encephalopathy, 29, MONDO:0014593
Early onset or syndromic epilepsy v2.237 GOT2 Arina Puzriakova Phenotypes for gene: GOT2 were changed from Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology to Epileptic encephalopathy, early infantile, 82, OMIM:618721; Developmental and epileptic encephalopathy, 82, MONDO:0032880
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Tag new-gene-name tag was added to gene: NARS.
Tag for-review tag was added to gene: NARS.
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag)
Early onset or syndromic epilepsy v2.236 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.235 NARS Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.235 NARS Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Early onset or syndromic epilepsy v2.234 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
Early onset or syndromic epilepsy v2.233 FBXO28 Zornitza Stark gene: FBXO28 was added
gene: FBXO28 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO28 were set to 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy
Review for gene: FBXO28 was set to GREEN
Added comment: Nine new individuals with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and all 10 known cases reviewed to delineate the phenotypic spectrum. All had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features.
Sources: Literature
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Tag for-review tag was added to gene: LARS.
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Seizures are prevalent among affected individuals, often triggered by infections. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).
Early onset or syndromic epilepsy v2.233 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.232 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, MIM 614932 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Early onset or syndromic epilepsy v2.231 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.231 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Classified gene: PNPT1 as No list
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).
Early onset or syndromic epilepsy v2.230 PNPT1 Arina Puzriakova Gene: pnpt1 has been removed from the panel.
Early onset or syndromic epilepsy v2.229 PNPT1 Arina Puzriakova Tag for-review tag was added to gene: PNPT1.
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Classified gene: CEP85L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.229 CEP85L Arina Puzriakova Gene: cep85l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.228 CEP85L Arina Puzriakova gene: CEP85L was added
gene: CEP85L was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CEP85L.
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CEP85L were set to 32097630; 32097629
Phenotypes for gene: CEP85L were set to Lissencephaly 10, OMIM:618873; Lissencephaly 10, MONDO:0030031
Review for gene: CEP85L was set to GREEN
Added comment: - PMID: 32097630 (2020) - 13 patients from 9 unrelated families with lissencephaly and heterozygous variants in the CEP85L gene. Seizures are part of the phenotype, present in all cases (except 1 unknown) which were intractable in most. Age of seizure onset was variable, ranging from 5 months to 14 years. Mouse model supports a role of CEP85L in neuronal migration. Gene-disease association included in OMIM.
Sources: Literature
Early onset or syndromic epilepsy v2.227 ALDH7A1 Eleanor Williams reviewed gene: ALDH7A1: Rating: ; Mode of pathogenicity: None; Publications: 32969477; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Tag Skewed X-inactivation tag was added to gene: TFE3.
Early onset or syndromic epilepsy v2.227 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from to TFE3-related intellectual disability with pigmentary mosaicism
Early onset or syndromic epilepsy v2.226 TFE3 Arina Puzriakova Mode of inheritance for gene: TFE3 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v2.225 LMNB2 Sarah Leigh reviewed gene: LMNB2: Rating: RED; Mode of pathogenicity: None; Publications: 33033404; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.225 LMNB2 Sarah Leigh Publications for gene: LMNB2 were set to 16826530
Early onset or syndromic epilepsy v2.224 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency 608643; floppy child; dystonia; hypotonia; developmental delay; oculogyric crisis to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Early onset or syndromic epilepsy v2.223 LMNB1 Sarah Leigh changed review comment from: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 2 were found in patients (3 from 2 families) who also had epileptic seizures (PMID 32910914; 33033404).; to: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 5 variants reported in at least 5 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 1 was found in 2 unrelated patients who also had epileptic seizures (PMID 32910914; 33033404).
Early onset or syndromic epilepsy v2.223 LMNB1 Sarah Leigh Phenotypes for gene: LMNB1 were changed from Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis; LMNB1-associated developmental disorder
Early onset or syndromic epilepsy v2.222 LMNB1 Sarah Leigh Publications for gene: LMNB1 were set to 32910914
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Classified gene: LMNB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM (19/11/2020), but as confirmed Gen2Phen gene for LMNB1-associated developmental disorder. At least 7 variants reported in at least 7 unrelated cases. Each variant was associated with intellectual disability and microcephaly and 2 were found in patients (3 from 2 families) who also had epileptic seizures (PMID 32910914; 33033404).
Early onset or syndromic epilepsy v2.221 LMNB1 Sarah Leigh Gene: lmnb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.220 LMNB1 Sarah Leigh Tag watchlist tag was added to gene: LMNB1.
Early onset or syndromic epilepsy v2.220 FAM50A Arina Puzriakova Phenotypes for gene: FAM50A were changed from Mental retardation syndrome, X-linked, Armfield type (MIM #300261) to Mental retardation syndrome, X-linked, Armfield type, OMIM:300261; Armfield syndrome, MONDO:0010284
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Classified gene: FAM50A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber based on the evidence provided in one publication (PMID:32703943) reporting seizures in 3/6 individuals from 2 families with variants in this gene.
Early onset or syndromic epilepsy v2.219 FAM50A Arina Puzriakova Gene: fam50a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.218 PIGQ Sarah Leigh Added comment: Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, 618548 as the name for this phenotype (12/11/2020).
Early onset or syndromic epilepsy v2.218 PIGQ Sarah Leigh Phenotypes for gene: PIGQ were changed from Epileptic encephalopathy, early infantile, 77, 618548; Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome to Multiple congenital anomalies-hypotonia-seizures syndrome-4, OMIM:618548
Early onset or syndromic epilepsy v2.217 PIGQ Sarah Leigh Publications for gene: PIGQ were set to 24463883; 25558065; 31148362
Early onset or syndromic epilepsy v2.216 SCO1 Arina Puzriakova Phenotypes for gene: SCO1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 4, OMIM:619048
Early onset or syndromic epilepsy v2.215 TFE3 Sarah Leigh Publications for gene: TFE3 were set to 30595499; 31833172; https://doi.org/10.1126/scisignal.aax0926
Early onset or syndromic epilepsy v2.214 TFE3 Sarah Leigh Tag for-review tag was added to gene: TFE3.
Early onset or syndromic epilepsy v2.214 TFE3 Sarah Leigh reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30595499, 31833172, 32409512; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Tag for-review tag was added to gene: TBC1D2B.
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Classified gene: TBC1D2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32623794).

There are sufficient cases to rate this gene Green at the next GMS panel update (added 'for-review' tag) - all 4 individuals (3 families) present seizures, although the age of onset is variable (19-years, 18-months, 3-months).
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Gene: tbc1d2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.213 ABCA2 Arina Puzriakova Phenotypes for gene: ABCA2 were changed from Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808 to Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM:618808; Intellectual developmental disorder with poor growth and with or without seizures or ataxia, MONDO:0032930
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Classified gene: ABCA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as 1) only 2 cases with seizures; 2) epilepsy is not a prominent feature of the overall phenotype; 3) seizures were either resolved or managed by medication.
Early onset or syndromic epilepsy v2.212 ABCA2 Arina Puzriakova Gene: abca2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.211 ABCA2 Arina Puzriakova reviewed gene: ABCA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30237576, 29302074, 31047799; Phenotypes: Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.211 NUS1 Eleanor Williams Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa, 617082; Mental retardation, autosomal dominant 55, with seizures, 617831; Abnormality of extrapyramidal motor function to ?Congenital disorder of glycosylation, type 1aa OMIM:617082; Mental retardation, autosomal dominant 55, with seizures OMIM:617831; Abnormality of extrapyramidal motor function
Early onset or syndromic epilepsy v2.210 NUS1 Eleanor Williams Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779
Early onset or syndromic epilepsy v2.209 NUS1 Eleanor Williams edited their review of gene: NUS1: Added comment: 2 further heterozygous cases reported by Den et al 2019 (PMID: 31656175). 2 unrelated Japanese patients with a novel, recurrent, de novo NUS1 variant, who presented with epileptic seizures with involuntary movement, ataxia, intellectual disability and scoliosis. The variant c.691 + 1C > A, creates a new splice donor site resulting in a 91 bp deletion in exon 3.; Changed publications: 25066056, 29100083, 24824130, 30348779, 31656175
Early onset or syndromic epilepsy v2.209 PIGH Eleanor Williams Publications for gene: PIGH were set to 29603516; 29573052
Early onset or syndromic epilepsy v2.208 PIGH Eleanor Williams commented on gene: PIGH
Early onset or syndromic epilepsy v2.208 TMEM106B Arina Puzriakova Phenotypes for gene: TMEM106B were changed from Leukodystrophy, hypomyelinating, 16 (MIM #617964) to Leukodystrophy, hypomyelinating, 16, OMIM:617964; Leukodystrophy, hypomyelinating, 16, MONDO:0054791
Early onset or syndromic epilepsy v2.207 TMEM106B Arina Puzriakova Tag missense tag was added to gene: TMEM106B.
Early onset or syndromic epilepsy v2.207 TFE3 Sarah Leigh Publications for gene: TFE3 were set to 30595499; 31833172; https://doi.org/10.1126/scisignal.aax0926
Early onset or syndromic epilepsy v2.207 TFE3 Sarah Leigh Publications for gene: TFE3 were set to
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Classified gene: TMEM106B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only 2 individuals with seizures (both early-onset, before age 6 months) reported at present
Early onset or syndromic epilepsy v2.206 TMEM106B Arina Puzriakova Gene: tmem106b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.205 TMEM106B Arina Puzriakova reviewed gene: TMEM106B: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 29186371, 29444210, 30643851, 32595021; Phenotypes: Leukodystrophy, hypomyelinating, 16 OMIM:617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Classified gene: SPTBN4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: New gene identified and reviewed by Konstantinos Varvagiannis. Following discussion with Helen Brittain (Genomics England Clinical Team) it has been agreed that this gene should be added as Amber.

Although number of unrelated cases (3) reaches threshold for inclusion, only 2 patients presented severe intractable seizures (could not find any evidence of epilepsy in the case from Pehlivan et al, as stated by external expert review). Furthermore, epilepsy was not a consistent finding (total 11 individuals from 9 families). Rating set to Amber, awaiting further cases.
Early onset or syndromic epilepsy v2.205 SPTBN4 Arina Puzriakova Gene: sptbn4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.204 DMXL2 Arina Puzriakova Tag for-review tag was added to gene: DMXL2.
Early onset or syndromic epilepsy v2.204 SETD1A Arina Puzriakova Phenotypes for gene: SETD1A were changed from Epilepsy to Epilepsy, early-onset, with or without developmental delay, 618832
Early onset or syndromic epilepsy v2.203 SATB2 Zornitza Stark gene: SATB2 was added
gene: SATB2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SATB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SATB2 were set to 32446642
Phenotypes for gene: SATB2 were set to Glass syndrome, MIM# 612313
gene: SATB2 was marked as current diagnostic
Added comment: In a cohort of 101 individuals with SATB2-associated syndrome, 41 had at least one prior abnormal EEG. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six individuals with definite clinical seizures needed polytherapy (35%).
Sources: Literature
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Classified gene: ZNF335 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, but should be promoted to Green at the next GMS panel update (added 'for-review' tag) as there are sufficient unrelated cases to support a gene-disease association.
Early onset or syndromic epilepsy v2.203 ZNF335 Arina Puzriakova Gene: znf335 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.202 ZNF335 Arina Puzriakova gene: ZNF335 was added
gene: ZNF335 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: ZNF335.
Mode of inheritance for gene: ZNF335 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF335 were set to 23178126; 27540107; 29652087; 30500859; 31187448
Phenotypes for gene: ZNF335 were set to Microcephaly 10, primary, autosomal recessive, 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: Literature
Early onset or syndromic epilepsy v2.201 SLC5A6 Sarah Leigh commented on gene: SLC5A6: For review tag has been added, to allow for GMS discussion in relation to the metabolic role of this gene.
Early onset or syndromic epilepsy v2.201 SLC5A6 Sarah Leigh Tag for-review tag was added to gene: SLC5A6.
Early onset or syndromic epilepsy v2.201 SCN8A Arina Puzriakova Tag for-review tag was added to gene: SCN8A.
Early onset or syndromic epilepsy v2.201 SCN8A Arina Puzriakova commented on gene: SCN8A
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Classified gene: PIGP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.201 PIGP Arina Puzriakova Gene: pigp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.200 PIGP Arina Puzriakova Tag for-review tag was added to gene: PIGP.
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Classified gene: PUM1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Gene: pum1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.199 PUM1 Arina Puzriakova Tag for-review tag was added to gene: PUM1.
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Classified gene: RALGAPA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.199 RALGAPA1 Arina Puzriakova Gene: ralgapa1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.198 RALGAPA1 Arina Puzriakova Tag for-review tag was added to gene: RALGAPA1.
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Classified gene: RARS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.198 RARS Arina Puzriakova Gene: rars has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.197 RARS Arina Puzriakova Tag for-review tag was added to gene: RARS.
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Tag for-review tag was added to gene: RNF113A.
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Classified gene: RNF113A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.197 RNF113A Arina Puzriakova Gene: rnf113a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Classified gene: RNF13 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.196 RNF13 Arina Puzriakova Gene: rnf13 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.195 RNF13 Arina Puzriakova Tag for-review tag was added to gene: RNF13.
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Classified gene: SERPINI1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.195 SERPINI1 Arina Puzriakova Gene: serpini1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.194 SERPINI1 Arina Puzriakova Tag for-review tag was added to gene: SERPINI1.
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Classified gene: SETD1A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.194 SETD1A Arina Puzriakova Gene: setd1a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.193 SETD1A Arina Puzriakova Tag for-review tag was added to gene: SETD1A.
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Classified gene: SETD1B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.193 SETD1B Arina Puzriakova Gene: setd1b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.192 SETD1B Arina Puzriakova Tag for-review tag was added to gene: SETD1B.
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Classified gene: GAD1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.192 GAD1 Arina Puzriakova Gene: gad1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.191 GAD1 Arina Puzriakova Tag for-review tag was added to gene: GAD1.
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Classified gene: PCYT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.191 PCYT2 Arina Puzriakova Gene: pcyt2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.190 PCYT2 Arina Puzriakova Tag for-review tag was added to gene: PCYT2.
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Classified gene: ANKRD11 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.190 ANKRD11 Arina Puzriakova Gene: ankrd11 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.189 ANKRD11 Arina Puzriakova Tag for-review tag was added to gene: ANKRD11.
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.189 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.188 UGP2 Arina Puzriakova Tag for-review tag was added to gene: UGP2.
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Classified gene: TRAPPC4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.188 TRAPPC4 Arina Puzriakova Gene: trappc4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.187 TRAPPC4 Arina Puzriakova Tag for-review tag was added to gene: TRAPPC4.
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Classified gene: KAT8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.187 KAT8 Arina Puzriakova Gene: kat8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Classified gene: SEMA6B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.186 SEMA6B Arina Puzriakova Gene: sema6b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.185 SETD5 Arina Puzriakova Classified gene: SETD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.185 SETD5 Arina Puzriakova Gene: setd5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Classified gene: SETD5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.184 SETD5 Arina Puzriakova Gene: setd5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Classified gene: SNX27 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.183 SNX27 Arina Puzriakova Gene: snx27 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Classified gene: TMX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.182 TMX2 Arina Puzriakova Gene: tmx2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.181 TMX2 Arina Puzriakova Tag for-review tag was added to gene: TMX2.
Early onset or syndromic epilepsy v2.181 KAT8 Arina Puzriakova Tag for-review tag was added to gene: KAT8.
Early onset or syndromic epilepsy v2.181 SEMA6B Arina Puzriakova Tag for-review tag was added to gene: SEMA6B.
Early onset or syndromic epilepsy v2.181 SETD5 Arina Puzriakova Tag for-review tag was added to gene: SETD5.
Early onset or syndromic epilepsy v2.181 SNX27 Arina Puzriakova Tag for-review tag was added to gene: SNX27.
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Classified gene: PIGK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.181 PIGK Arina Puzriakova Gene: pigk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.180 PIGK Arina Puzriakova Tag for-review tag was added to gene: PIGK.
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Classified gene: TIMM50 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.
Early onset or syndromic epilepsy v2.180 TIMM50 Arina Puzriakova Gene: timm50 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.179 LMBRD2 Arina Puzriakova changed review comment from: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber but there is a sufficient number of unrelated cases with the relevant phenotype to rate this gene GREEN at the next major review.
Early onset or syndromic epilepsy v2.179 UBE3A Sarah Leigh Phenotypes for gene: UBE3A were changed from Angelman syndrome to Angelman syndrome 105830
Early onset or syndromic epilepsy v2.178 USP7 Arina Puzriakova Publications for gene: USP7 were set to 26365382; 19946331
Early onset or syndromic epilepsy v2.177 USP7 Arina Puzriakova Phenotypes for gene: USP7 were changed from Intellectual disability, autism, epilepsy, aggressive behaviour, hypotonia, and hypogonadism to Hao-Fountain syndrome, 616863
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Classified gene: CARS2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to support a gene-disease association. This gene has been added with an Amber rating but should be promoted to Green at the GMS panel update (added 'for-review' tag).

Note this is a metabolic gene and is already Green on the Inborn errors of metabolism (v2.3) panel.
Early onset or syndromic epilepsy v2.176 CARS2 Arina Puzriakova Gene: cars2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.175 CARS2 Arina Puzriakova gene: CARS2 was added
gene: CARS2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CARS2.
Mode of inheritance for gene: CARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CARS2 were set to 25361775; 25787132; 30139652; 32571458; 32348839
Phenotypes for gene: CARS2 were set to Combined oxidative phosphorylation deficiency 27, 616672
Review for gene: CARS2 was set to GREEN
Added comment: Associated with phenotype in OMIM and as a probable gene for Epileptic encephalopathy with complex movement disorder and regression in Gen2Phen.

At least 6 individuals from 5 unrelated families, all with different biallelic variants in CARS2 and a neurodegenerative disorder which includes early-onset seizures.
Sources: Literature
Early onset or syndromic epilepsy v2.174 TRPM3 Arina Puzriakova Publications for gene: TRPM3 were set to 31278393; 29156220
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Classified gene: TRPM3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for review at the next GMS panel update, in view of recently published functional data and expert reviews.
Early onset or syndromic epilepsy v2.173 TRPM3 Arina Puzriakova Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.172 TRPM3 Arina Puzriakova reviewed gene: TRPM3: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32439617, 32343227, 32427099; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.172 FDFT1 Arina Puzriakova Phenotypes for gene: FDFT1 were changed from Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face to Squalene synthase deficiency, 618156
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Tag watchlist tag was added to gene: FDFT1.
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Classified gene: FDFT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Added comment: Comment on list classification: Expert review on FDFT1 following a publication by Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

FDFT1 is in OMIM based on this paper. As there are only two families classifying FDFT1 as Amber until more evidence is available (added 'watchlist' tag).
Early onset or syndromic epilepsy v2.171 FDFT1 Arina Puzriakova Gene: fdft1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.170 KAT5 Arina Puzriakova Phenotypes for gene: KAT5 were changed from to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Early onset or syndromic epilepsy v2.169 KAT5 Arina Puzriakova Publications for gene: KAT5 were set to
Early onset or syndromic epilepsy v2.168 KAT5 Arina Puzriakova Mode of inheritance for gene: KAT5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Classified gene: KAT5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber. There is a sufficient number of unrelated cases reported in PMID:32822602 to promoted this gene to Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Gene: kat5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.166 KAT5 Arina Puzriakova Tag for-review tag was added to gene: KAT5.
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Classified gene: SCAF4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green at the next GMS panel update - sufficient number of unrelated cases presenting seizures due to distinct variants in SCAF4
Early onset or syndromic epilepsy v2.166 SCAF4 Arina Puzriakova Gene: scaf4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.165 SCAF4 Arina Puzriakova gene: SCAF4 was added
gene: SCAF4 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: SCAF4.
Mode of inheritance for gene: SCAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAF4 were set to 32730804
Phenotypes for gene: SCAF4 were set to SCAF4-related Neurodevelopmental Disorder; Intellectual disability; Seizures; Behavioural abnormalities
Review for gene: SCAF4 was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on 23/09/2014), but is a probable gene SCAF4-related Neurodevelopmental Disorder in Gen2Phen.

PMID: 32730804 (2020) - At least 8 unrelated patients with likely pathogenic variants in SCAF4 and mild DD/ID, behavioural abnormalities, and various skeletal, renal and cardiac anomalies. 7 de novo and 1 inherited variant. Seizures occurred in 4 individuals (50%) and included myoclonic seizures in two and intractable seizures in one.
Sources: Literature
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Classified gene: USP18 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update - seizures reported in all families described to date.
Early onset or syndromic epilepsy v2.164 USP18 Arina Puzriakova Gene: usp18 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.163 USP18 Arina Puzriakova commented on gene: USP18: Added 'treatable' tag as clinical remission was achieved in a patient following rapid genetic diagnosis and subsequent treatment with the JAK inhibitor ruxolitinib
Early onset or syndromic epilepsy v2.163 USP18 Arina Puzriakova gene: USP18 was added
gene: USP18 was added to Genetic epilepsy syndromes. Sources: Literature
treatable, for-review tags were added to gene: USP18.
Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP18 were set to 12833411; 27325888; 31940699
Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2, 617397
Review for gene: USP18 was set to GREEN
Added comment: - PMID: 27325888 (2016) - Three sibs from a consanguineous Turkish family with a homozygous variant (c.652C>T, p.Q218X) in USP18. Antenatal presentation in one sib led to termination of pregnancy at 22 wk of gestation, and in the remaining two children presentation was neonatal and resulted in death within 2 weeks of life. In the latter two individuals manifestations included severe intracerebral haemorrhages, liver dysfunction, ascites, and lactic acidosis. One sib additionally had severe thrombocytopenia with petechiae, while the other developed seizures.

Two German sibs, previously reported in PMID: 12833411 (2013), were found to be compound het for the same p.Q218X variant and a cryptic 3-prime deletion of the USP18 gene. They presented thrombocytopenia, petechiae, ascites, hepatomegaly, and systemic calcifications. Within the first days of life, they developed seizures and died from severe cerebral haemorrhage.

Haplotype analysis of the region containing the Q218X mutation suggested a common ancestor between the 2 families and a founder effect.

- PMID: 31940699 (2020) - One Saudi Arabian boy with a homozygous splice-site variant (c.1073+1G>A) in USP18, presented hydrocephalus with seizures, intraventricular haemorrhage, brain calcifications, necrotizing cellulitis, systemic inflammation, multiple organ failure, and respiratory failure. This was the only patient to survive beyond the perinatal period owing to supportive care and prompt treatment with ruxolitinib. At the time of publication, the child was 3-years-old and was in full remission of clinical manifestations while continuing to receive oral ruxolitinib. He continues to grow normally, however authors note delay in developmental milestones.
Sources: Literature
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Tag for-review tag was added to gene: MADD.
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Classified gene: MADD as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There is enough evidence to support a gene-disease association. The gene has been given an Amber rating and will be promoted to Green at the next review.
Early onset or syndromic epilepsy v2.162 MADD Ivone Leong Gene: madd has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Classified gene: DLL1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Added comment: Comment on list classification: There is a sufficient number of cases to rate this gene Green at the next GMS panel update.
Early onset or syndromic epilepsy v2.161 DLL1 Catherine Snow Gene: dll1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.160 DLL1 Catherine Snow reviewed gene: DLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31353024; Phenotypes: Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, 618709; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.160 MADD Ivone Leong Phenotypes for gene: MADD were changed from Global developmental delay / Intellectual disability / Seizures; Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system to Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Classified gene: YIF1B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Added comment: Comment on list classification: Seizures reported in only 2 unrelated individuals (PMID:32006098). Rating Amber in anticipation of further publications/clinical evidence to support this association.
Early onset or syndromic epilepsy v2.159 YIF1B Arina Puzriakova Gene: yif1b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Classified gene: UGDH as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Multiple patients from over 20 unrelated families with severe epilepsy, mostly ranging from neonatal to infantile onset developmental epileptic encephalopathy.
Early onset or syndromic epilepsy v2.158 UGDH Arina Puzriakova Gene: ugdh has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.157 UGDH Arina Puzriakova Tag for-review tag was added to gene: UGDH.
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 7 unrelated cases presenting seizures, including tonic clonic, generalised, absence, and focal seizures.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 6 unrelated cases presenting epilepsy in association with different NR4A2 variants, including tonic clonic, generalised, absence, and focal seizures.
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Classified gene: NR4A2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

At least 7 unrelated cases presenting seizures, including tonic clonic, generalised, absence, and focal seizures.
Early onset or syndromic epilepsy v2.157 NR4A2 Arina Puzriakova Gene: nr4a2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.156 NR4A2 Arina Puzriakova Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396
Early onset or syndromic epilepsy v2.155 NR4A2 Arina Puzriakova Tag for-review tag was added to gene: NR4A2.
Early onset or syndromic epilepsy v2.155 KPTN Zornitza Stark edited their review of gene: KPTN: Added comment: Two further publications (PMID 32358097; 32808430), more individuals reported with seizures, suggest upgrade to Green.; Changed publications: 32358097, 32808430
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Classified gene: CUL3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on external expert review and evidence provided by Konstantinos Varvagiannis. Only two unrelated cases reported and therefore not yet reaching threshold for inclusion.
Early onset or syndromic epilepsy v2.155 CUL3 Arina Puzriakova Gene: cul3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.154 MECP2 Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v2.154 DHX16 Sarah Leigh Tag watchlist tag was added to gene: DHX16.
Early onset or syndromic epilepsy v2.154 DHX16 Sarah Leigh Classified gene: DHX16 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.154 DHX16 Sarah Leigh Gene: dhx16 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.153 DHX16 Sarah Leigh gene: DHX16 was added
gene: DHX16 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures 618733
Review for gene: DHX16 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Intellectual Disability, Central Nervous System anomalies and Seizures. At least 4 variants reported as de novo heterozygous variants in 4 unrelated probands as a result of trio exome sequencing and seizures were reported in 2 of these cases. No functional studies were reported.
Sources: Literature
Early onset or syndromic epilepsy v2.152 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to AMBER
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Early onset or syndromic epilepsy v2.152 TANC2 Arina Puzriakova Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Seizures; Epilepsy to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Three patients from two unrelated families with myoclonic seizures, and additional focal epilepsy with versive head movement in one patient (onset at birth/6 months, respectively).

Additional unrelated cases required before inclusion on a diagnostic panel; and therefore, rating Amber in anticipation of further publications (added to watchlist).
Early onset or syndromic epilepsy v2.150 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.149 EXOC7 Arina Puzriakova Tag watchlist tag was added to gene: EXOC7.
Early onset or syndromic epilepsy v2.149 EXOC7 Arina Puzriakova gene: EXOC7 was added
gene: EXOC7 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to Brain atrophy; Seizures; Developmental delay; Microcephaly
Added comment: PMID: 32103185 (2020) - 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Literature
Early onset or syndromic epilepsy v2.148 TRIP13 Zornitza Stark changed review comment from: Phenotype is highly variable but seizures reported in 2/6 cases.; to: Phenotype is highly variable but seizures reported in 2/6 cases. Note 5/6 families had the same homozygous variant, p.Arg354X, suggestive of founder effect.
Early onset or syndromic epilepsy v2.148 TRIP13 Zornitza Stark edited their review of gene: TRIP13: Changed rating: AMBER
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Classified gene: LMBRD2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.
Early onset or syndromic epilepsy v2.148 LMBRD2 Arina Puzriakova Gene: lmbrd2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.147 LMBRD2 Arina Puzriakova Tag for-review tag was added to gene: LMBRD2.
Early onset or syndromic epilepsy v2.147 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Early onset or syndromic epilepsy v2.146 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least four unrelated individuals with three distinct TUBGCP2 variants, associated with generalised seizures.
Early onset or syndromic epilepsy v2.146 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.145 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: TUBGCP2.
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive microcephaly (4/4), developmental delay (5/5, mild-severe), generalised seizures (4/5, onset at 6yrs-9m, 5m, and 7m). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Classified gene: DDC as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Added comment: Comment on list classification: This is a metabolic gene and is green on the Inborn errors of metabolism (https://panelapp.genomicsengland.co.uk/panels/467/gene/DDC/), therefore it is rated as amber on the Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.144 DDC Sarah Leigh Gene: ddc has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.143 DDC Sarah Leigh Tag for-review tag was added to gene: DDC.
Early onset or syndromic epilepsy v2.143 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.143 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Genetic epilepsy syndromes. 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
Early onset or syndromic epilepsy v2.143 MADD Konstantinos Varvagiannis gene: MADD was added
gene: MADD was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MADD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MADD were set to 28940097; 29302074; 32761064
Phenotypes for gene: MADD were set to Global developmental delay / Intellectual disability / Seizures; Global developmental delay / Intellectual disability / Seizures / Abnormality of the endocrine system / Exocrine pancreatic insufficiency / Constipation / Diarrhea / Anemia / Thrombocytopenia / Abnormality of the autonomic nervous system
Penetrance for gene: MADD were set to Complete
Review for gene: MADD was set to GREEN
Added comment: There are 3 reports on the phenotype of individuals with biallelic pathogenic MADD variants. Clinical presentation appears to be relevant for inclusion of this gene in both ID and epilepsy panels. A recent study provides extensive clinical details and suggests that the phenotype may range from DD/ID to a severe pleiotropic disorder characterized by severe DD (and ID), sensory and autonomic dysfunction, exocrine and endocrine insufficiency and haematological anomalies). Seizures have been reported in several individuals with either presentation.
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Anazi et al (2017 - PMID: 28940097) identified MADD as a potential ID gene. The authors described a girl with profound DD and seizures among other features. The child, deceased at the age of 14m, was born to consanguineous Saoudi parents and was found to harbour a homozygous missense SNV [NM_003682.3:c.2930T>G:p.(Val977Gly)]. Through GeneMatcher, the authors identified a further 6 y.o. girl, compound heterozygous for a missense and a stopgain variant [NM_003682.3:c.593G>A:p.(Arg198His) and c.979C>T:p.(Arg327*)]. The child had normal development and milestones until the age of 15m, when she demonstrated delay in speech, social interactions, poor eye contact and was later diagnosed with ASD.
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Hu et al (2019 - PMID: 29302074) provided details on a 22- and 30- y.o. female born to (reportedly) unrelated parents. Formal evaluation (WAIS-IV) suggested ID in the mild to moderate range(IQs of 50 and 60 respectively). Both were homozygous for an indel [NM_003682:c.3559del / p.(Met1187*)].
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Schneeberger et al (2020 - PMID: 32761064) report on 23 affected subjects.

The authors categorized the phenotypes in 2 groups. 9 individuals belonging to group 1 presented with hypotonia, DD (9/9) with speech impaiment, ID (5/5) and seizures (6/9). 14 patients, belonging to group 2 had DD (9/9 - severe), ID (3/3), seizures (9/14), endo- and exocrine dysfunction, impairment of sensory and autonomic nervous system, haematological anomalies. The course was fatal in some cases, within the later group. Some facial features appeared to be more frequent (e.g. full cheeks, small mouth, tented upper lip - small palpebral fissures in some, etc). Genital anomalies were also common in males from both groups.

All were found to harbor biallelic MADD variants (21 different - missense and pLoF SNVs as well as an intragenic deletion). Variants in all cases affected all 7 isoforms. Data did not allow genotype-phenotype correlations e.g. individuals with missense and a pLoF variant (in trans) were identified within either group.

Studies using patient-derived fibroblasts supported the role of the variants, e.g. lower mRNA levels for those where NMD would apply, deficiency or drastic reduction of the protein upon immunobloting (also the case for missense variants) and mRNA analyses demonstrating aberrant transcripts for 2 relevant variants.

MADD encodes the MAPK-activating protein containing a death domain implicated among others in neurotransmission (Rab3 GEF and effector playing a role in formation/trafficking of synaptic vessicles), cell survival (pro-apoptotic effects/protection against apoptosis upon TNF-a treatment), etc. The gene has relevant expression pattern in fetal and adult brain (discussed by Hu et al).

Studies in patient fibroblasts provide evidence of reduced activation of MAP kinases ERK1/2 upon treatment with TNF-a, activation of the intrinsic (TNF-a-dependent-) apoptosis. MADD deficiency was shown to result to decreased EGF endocytosis (likely mediated by Rab3).

Mouse model further supports the role of MADD (summary by MGI: "Mice homozygous for a knock-out allele die shortly after birth due to respiratory failure, are hyporesponsive to tactile stimuli, and exhibit defects in neurotransmitter release with impaired synaptic vesicle trafficking and depletion of synaptic vesicles at the neuromuscular junction.").

You may consider inclusion in other gene panels e.g. for hematologic (low Hb and thrombocytopenia in several) or GI (e.g diarrhea) disorders.
Sources: Literature
Early onset or syndromic epilepsy v2.143 FAM50A Konstantinos Varvagiannis gene: FAM50A was added
gene: FAM50A was added to Genetic epilepsy syndromes. 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
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Tag for-review tag was added to gene: TET3.
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh edited their review of gene: TET3: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Added comment: Comment on phenotypes: This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Early onset or syndromic epilepsy v2.143 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#). to Beck-Fahrner syndrome 618798
Early onset or syndromic epilepsy v2.142 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face to This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#).
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Classified gene: TET3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases. Seizures were reported in 2 unrelated cases of monoallelic and 2 unrelated cases of biallelic 2 cases TET3 DNA Demethylation Disorder.
Early onset or syndromic epilepsy v2.141 TET3 Sarah Leigh Gene: tet3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.140 TET3 Sarah Leigh Tag watchlist tag was added to gene: TET3.
Early onset or syndromic epilepsy v2.140 TET3 Sarah Leigh Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Early onset or syndromic epilepsy v2.139 TET3 Sarah Leigh Mode of inheritance for gene: TET3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.138 AFF3 Sarah Leigh Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh edited their review of gene: OXR1: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Tag for-review tag was added to gene: OXR1.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Classified gene: OXR1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Early onset or syndromic epilepsy v2.137 OXR1 Sarah Leigh Gene: oxr1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.136 OXR1 Sarah Leigh Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Early onset or syndromic epilepsy v2.135 OXR1 Sarah Leigh Phenotypes for gene: OXR1 were changed from Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh edited their review of gene: MTHFS: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Tag for-review tag was added to gene: MTHFS.
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Classified gene: MTHFS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases.
Early onset or syndromic epilepsy v2.134 MTHFS Sarah Leigh Gene: mthfs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.133 PIGQ Konstantinos Varvagiannis reviewed gene: PIGQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 32588908, 24463883, 25558065, 31148362; Phenotypes: Epileptic encephalopathy, early infantile, 77 (MIM #618548); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Classified gene: EIF2AK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Added comment: Comment on list classification: Currently, only half of reported cases present seizures which seem to follow after developmental concerns are apparent. Therefore rated Amber, awaiting further publications/clinical evidence to elucidate the contribution of EIF2AK2 variants to this phenotype.
Early onset or syndromic epilepsy v2.133 EIF2AK2 Arina Puzriakova Gene: eif2ak2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.132 EIF2AK2 Arina Puzriakova gene: EIF2AK2 was added
gene: EIF2AK2 was added to Genetic epilepsy syndromes. 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 Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877
Added comment: Association with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation reported in both OMIM and G2P (probable).

PMID: 32197074 (2020) - Distinct de novo missense variants were identified in eight unrelated individuals who all share a notable phenotypic overlap of developmental delay, cognitive impairment, white matter alterations, dysarthria or lack of speech, and neurologic regression with febrile illness. Other variable features included hypotonia (7/8), hypertonia (7/8), ataxia (6/8), dystonia (5/8), tremor (3/8) and seizures (4/8). Functional data confirm reduced kinase activity compared to the wildtype protein product, and authors predict a dominant-negative effect.
Sources: Literature
Early onset or syndromic epilepsy v2.131 NDUFA2 Arina Puzriakova reviewed gene: NDUFA2: Rating: ; Mode of pathogenicity: None; Publications: 18513682, 28857146, 32154054; Phenotypes: Mitochondrial complex I deficiency, nuclear type 13, 618235; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.131 NARS Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Early onset or syndromic epilepsy v2.131 NARS Konstantinos Varvagiannis gene: NARS was added
gene: NARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225
Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1]

Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families.

Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features.

NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported.

Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all].

The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model).

As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy.
Sources: Literature
Early onset or syndromic epilepsy v2.131 LMAN2L Arina Puzriakova Classified gene: LMAN2L as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.131 LMAN2L Arina Puzriakova Gene: lman2l has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.130 LMAN2L Arina Puzriakova gene: LMAN2L was added
gene: LMAN2L was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMAN2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMAN2L were set to 31020005; 26566883
Phenotypes for gene: LMAN2L were set to Intellectual disability; Epilepsy
Review for gene: LMAN2L was set to AMBER
Added comment: PMID: 26566883 (2015) - One consanguineous family with 7 individuals with ID and epilepsy. Five individuals presented mild epileptic seizures in the first year of life, until the age of 5 years when seizures stopped spontaneously without any medication. Typical seizure episodes lasted for 3 to 5 min. Epilepsy was also reported in two other family members, who died at the age of 7 and 16 years and therefore could not be included in the study. A homozygous LMAN2L missense variant (c.158 G>A, p.R53Q) segregated with disease in family, and unaffected family members were heterozygous variant carriers. No functional studies.

PMID: 31020005 (2019) - One non-consanguineous family with 4 affected, harbouring a heterozygous frameshift LMAN2L variant (c.1073delT, p.Phe358Serfs*16) which segregated with disease in the family. All suffered generalised tonic‐clonic seizures in childhood, however all had undergone remission with normalized EEG by adolescence. Functional studies show the variant eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane.
Sources: Literature
Early onset or syndromic epilepsy v2.129 TUBB2A Arina Puzriakova reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32571897; Phenotypes: Cortical dysplasia, complex, with other brain malformations 5, 615763; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.129 SETD1B Arina Puzriakova reviewed gene: SETD1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams changed review comment from: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1AS null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.; to: PMID: 32160274 - Davies et al 2020 - several reports of de novo missense mutations in EEF1A2 associated with neurodevelopmental disorders but no clear loss of function mutations. They created mice with a missense mutation in EEF1A2 (D252H) in both heterozygous and homozygous state and EEF1A2 null mutant mice and analysed using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. They found the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. The results suggest that the D252H mutation results in a gain of function.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams Tag for-review tag was added to gene: EEF1A2.
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams edited their review of gene: EEF1A2: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 32160274
Early onset or syndromic epilepsy v2.129 EEF1A2 Eleanor Williams commented on gene: EEF1A2
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Classified gene: HERC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 distinct variants in unrelated cases presenting the relevant phenotype.
Early onset or syndromic epilepsy v2.129 HERC2 Arina Puzriakova Gene: herc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.128 HERC2 Arina Puzriakova Tag for-review tag was added to gene: HERC2.
Early onset or syndromic epilepsy v2.128 SEC31A Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature
Early onset or syndromic epilepsy v2.128 LARS Konstantinos Varvagiannis gene: LARS was added
gene: LARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 32699352
Phenotypes for gene: LARS were set to Infantile liver failure syndrome 1, MIM# 615438
Penetrance for gene: LARS were set to Complete
Review for gene: LARS was set to GREEN
Added comment: Please consider inclusion with amber/green rating in the current panel.

Biallelic pathogenic LARS1 variants cause Infantile liver failure syndrome 1, MIM# 615438.

Lenz et al (2020 - PMID: 32699352) review the phenotype of 25 affected individuals from 15 families.

Seizures occurred in 19/24 and were commonly associated with infections. Encephalopathic episodes (in 13 patients) accompanied by seizures up to status epilepticus occurred independently of hepatic decompensation.

In addition 22/24 presented with neurodevelopmental delay. The authors comment that cognitive impairment was present in 13/17 individuals (mild-severe) whereas most presented with learning disabilities.

These patients will be most likely investigated for their liver disease (although presentation was highly variable and/or very mild in few).

The gene encodes a cytoplasmic amino-acyl tRNA synthetase (ARS) with neurologic manifestations observed in almost all patients (and seizures / DD and ID common to other disorders due to mutations in other genes encoding for ARSs).

Please note that the HGNC approved symbol for this gene is LARS1.
Sources: Literature
Early onset or syndromic epilepsy v2.128 ASTN1 Arina Puzriakova edited their review of gene: ASTN1: Changed rating: RED
Early onset or syndromic epilepsy v2.128 EIF2A Arina Puzriakova gene: EIF2A was added
gene: EIF2A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EIF2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIF2A were set to 31130284
Phenotypes for gene: EIF2A were set to Intellectual disability; Seizures; ASD
Review for gene: EIF2A was set to RED
Added comment: Gene is not associated with any phenotype in OMIM or G2P.

PMID: 31130284 - Distinct homozygous variants were identified in two cases presenting an overlapping phenotype of ID and epilepsy (intractable in one patient), as part of a large screening study of a highly consanguineous Saudi population. However, no segregation or follow-up functional studies were conducted to validate the variants, and there is currently no other publication data supporting this candidate gene and the relationship with epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Classified gene: ASTN1 as Red List (low evidence)
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Added comment: Comment on list classification: Epilepsy only reported in a single patient. Further cases required to ascertain the contribution of ASTN1 variants to this phenotype.
Early onset or syndromic epilepsy v2.127 ASTN1 Arina Puzriakova Gene: astn1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.126 ASTN1 Arina Puzriakova reviewed gene: ASTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26539891, 27431290, 29706646; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.126 LIPT1 Sarah Leigh Publications for gene: LIPT1 were set to 29681092; 31042466
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Classified gene: LIPT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Added comment: Comment on list classification: This metabolic gene is associated with Lipoyltransferase 1 deficiency 616299 in OMIM and as a probable gene for Leigh syndrome with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. In addition to the six variants that have been reported in five cases Lipoyltransferase 1 deficiency 616299, two further variants have been reported in two unrelated cases of Lipoyltransferase 1 deficiency 616299 who also have epieptic seizures (PMID 29681092; 31042466).
Early onset or syndromic epilepsy v2.125 LIPT1 Sarah Leigh Gene: lipt1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.124 LIPT1 Sarah Leigh gene: LIPT1 was added
gene: LIPT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LIPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIPT1 were set to 29681092; 31042466
Phenotypes for gene: LIPT1 were set to Lipoyltransferase 1 deficiency 616299
Review for gene: LIPT1 was set to AMBER
Added comment: Sources: Literature
Early onset or syndromic epilepsy v2.123 PTPN23 Eleanor Williams Added comment: Comment on phenotypes: Added disease association from OMIM.
Early onset or syndromic epilepsy v2.123 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Rare severe autosomal-recessive developmental and epileptic encephalopathy to Rare severe autosomal-recessive developmental and epileptic encephalopathy; Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity MIM#618890
Early onset or syndromic epilepsy v2.122 ADARB1 Arina Puzriakova changed review comment from: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures, which were intractable in three of the individuals. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature; to: Gene is associated with phenotype in OMIM and G2P.

PMID: 32220291 - Bi-allelic variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures. Functional studies demonstrate variants result in reduction in ADARB1 product activity or changes in splicing.
PMID: 10894545 - Homozygous knockout mice presented with siezures and early death, supporting the role of ADARB1 in brain function

This gene has also been added to the Intellectual Disability and Severe Microcephaly panels with a suggested Green classification at the next major review.
Early onset or syndromic epilepsy v2.122 TMEM106B Konstantinos Varvagiannis gene: TMEM106B was added
gene: TMEM106B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964)
Penetrance for gene: TMEM106B were set to Complete
Mode of pathogenicity for gene: TMEM106B 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: TMEM106B was set to AMBER
Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021).

While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al].

All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al).

As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin.

Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect.

Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel.

Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating.
Sources: Literature
Early onset or syndromic epilepsy v2.122 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Genetic epilepsy syndromes. 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 GREEN
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
Early onset or syndromic epilepsy v2.122 ABCA2 Konstantinos Varvagiannis gene: ABCA2 was added
gene: ABCA2 was added to Genetic epilepsy syndromes. 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
Early onset or syndromic epilepsy v2.122 HERC2 Konstantinos Varvagiannis gene: HERC2 was added
gene: HERC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: HERC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HERC2 were set to 23065719; 23243086; 30902390; 32571899; 27848944; 26077850; 27759030
Phenotypes for gene: HERC2 were set to Mental retardation, autosomal recessive 38 (MIM 615516)
Penetrance for gene: HERC2 were set to Complete
Review for gene: HERC2 was set to GREEN
Added comment: Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516).

The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27):
- 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390)
- 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390)
- 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al.
- 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available.

Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. :
- Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver.
- Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified).

Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc).

Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al.

Overall this gene can be included in the ID and epilepsy panels with green rating.
Sources: Literature
Early onset or syndromic epilepsy v2.122 SEC31A Sarah Leigh gene: SEC31A was added
gene: SEC31A was added to Genetic epilepsy syndromes. Sources: Literature
watchlist tags were added to gene: SEC31A.
Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC31A were set to 30464055
Phenotypes for gene: SEC31A were set to Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651
Review for gene: SEC31A was set to AMBER
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. One homozygous terminating variant reported in sibs of consanguineous Bedouin parents, together with a Drosophila model in which loss of sec31a was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
Sources: Literature
Early onset or syndromic epilepsy v2.121 RUSC2 Sarah Leigh edited their review of gene: RUSC2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported in at least 2 unrelated cases. No functional studies have been reported, although authors of PMID 27612186 suggest that p.R866* results in total loss of function as the sibs biallelic with this variant have a more severe phenotype than the case who is biallelic for p.R1318*, which they conclude results in partial loss of function. Refractory seizures were seen in the sibs with p.R866*.; Changed rating: RED
Early onset or syndromic epilepsy v2.121 RUSC2 Sarah Leigh Phenotypes for gene: RUSC2 were changed from to Mental retardation, autosomal recessive 61 617773
Early onset or syndromic epilepsy v2.120 RUSC2 Sarah Leigh Publications for gene: RUSC2 were set to
Early onset or syndromic epilepsy v2.119 OTUD7A Sarah Leigh commented on gene: OTUD7A: Review by Zornitza Stark on Intellectual disability panel https://panelapp.genomicsengland.co.uk/panels/285/: One patient with severe global developmental delay, language impairment and epileptic encephalopathy reported. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Mouse model and other data support the role of this gene in neurodevelopmental phenotypes but nevertheless, single family to date.
Early onset or syndromic epilepsy v2.119 OTUD7A Sarah Leigh gene: OTUD7A was added
gene: OTUD7A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: OTUD7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTUD7A were set to 31997314; 29395075; 29395074
Phenotypes for gene: OTUD7A were set to Epileptic encephalopathy, intellectual disability
Review for gene: OTUD7A was set to RED
Added comment: Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association.
Sources: Literature
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Classified gene: GALNT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review, depending on the policy of inclusion of metabolic genes on this panel.
Early onset or syndromic epilepsy v2.118 GALNT2 Sarah Leigh Gene: galnt2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.117 GALNT2 Sarah Leigh gene: GALNT2 was added
gene: GALNT2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: GALNT2.
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 27508872; 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation, type IIt 618885
Review for gene: GALNT2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in at least 5 unrelated cases, together with mouse and rat models (PMID 27508872;32293671).
Sources: Literature
Early onset or syndromic epilepsy v2.116 ADARB1 Sarah Leigh Classified gene: ADARB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.116 ADARB1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.116 ADARB1 Sarah Leigh Gene: adarb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.115 ADARB1 Sarah Leigh Tag for-review tag was added to gene: ADARB1.
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh changed review comment from: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature; to: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous (p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Classified gene: ALG14 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel.
Early onset or syndromic epilepsy v2.115 ALG14 Sarah Leigh Gene: alg14 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.114 ALG14 Sarah Leigh gene: ALG14 was added
gene: ALG14 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: ALG14.
Mode of inheritance for gene: ALG14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG14 were set to 28733338; 23404334; 30221345
Phenotypes for gene: ALG14 were set to Congenital myasthenic syndrome; ?Myasthenic syndrome, congenital, 15, without tubular aggregates, 616227
Review for gene: ALG14 was set to AMBER
Added comment: Associated with Myasthenic syndrome, congenital, 15, without tubular aggregates 616227 in OMIM, but not associated with phenotype in Gen2Phen. At least 6 variants reported in at least 5 cases with varying phenotypes. PMID 23404334 reports compound heterozygous (p.P65L, P.R104*) sibs, who manifested with myasthenic syndromes, but did not have intellectural disability nor seizures and were 62 and 51 years old when reported. PMID 28733338 reports two compound heterozygous (p.D74N, pV141G), (p.D74N, p.R109Q) cases and a homozygous ((p.D74N), with early and lethal neurodegeneration with myasthenic and myopathic features, but the cases died before intellectual disability was manifiest. However, seizures were evident in two compound heterozygous families. PMID 30221345 reports a homozygous splicing variant in a case with intellectual disability and seizures. Functional studies were presented showing that this variant resulting in exon skipping, however, this was not completely prenetrant as wild type protein was detected at a low level in the patient.
Sources: Literature
Early onset or syndromic epilepsy v2.113 ADARB1 Arina Puzriakova gene: ADARB1 was added
gene: ADARB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ADARB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADARB1 were set to 32220291
Phenotypes for gene: ADARB1 were set to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Review for gene: ADARB1 was set to GREEN
Added comment: Variants reported in four unrelated individuals with severe/profound intellectual disability, microcephaly, and seizures, which were intractable in three of the individuals. Functional studies demonstrate variants result in reduction of ADARB1 product activity or changes in splicing (PMID: 32220291). Homozygous knockout mice presented with seizures and early death, supporting the role of ADARB1 in brain function (PMID: 10894545)

Gene is associated with phenotype in OMIM and G2P.
Sources: Literature
Early onset or syndromic epilepsy v2.113 SLC5A6 Sarah Leigh commented on gene: SLC5A6: Watchlist tag was added to take account of the potential therapeutic options of this cause of seizures.
Early onset or syndromic epilepsy v2.113 SLC5A6 Sarah Leigh Tag watchlist tag was added to gene: SLC5A6.
Early onset or syndromic epilepsy v2.113 PTEN Sarah Leigh reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.113 PTEN Sarah Leigh Tag mosaicism was removed from gene: PTEN.
Tag somatic was removed from gene: PTEN.
Tag for-review tag was added to gene: PTEN.
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh commented on gene: NRROS: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh Classified gene: NRROS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.113 NRROS Sarah Leigh Gene: nrros has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.112 NRROS Sarah Leigh gene: NRROS was added
gene: NRROS was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: NRROS.
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075; 28459434
Phenotypes for gene: NRROS were set to Seizures, early-onset, with neurodegeneration and brain calcification 618875
Review for gene: NRROS was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for NRROS-related Infantile-Onset Neurodegeneration with Intracranial Calcification. At least 6 variants reported in at least 5 unrelated cases (PMIDs 32100099;32197075), together with supportive mouse model (PMID 28459434).
Sources: Literature
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh edited their review of gene: CDK19: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Sources: Literature; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417). PMID 20563892 reports a de novo pericentric inversion in chromosome 6 with breakpoints in 6p12.1 and 6q21 reported in a female patient with microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation. Supporting in vitro and drosophila model data also included.
Sources: Literature
Early onset or syndromic epilepsy v2.111 CDK19 Sarah Leigh Phenotypes for gene: CDK19 were changed from to Epileptic encephalopathy, early infantile 87 618916
Early onset or syndromic epilepsy v2.110 CDK19 Sarah Leigh Publications for gene: CDK19 were set to
Early onset or syndromic epilepsy v2.109 CDK19 Sarah Leigh Classified gene: CDK19 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.109 CDK19 Sarah Leigh Gene: cdk19 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.108 CDK19 Sarah Leigh gene: CDK19 was added
gene: CDK19 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: CDK19.
Mode of inheritance for gene: CDK19 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: CDK19 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive Drosophila, demonstating the effects of the variants (PMID 32330417).
Sources: Literature
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh edited their review of gene: CACNB4: Added comment: There is enough evidence for this gene to be rated GREEN for epilepsy at the next major review.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh Tag for-review tag was added to gene: CACNB4.
Early onset or syndromic epilepsy v2.107 CACNB4 Sarah Leigh Publications for gene: CACNB4 were set to 20561025; 20378313; 10762541; 32176688 25529582
Early onset or syndromic epilepsy v2.106 CACNB4 Sarah Leigh Phenotypes for gene: CACNB4 were changed from to {Epilepsy, idiopathic generalized, susceptibility to, 9}, 607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, 607682; Episodic ataxia, type 5, 613855; Intellectual disability
Early onset or syndromic epilepsy v2.105 CACNB4 Sarah Leigh Publications for gene: CACNB4 were set to
Early onset or syndromic epilepsy v2.104 CACNB4 Sarah Leigh Mode of inheritance for gene: CACNB4 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Classified gene: CACNB4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional data.
Early onset or syndromic epilepsy v2.103 CACNB4 Sarah Leigh Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.102 MCM3AP Eleanor Williams gene: MCM3AP was added
gene: MCM3AP was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MCM3AP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM3AP were set to 32202298
Phenotypes for gene: MCM3AP were set to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development 618124
Review for gene: MCM3AP was set to RED
Added comment: PMID: 32202298 - Woldegebriel et al 2020 - report a further two families, one in the Netherlands and one in Estonia, with probands with compound heterozygous variants in MCM3AP and a peripheral neuropathy with or without impaired intellectual development (MIM 618124) phenotype. The two siblings from the Estonian family had severe generalized epilepsy and mild spastic diplegia. Functional studies using skin fibroblasts from these and other affected patients showed that disease variants result in depletion of GANP (encoded by MCM3AP) except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants.
Sources: Literature
Early onset or syndromic epilepsy v2.101 DMXL2 Eleanor Williams Added comment: Comment on mode of inheritance: All cases with epilepsy have been biallelic
Early onset or syndromic epilepsy v2.101 DMXL2 Eleanor Williams Mode of inheritance for gene: DMXL2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Classified gene: DMXL2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Added comment: Comment on list classification: Promoting to amber for now. There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.100 DMXL2 Eleanor Williams Gene: dmxl2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.99 DMXL2 Eleanor Williams Phenotypes for gene: DMXL2 were changed from Epileptic encephalopathy, early infantile, 81, MIM 618663; ?Polyendocrine-polyneuropathy syndrome, MIM 616113 to Epileptic encephalopathy, early infantile, 81, MIM 618663; Ohtahara syndrome
Early onset or syndromic epilepsy v2.98 DMXL2 Eleanor Williams Mode of inheritance for gene: DMXL2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.97 DMXL2 Eleanor Williams reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31688942, 30237576; Phenotypes: Ohtahara syndrome, Epileptic encephalopathy, early infantile, 81, 618663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.97 PIGS Sarah Leigh Tag watchlist tag was added to gene: PIGS.
Early onset or syndromic epilepsy v2.97 PIGS Sarah Leigh Phenotypes for gene: PIGS were changed from Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143 to Glycosylphosphatidylinositol biosynthesis defect 18 618143
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Classified gene: PIGS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in at least 3 unrelated cases, seizures were evident in 2 unrelated cases.
Early onset or syndromic epilepsy v2.96 PIGS Sarah Leigh Gene: pigs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Classified gene: PIGK as Green List (high evidence)
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Added comment: Comment on list classification: Zornitza Stark loaded PIGK as a green gene on Intellectual disability (https://panelapp.genomicsengland.co.uk/panels/285/gene/PIGK/#!review). and suggested that it was also suitable for the Genetic epilepsy syndromes panel.
Early onset or syndromic epilepsy v2.95 PIGK Sarah Leigh Gene: pigk has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.94 PIGK Sarah Leigh gene: PIGK was added
gene: PIGK was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: PIGK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGK were set to 32220290
Phenotypes for gene: PIGK were set to Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures 618879
Review for gene: PIGK was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for PIGK-associated Neurodevelopmental Syndrome. At least 7 variants reported in at least 5 unrelated cases with seizures.
Sources: Expert list
Early onset or syndromic epilepsy v2.93 DDC Lothar Schlueter edited their review of gene: DDC: Changed publications: 28100251, 30952622, 20505134, 19172410, 32369189, 18754761, 32409695
Early onset or syndromic epilepsy v2.93 DDC Lothar Schlueter changed review comment from: Seizures are not a key symptom for aromatic L-amino acid decarboxylase deficiency (AADCD). However, some patients have seizures. Oculogyric crises, which are a key symptom, could be mistaken for epileptic seizures. In the review paper of Wassenberg et al. (2017) about 8% of AADCD patients suffer from seizures (9/117). Manegold et al. (2009) found 3 patients with seizures and corresponding EEG abnormalities in a cohort of 9 patients. They also point out, that it was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. Another review by Brun et al. (2010) mentions abnormal EEG in 10 out of 78 patients without further detail about seizures.
Sources: Literature; to: Seizures are not a key symptom for aromatic L-amino acid decarboxylase deficiency (AADCD). However, some patients have seizures. Oculogyric crises, which are a key symptom, could be mistaken for epileptic seizures. In the review paper of Wassenberg et al. (2017) about 8% of AADCD patients suffer from seizures (9/117). Manegold et al. (2009) found 3 patients with seizures and corresponding EEG abnormalities in a cohort of 9 patients. They also point out, that it was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. Another review by Brun et al. (2010) mentions abnormal EEG in 10 out of 78 patients without further detail about seizures. In recent cohort analysis they concluded that about 30% of AADCD patients have been initially diagnosed with epilepsy (Pearson et al.2020, Wen et al. 2020)
Sources: Literature

Update: Added more literature
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo, however, one of these cases also had a 290Kb deletion at
13q12.11.
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.93 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.92 CDC42BPB Sarah Leigh Added comment: Comment on mode of inheritance: Unknown mode of inheritance has been assigned as the majority of variants in this gene (11/14) in PMID 32031333 are de novo.
Early onset or syndromic epilepsy v2.92 CDC42BPB Sarah Leigh Mode of inheritance for gene: CDC42BPB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and of these cases were de novo.; to: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and all of these cases were de novo.
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Classified gene: CDC42BPB as Green List (high evidence)
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene. At least 12 variants reported in 14 unrelated cases of CDC42BPB-related Neurodevelopmental Disorder. Seizures were apparent in 3/12 cases and of these cases were de novo.
Early onset or syndromic epilepsy v2.91 CDC42BPB Sarah Leigh Gene: cdc42bpb has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.90 CDC42BPB Sarah Leigh Added comment: Comment on phenotypes: CDC42BPB-related Neurodevelopmental Disorder is assigned by Gen2Phen.
Early onset or syndromic epilepsy v2.90 CDC42BPB Sarah Leigh Phenotypes for gene: CDC42BPB were changed from Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality to CDC42BPB-related Neurodevelopmental Disorder; Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Early onset or syndromic epilepsy v2.89 GRM7 Zornitza Stark gene: GRM7 was added
gene: GRM7 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 32286009; 32248644
Phenotypes for gene: GRM7 were set to Epilepsy, microcephaly, developmental delay
Review for gene: GRM7 was set to GREEN
gene: GRM7 was marked as current diagnostic
Added comment: Eleven individuals from six families reported, three different homozygous variants (two missense, one LoF). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Supportive mouse model.
Sources: Literature
Early onset or syndromic epilepsy v2.89 STARD7 Rebecca Foulger changed review comment from: Comment on list classification: Added as Amber awaiting clinical review as to whether gene and/or a new STR should be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.; to: Comment on list classification: Added gene as Amber based on advice from Genomics England Clinical team: the causative variants are the repeat expansion, and therefore the STR will be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Classified gene: SRPX2 as Red List (low evidence)
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Added comment: Comment on list classification: Based evidence that the gene / disease associate has been refuted (PMID 24995671).
Early onset or syndromic epilepsy v2.89 SRPX2 Sarah Leigh Gene: srpx2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Classified gene: SNX27 as Green List (high evidence)
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited on 05/23/2012) or in Gen2Phen. However, five variants in three unrelated cases (displaying seizures), together with supportive functional studies and mouse model.
Early onset or syndromic epilepsy v2.88 SNX27 Sarah Leigh Gene: snx27 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.87 SLC5A6 Sarah Leigh Publications for gene: SLC5A6 were set to 31754459; 27904971
Early onset or syndromic epilepsy v2.86 SLC5A6 Sarah Leigh Phenotypes for gene: SLC5A6 were changed from Developmental delay; epilepsy; neurodegeneration to SLC5A6-related Neurodevelopmental Disorder
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM and as possible Gen2Phen gene for SLC5A6-related Neurodevelopmental Disorder. At least 4 variants published in two unrelated famililies (3 cases total) with SLC5A6-related Neurodevelopmental Disorder, together with supportive functional studies. One of the cases had mixed semiology seizures including focal dyscognitive, absence, tonic spasms and generalised convulsive seizures with electrographic features of encephalopathy with generalised and independent multifocal spike-wave discharges (PMID 31754459).
Early onset or syndromic epilepsy v2.85 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.84 RNF113A Sarah Leigh Tag Skewed X-inactivation tag was added to gene: RNF113A.
Early onset or syndromic epilepsy v2.84 PIGA Sarah Leigh Tag Skewed X-inactivation tag was added to gene: PIGA.
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Classified gene: SETD5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Added comment: Comment on list classification: Review article PMID 29484850 reports seizures in 10/42 (23.8%) cases of autism spectrum disorders carrying heterozygous SETD5 variants.
Early onset or syndromic epilepsy v2.84 SETD5 Sarah Leigh Gene: setd5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.83 SETD5 Sarah Leigh Publications for gene: SETD5 were set to 25138099; 24680889
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger changed review comment from: PMID:27000257. Alrayes et al., 2016 report a homozygous frameshift variant in AGMO- p.(Glu324LysfsTer12) in 2 brothers from a consanguineous Saudi family with syndromic microcephaly, and global developmental delay. Epilepsy is not mentioned amongst their phenotypes.; to: PMID:27000257 (2016) Alrayes et al., 2016 enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. They identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene in 2 brothers. Population screening of 178 ethnically matched control chromosomes and consultation of the ExAC database confirmed that this variant was not present outside the family. Epilepsy is not mentioned amongst their phenotypes.
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Classified gene: AGMO as Red List (low evidence)
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Amber by Zornitza Stark. Only 1 of the 3 individuals from PMIDs:31555905 and 27000257 is reported with epilepsy. Therefore rated Red awaiting further evidence.
Early onset or syndromic epilepsy v2.82 AGMO Rebecca Foulger Gene: agmo has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl had variants p.Trp130Ter & p.Gly238Cys. The boy had variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl harboured variants p.Trp130Ter & p.Gly238Cys. The boy harboured variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger changed review comment from: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. They demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.; to: PMID:31555905. Okur et al., report rare nonsense in-frame deletion and missense compound heterozygous variants in AGMO in 2 unrelated individuals- an 8 year old European girl, and 4-year old Ashkenazi Jewish boy. The girl had variants p.Trp130Ter & p.Gly238Cys. The boy had variants p.Gly144Arg and p.Tyr236del. Note that there is one individual in gnomAD who is homozygous for the p.Gly144Arg variant. Table 1 also mentions 'MTHFR C677T homozygous' for the boy, but this is not referred to within the text. The authors demonstrated significantly diminished enzyme activity for all disease-associated variants. Seizures were reported for the girl with generalized tonic-clonic seizures beginning age 2 months (and controlled with medication). Seizures were not reported for the boy, though he has a nephew with epilepsy.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger commented on gene: AGMO: PMID:27000257. Alrayes et al., 2016 report a homozygous frameshift variant in AGMO- p.(Glu324LysfsTer12) in 2 brothers from a consanguineous Saudi family with syndromic microcephaly, and global developmental delay. Epilepsy is not mentioned amongst their phenotypes.
Early onset or syndromic epilepsy v2.81 AGMO Rebecca Foulger Phenotypes for gene: AGMO were changed from microcephaly; intellectual disability; epilepsy to microcephaly; intellectual disability; epilepsy; generalized tonic-clonic seizures
Early onset or syndromic epilepsy v2.80 AGMO Rebecca Foulger commented on gene: AGMO
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger changed review comment from: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype.; to: Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype. Therefore updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Classified gene: SEMA6B as Green List (high evidence)
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype.
Early onset or syndromic epilepsy v2.80 SEMA6B Rebecca Foulger Gene: sema6b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.79 SEMA6B Rebecca Foulger Added comment: Comment on mode of pathogenicity: The authors of PMID:32169168 suggest a dominant-negative or gain-of-function effect rather than haploinsufficiency.
Early onset or syndromic epilepsy v2.79 SEMA6B Rebecca Foulger Mode of pathogenicity for gene: SEMA6B was changed from None to Other
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger changed review comment from: PMID:32169168. In 4 unrelated patients (2 Japanese, ISraeli and Malaysian) with progressive myoclonic epilepsy, Hamanaka et al. (2020) identified de novo heterozygous frameshift mutations in the last exon of the SEMA6B gene. Variants were predicted to result in truncated proteins. Truncating variants in this region of the gene were not observed in the gnomAD database, although truncating variants in other regions of the gene were observed in gnomAD. The authors postulated a dominant-negative or gain-of-function effect rather than haploinsufficiency. In an animal model, the authors found that zebrafish with truncating sema6b variants were more susceptible to seizures.; to: PMID:32169168. In 4 unrelated patients (2 Japanese, 1 Israeli and 1 Malaysian) with progressive myoclonic epilepsy, Hamanaka et al. (2020) identified de novo heterozygous frameshift mutations in the last exon of the SEMA6B gene. Variants were predicted to result in truncated proteins. Truncating variants in this region of the gene were not observed in the gnomAD database, although truncating variants in other regions of the gene were observed in gnomAD. The authors postulated a dominant-negative or gain-of-function effect rather than haploinsufficiency. In an animal model, the authors found that zebrafish with truncating sema6b variants were more susceptible to seizures.
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger commented on gene: SEMA6B
Early onset or syndromic epilepsy v2.78 SEMA6B Rebecca Foulger Phenotypes for gene: SEMA6B were changed from Progressive myoclonic epilepsy to Epilepsy, progressive myoclonic, 11, 618876
Early onset or syndromic epilepsy v2.77 KAT8 Rebecca Foulger Mode of pathogenicity for gene: KAT8 was changed from None to Other
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger Tag missense tag was added to gene: KAT8.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger commented on gene: KAT8: Added 'missense' tag because all de novo variants in PMID:31794431 are missense. Note that for the biallelic case in the same paper, one of the variants is nonsense.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger changed review comment from: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.; to: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. Not yet associated with a disorder in OMIM or G2P. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.
Early onset or syndromic epilepsy v2.76 KAT8 Rebecca Foulger Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.75 KAT8 Rebecca Foulger Added comment: Comment on mode of inheritance: Individual T9 inherited biallelic variants from her asymptomatic parents. Her sister carried 1 variant and showed no obvious symptoms. This may be due to incomplete genetic penetrance, or the two variants act differently from the de novo heterozygous variants identified. Since this is the only example of biallelic variants so far, I have set the MOI to 'monoallelic'.
Early onset or syndromic epilepsy v2.75 KAT8 Rebecca Foulger Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Classified gene: KAT8 as Green List (high evidence)
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Added comment: Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). Seizures were reported in 5/8 heterozygous individuals (Supplementary materials) plus individual T2 had febrile seizure. Seizures were also reported in the biallelic individual. Sufficient cases in the heterozygous individuals, and seizure is a consistent feature.
Early onset or syndromic epilepsy v2.74 KAT8 Rebecca Foulger Gene: kat8 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Tag watchlist was removed from gene: TIMM50.
Tag for-review tag was added to gene: TIMM50.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger commented on gene: TIMM50: Removed 'watchlist' tag, since this gene is no longer Amber. Note that TIMM50 is Green on the Intellectual disability panel (V3.73) and on the IEM panel (V2.8). Therefore added 'for-review' tag for discussion of alignment of epilepsy and metabolism panels.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Deleted their comment
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Classified gene: TIMM50 as Green List (high evidence)
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Added comment: Comment on list classification: Previous Amber rating was based on insufficient evidence (PMID:27573165/Shahrour et al 2017 who report 4 cases from 2 consanguineous families, plus a conference abstract reporting 3 further siblings). Zornitza Stark and Konstantinos Varvagiannis point out 2 new papers each with an additional case of TIMM50 variants in epileptic patients. Therefore have updated the rating from Amber to Green.
Early onset or syndromic epilepsy v2.73 TIMM50 Rebecca Foulger Gene: timm50 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.72 TIMM50 Rebecca Foulger Phenotypes for gene: TIMM50 were changed from 3-methylglutaconic aciduria, type IX, 617698; intellectual disability and seizure; epilepsy and developmental delay to 3-methylglutaconic aciduria, type IX, 617698; intellectual disability and seizure; epilepsy and developmental delay; epileptic encephalopathy
Early onset or syndromic epilepsy v2.71 TIMM50 Rebecca Foulger Publications for gene: TIMM50 were set to 27573165; Serajee F, Hu A. A distinct type of 3-methylglutaconic aciduria due to a mutation in the Translocase of Inner Mitochondrial Membrane 50 (TIMM50) gene. ASHG meeting 2015 Abstract Nr 2299, 2015.
Early onset or syndromic epilepsy v2.70 TIMM50 Rebecca Foulger Added comment: Comment on publications: 27573165; 30190335; 31058414; Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T)
Early onset or syndromic epilepsy v2.70 TIMM50 Rebecca Foulger Publications for gene: TIMM50 were set to 27573165; Serajee F, Hu A. A distinct type of 3-methylglutaconic aciduria due to a mutation in the Translocase of Inner Mitochondrial Membrane 50 (TIMM50) gene. ASHG meeting 2015 Abstract Nr 2299, 2015.
Early onset or syndromic epilepsy v2.69 TIMM50 Rebecca Foulger commented on gene: TIMM50: PMID:31058414 (Tort et al., 2019) report compound het TIMM50 variants in a boy with 3-MGA-uria (p.Arg114Gln, p.Gly269Ser). At 3.5 months, a diagnosis of West syndrome was made, and he showed a good response to ACTH and antiepileptic treatment.
Early onset or syndromic epilepsy v2.69 TIMM50 Rebecca Foulger commented on gene: TIMM50: PMID:30190335. Reyes et al., 2018 report a third unrelated family. WES identified compound het pathogenic TIMM50 variants (p.S112* and p.G190A) in an infant with rapidly progressive, severe encephalopathy, including infantile seizures and severe epilepsy. Sanger sequencing confirmed the two variants in the proband and showed that the two parents were each heterozygous for one of them. In the ExAc database, the p.G190A variant was present in <200,000 alleles, with the nonsense change not reported.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence (PMID:31735293). Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Classified gene: TMX2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Gene: tmx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.68 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures; Primary microcephaly, cortical malformation and epileptic encephalopathy
Early onset or syndromic epilepsy v2.67 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730 to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures
Early onset or syndromic epilepsy v2.66 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Classified gene: TRAPPC4 as Green List (high evidence)
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Konstantinos Varvagiannis. Subsequent Green review by Zornitza Stark. Updated rating from Grey to Green: 7 children from 3 unrelated families with MIM:618741 reported by, Van Bergen et al. (2020) with a recurring homozygous splice site variant in TRAPPC4 resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The variant segregated within the disorder within the families and was only found in heterozygous state in gnomAD. Appropriate phenotype and cases just reach threshold for inclusion.
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Gene: trappc4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.64 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Early onset or syndromic epilepsy v2.63 TRPM3 Rebecca Foulger Tag for-review tag was added to gene: TRPM3.
Early onset or syndromic epilepsy v2.63 TRPM3 Rebecca Foulger commented on gene: TRPM3: Excluding the individual harbouring a VUS, 7 individuals from PMID:31278393 (Dyment et al 2019) had the same de novo heterozygous variant in TRPM3 (p.Val837Met). This paper was considered when previously reviewed by GLHs. An Amber rating was chosen because public databases confirm that heterozygous loss-of-function variants of TRPM3 are observed in the general population (heterozygous gnomAD truncating variants occur in 18 of 25 canonical coding exons) and therefore the authors reasoned that simple haploinsufficiency was unlikely to be the mechanism of disease in their cohort. Therefore added 'for-review' tag, for reassesment at next GLH review.
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Classified gene: TUBA8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now, following Zornitza Stark's recent (Jan 2020) review. Additional case in PMID:31481326 (2020) but 2 Pakistani families (4 patients) previously reported may be related so remains a borderline case.
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.62 TUBA8 Rebecca Foulger commented on gene: TUBA8: Reviewing 2020 review comment by Zornitza noting additional publication: PMID:31481326. PMID:31481326. Lee et al., 2020 used targeted gene sequencing to identify malformations of cortical development in 81 patients. A homozygous TUBA8 p.Asn356ProfsTer63 variant was identified in one patient with 'Polymicrogyria, agenesis of CC, ventriculomegaly'. All patients had a confirmed diagnosis of epilepsy or DD.
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Classified gene: UGP2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Konstantinos Varvagiannis. Subsequently reviewed Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (MIM:618744) for inclusion on panel: 20 patients from 13 unrelated families all with the same variant identified in PMID:31820119 (2019 publication). Therefore updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Gene: ugp2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.61 UGP2 Rebecca Foulger Phenotypes for gene: UGP2 were changed from Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Epileptic encephalopathy, early infantile, 83, 618744; seizures
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger commented on gene: WDR45B: Added 'for-review' tag based on Zornitza's Green review on a gene where an Amber rating was decided at the last GLH review. Of the publications listed, PMID:28503735 (Suleiman et al) report 3 families (2 with seizures). PMID:21937992. Najmabadi et al 2011 identify WDR45B (WDR45L) as a candidate gene for ID. PMID:27431290 (Anazi et al., 2017) identified likely pathogenic alleles in WDR45B in ID individuals. Little information provided about WDR45B phenotype.
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger Tag for-review tag was added to gene: WDR45B.
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger Publications for gene: WDR45B were set to 21937992; 28503735
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Classified gene: ANKRD11 as Green List (high evidence)
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Added comment: Comment on list classification: Added to panel and reviewed Green by Tracy Lester. Although KBG syndrome has variable symptoms, epilepsy can be amongst the phenotypes. Based on literature review and Tracy Lester's review, updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Gene: ankrd11 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger commented on gene: ANKRD11: PMID:27900361. Kleyner et al., 2016 describe a 13 yr old male with phenotypes including epilepsy, severe DD, distinct facial features and hand anomalies. Exome sequencing identified a novel de novo heterozygous LOF single bp duplication (c.6015dupA) in ANKRD11, leading to a premature stop codon.
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger commented on gene: ANKRD11: PMID:25543316. Samanta et al., 2015 report a 7 yr old boy with a ANKRD11 variant and developmental delay, focal epilepsy and behavioral concerns. He had frequent focal seizures but had enjoyed seizure-free state intermittently up to 9 months. He also had rare secondarily generalized tonic–clonic seizures, less than one episode in a year. After normal EEGs age 1 and 3, an EEG age 5 revealed EEG abnormalities.
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger Publications for gene: ANKRD11 were set to 29565525
Early onset or syndromic epilepsy v2.57 ANKRD11 Rebecca Foulger commented on gene: ANKRD11
Early onset or syndromic epilepsy v2.57 ANKRD11 Rebecca Foulger Phenotypes for gene: ANKRD11 were changed from KBG syndrome to KBG syndrome, 148050
Early onset or syndromic epilepsy v2.56 ANKRD11 Tracy Lester gene: ANKRD11 was added
gene: ANKRD11 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: ANKRD11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD11 were set to 29565525
Phenotypes for gene: ANKRD11 were set to KBG syndrome
Penetrance for gene: ANKRD11 were set to Complete
Review for gene: ANKRD11 was set to GREEN
Added comment: KBG syndrome - EEG abnormalities, with or without seizures, have been reported in about 50% of affected individuals [Skjei et al 2007]. Age of onset can range from infancy to the teenage years [Low et al 2016]. The type of epilepsy is variable. Although tonic-clonic seizures are most common, no one specific type of epilepsy has been associated with the syndrome. Treatment with antiepileptic medication has proven effective in the majority of affected individuals. Many have remission of symptoms after adolescence [Lo-Castro et al 2013]. A few affected individuals have reportedly had severe seizures at a young age (described as infantile spasms / epileptic encephalopathy), in some cases drug resistant [C Ockeloen, personal communication; Samanta & Willis 2015]. - taken from GeneReviews, KBG syndrome, last updated Mar2018.
Penetrance of KBG syndrome is thought to be complete, but with variable expressivity.
Also associated with 16q24.3 deletions.
Sources: Expert Review
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger Tag for-review tag was added to gene: ALKBH8.
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger commented on gene: ALKBH8: Kept rating as Amber following advice from the Genomics England Clinical Team since Amber was the GLH opinion. This is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Have added 'for-review' tag to highlight the Green review from Zornitza. Note that Zornitza's review focuses on the differing ratings of ALKBH8 on the ID and Epilepsy panels, which I will align for consistency: no new evidence in the review.
Early onset or syndromic epilepsy v2.56 STARD7 Rebecca Foulger Phenotypes for gene: STARD7 were changed from Epilepsy, familial adult myoclonic, 2, 607876 to Epilepsy, familial adult myoclonic, 2, 607876; Familial adult myoclonic epilepsy-2; FAME-2
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Classified gene: STARD7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Added comment: Comment on list classification: Added as Amber awaiting clinical review as to whether gene and/or a new STR should be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Gene: stard7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.54 STARD7 Rebecca Foulger gene: STARD7 was added
gene: STARD7 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: STARD7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STARD7 were set to 11701600; 24114805; 31664034
Phenotypes for gene: STARD7 were set to Epilepsy, familial adult myoclonic, 2, 607876
Added comment: PMID:31664034. Corbett et al., 2019. In 158 affected individuals from 22 unrelated families with MIM:607876, Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion, (ATTTC)n, in the STARD7 gene. The cohort included 2 families who had previously been identified as having an ins/del mutation in the ADRA2B gene (Guerrini et al., 2001 PMID:11701600, and De Fusco et al., 2014, PMID:24114805), suggesting the the ADRA2B allele is not causative.

OMIM disorder 'Epilepsy, familial adult myoclonic, 2, 607876' (previously associated with ADRA2B) is now associated with the STARD7 gene.
Sources: Literature, Other
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger commented on gene: ADRA2B: Added 'for-review' tag to alert GLH to downgraded rating.
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Classified gene: ADRA2B as Red List (low evidence)
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Added comment: Comment on list classification: Downgraded rating from Amber to Red following PMID:31664034 (2019) publication that finds an alternative cause for epilepsy in the earlier reported patients, suggesting the the ADRA2B allele is not causative. MIM:607876 is now associated with a repeat expansion in STARD7, and not ADRA2B.
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Gene: adra2b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.52 ADRA2B Rebecca Foulger Publications for gene: ADRA2B were set to 11701600
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger commented on gene: ADRA2B: PMID:18231815: Direct sequencing of the ADRA2B gene in pedigrees from southern Italy that were described as having familial adult myoclonic epilepsy by Madia et al. (2008) did not reveal any pathogenic mutations.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger commented on gene: ADRA2B: PMID:31664034. Corbett et al., 2019. In 158 affected individuals from 22 unrelated families with MIM:607876, Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion, (ATTTC)n, in the STARD7 gene. The cohort included 2 families who had previously been identified as having an ins/del mutation in the ADRA2B gene (Guerrini et al., 2001 PMID:11701600, and De Fusco et al., 2014, PMID:24114805), suggesting the the ADRA2B allele is not causative.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger Added comment: Comment on phenotypes: OMIM disorder 'Epilepsy, familial adult myoclonic, 2, 607876' is now associated with the STARD7 gene. Therefore removed MIM:607876 from the phenotype field of ADRA2B.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger Phenotypes for gene: ADRA2B were changed from Epilepsy, myoclonic, familial adult, 2, 607876 to Cortical myoclonus and epilepsy
Early onset or syndromic epilepsy v2.50 PCYT2 Eleanor Williams Phenotypes for gene: PCYT2 were changed from Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy; Spastic paraplegia 82, autosomal recessive, 618770
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Classified gene: PCYT2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to panel and rated Green by Konstantinos Varvagiannis. Green rating confirmed by Genomics England Clinical Team.
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Gene: pcyt2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.48 WASF1 Rebecca Foulger Phenotypes for gene: WASF1 were changed from ID associated with autistic features, seizures, and developmental delay; Intellectual disability to Neurodevelopmental disorder with absent language and variable seizures, 618707
Early onset or syndromic epilepsy v2.47 NR4A2 Konstantinos Varvagiannis gene: NR4A2 was added
gene: NR4A2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NR4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396
Phenotypes for gene: NR4A2 were set to Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility
Penetrance for gene: NR4A2 were set to unknown
Review for gene: NR4A2 was set to GREEN
Added comment: Seizures have been reported in at least 6 unrelated individuals with NR4A2 variants (not including cases with contiguous gene deletions spanning also this gene). Please consider inclusion with amber or green rating.
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Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).

Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3).

8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).

Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).

As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).

The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.

Previous reviews for the ID panel:
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In a study of 457 autism families (Feliciano et al. - doi.org/10.1101/516625) the authors provide phenotypic information on a further individual with ASD and ID. This subject (SP0041645 - SPARK cohort) harbored a de novo frameshift variant (p.G231fs using ENST00000409572.1 as reference). Table 2 includes also the individual previously reported by Iossifov et al. who also presented with ASD and ID (11172.p1 - SSC cohort - PMID and details discussed below).
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Recent publications provide several lines of evidence that pathogenic NR4A2 variants cause DD/ID and/or autism spectrum disorder (ASD).

Lévy et al. (PMID: 29770430) summarize the phenotype of 2q24.1 microdeletions spanning either only NR4A2 [2 new patients as well as an individual reported by Reuter et al (PMID: 28544326)] or both NR4A2 and GPD2 (1 patient from this study as well as 2 further from Leppa et al. (PMID: 27569545) and Barge-Schaapveld et al. (PMID: 23554088)]. All these CNVs had occurred as de novo events. Common features included - among others - language impairment (6/6), ID (6/6), ASD (3/4) or abnormal behaviour (4/4).

As the authors note, NR4A2 belongs to a subfamily of highly conserved transcription factors. The gene is involved in several developmental processes, among others in neuronal development. Previous studies have also shown high expression in human fetal brain as well as a role in the development of language-related brain regions.

The absence of CNVs in general population encompassing NR4A2 (and presence of such CNVs spanning GDP2) as well as the minimal deletions confined to NR4A2 suggest that happloinsufficiency of NR4A2 is responsible for the DD/ID/ASD phenotypes. This is also supported by the HI index of 1.28 as well as pLI of 0.99.

Guo et al. (PMID: 30504930) report on a patient with de novo frameshift variant (p.P201Rfs*82) and provide a summary of individuals with de novo missense variants (schematic overview in suppl. fig. S4) previously reported in larger DD/ID/ASD cohorts, namely :

- The DDD study (PMID: 28135719) : subjects DDD4K.00386 (R312Q - https://decipher.sanger.ac.uk/ddd/research-variant/1e7622c3a0ba1b506c5808ccea46e759#overview) and DDD4K.04161 (R289P - https://decipher.sanger.ac.uk/ddd/research-variant/673e8e570d28dd0c5797ddafb22e53eb#overview)

- By Lelieveld et al. (PMID: 27479843) : patient with ID and V307G

- By Iossifov et al. (PMID: 25363768) : subject with ASD and Y275H.

[All these appear to cluster in a region of missense constraint : https://decipher.sanger.ac.uk/gene/NR4A2#overview/protein-info].

NR4A2 is not associated with any phenotype in OMIM, nor in G2P.

The gene is included in gene panels for intellectual disability offered by diagnostic laboratories (incl. Radboudumc).

As a result, it could be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Sources: Literature
Early onset or syndromic epilepsy v2.47 CUL3 Konstantinos Varvagiannis gene: CUL3 was added
gene: CUL3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CUL3 were set to 32341456
Phenotypes for gene: CUL3 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496
Penetrance for gene: CUL3 were set to unknown
Review for gene: CUL3 was set to AMBER
Added comment: Epilepsy has been reported in at least 2 relevant individuals in the literature.
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Nakashima et al (2020 - PMID:32341456) provide clinical details on 3 unrelated individuals with de novo CUL3 variants.

Features included DD, variable degrees of ID (P1: severe, P3: mild, P2: NA although he displayed motor and severe speech and language delay and had severe learning difficulties). Two out of three had intractable seizures (onset 2 - 6 months). One presented with congenital heart defects (ASD, PV stenosis) and another submucosal palatoschisis/bifid uvula. There were no facial dysmorphisms reported.

CUL3 encodes Cullin-3, a core piece of the E3 ubiquitin ligase complex, thus playing a role in the ubiquitin-proteasome system. [ https://ghr.nlm.nih.gov/gene/CUL3 ]. Germline variants in some other Cullin family genes (eg. CUL4B, CUL7) cause disorders with ID as a feature.

The 3 individuals reported by Nakashima had variable previous investigations (karyotype, CMA, metabolic testing) which were non-diagnostic. Singleton or trio exome sequencing identified 2 frameshift and 1 missense variant (NM_003590.4:c.854T>C / p.Val285Ala), further confirmed with Sanger sequencing. De novo occurrence was confirmed by analysis of microsatellite markers in an individual with singleton ES.

While the frameshift variants were presumed to lead to NMD (not studied), studies in HEK293T cells suggested that the Val285Ala reduced binding ability with KEAP1, possibly leading to instability of the Cullin-RING ligase (CRL) complex and impairment of the ubiquitin-proteasome system.

In OMIM, the phenotype associated with heterozygous CUL3 mutations is Pseudohypoaldosteronism type IIE (PHA2E - # 614496). As OMIM and Nakashima et al comment, PHA2E-associated variants are clustered around exon 9, most lead to skipping of exon 9 and produce an in-frame deletion of 57 aa in the cullin homology domain. Few (probably 3) missense variants in exon 9 have also been reported. Individuals with PHA2E do not display DD/ID and conversely individuals with NDD did not display features of PHA2E.

Nakashima et al summarize the phenotypes associated with 12 further de novo CUL3 variants in the literature with most pLOF ones detected in individuals with autism and/or developmental disorders and in few cases with congenital heart disease. Few additional missense variants and a stoploss one have been reported in individuals with NDD and one in SCZ.

Heterozygous Cul3 (/tissue-specific) deletion in mice resulted in autism-like behavior. Cul3 deficient mice also demonstrated NMDAR hypofunction and decreased spine density. [PMIDs cited : 31455858, 31780330]

Overall haploinsufficiency is favored as the underlying mechanism of variants associated with NDD. Nakashima et al comment that the pathogenesis of missense variants remains unknown and/or that a dominant-negative effect on CRL may be possible.

Studies on larger cohorts reporting on individuals with relevant phenotypes due to de novo CUL3 variants (eg. DDD study - PMID: 28135719, Lelieveld et al - PMID: 27479843), are better summarized in denovo-db (after filtering for coding variants):

http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=cul3
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Please consider inclusion in other panels if appropriate (e.g. for ASD).
Sources: Literature
Early onset or syndromic epilepsy v2.47 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Early onset or syndromic epilepsy v2.47 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to AMBER
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature
Early onset or syndromic epilepsy v2.47 SPTBN4 Konstantinos Varvagiannis gene: SPTBN4 was added
gene: SPTBN4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519
Penetrance for gene: SPTBN4 were set to Complete
Review for gene: SPTBN4 was set to GREEN
Added comment: Biallelic pathogenic SPTBN4 variants cause Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MIM #617519).

There are several reports on the phenotype of relevant affected individuals with severe/profound DD/ID in at least 9 individuals :

- Knierim et al (2017 - PMID: 28540413) [1 affected individual]
- Anazi et al (2017 - PMID: 28940097) [1]
- Wang et al (2018 - PMID: 29861105) [6]
- Pehlivan et al (2019 - PMID: 31230720) [1]

A recent article by Häusler et al (2019 - PMID: 31857255) describes the phenotype of 2 sibs, both presenting with motor and speech delay, although the older one had reportedly 'normal' cognitive performance allowing attendance of regular school at the age of 6 years.

Features include congenital hypotonia, severe DD and ID (in most as outlined above, ID was the primary indication for testing on several occasions), poor or absent reflexes and weakness secondary to axonal motor neuropathy, feeding and respiratory difficulties, hearing and visual impairment. Seizures have been reported in at least 4 unrelated individuals (3 by Wang et al / 1 by Pehlivan et al).

Variants in most cases were nonsense/frameshift although biallelic missense variants have also been reported. Sibs in the report by Häusler et al harbored a homozygous splicing variant.

SPTBN4 encodes a member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle.

βIV spectrin links ankyrinG and clustered ion channels (at axon initial segments and nodes of Ranvier) to the axonal cytoskeleton. Pathogenic variants are proposed to disrupt the cytoskeletal machinery controlling proper localization of ion channels and function of axonal domains where ion channels are normally clustered in high density. Among the evidence provided : nerve biopsies from an affected individual displayed reduced nodal Na+ channels and no nodal KCNQ2 K+ channels / Loss of AnkyrinG and βIV spectrin in animal model resulted in loss of KCNQ2- and KCNQ3- subunit containing K+ channels.

Apart from the ID / epilepsy panels please consider inclusion in other relevant ones.
Sources: Literature
Early onset or syndromic epilepsy v2.47 CDC42BPB Konstantinos Varvagiannis gene: CDC42BPB was added
gene: CDC42BPB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CDC42BPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDC42BPB were set to 32031333
Phenotypes for gene: CDC42BPB were set to Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Penetrance for gene: CDC42BPB were set to unknown
Review for gene: CDC42BPB was set to AMBER
Added comment: Chilton et al (2020 - PMID: 32031333) report on 14 individuals with missense and loss-of-function CDC42BPB variants.

Features included hypotonia (8/11), DD (12/13 - the 14th was a fetus), ID (7/13), ASD (8/12), clinical seizures (in 3 - a 4th had abnormal EEG without seizures), behavioral abnormalities. Variable non-specific dysmorphic features were reported in some (sparse hair being the most frequent - 4/8). Additional features were observed in few (=<4) incl. cryptorchidism, ophthalmological issues, constipation, kidney abnormalities, micropenis, etc.

All individuals had non-diagnostic prior genetic testing (incl. CMA, FMR1, MECP2, Angelman/Prader-Willi methylation studies, autism gene panel - suggesting relevance to the current panel) or metabolic testing.

Variants were identified following clinical exome sequencing with Sanger confirmation. Most occurred as de novo events (11/14) while inheritance was not available for few (3/14). Missense variants did not display (particular) clustering.

Almost all variants were absent from gnomAD and were predicted to be deleterious in silico (among others almost all had CADD scores >25).

As the authors comment, CDC42BPB encodes myotonic dystrophy-related Cdc42-binding kinase β (MRCKβ) a serine/threonine protein kinase playing a role in regulation of cytoskeletal reorganization and cell migration in nonmuscle cells (through phosporylation of MLC2).

Previous studies have demonstrated that it is ubiquitously expressed with prenatal brain expression.

The gene appears to be intolerant to pLoF (pLI of 1) as well as to missense variants (Z-score of 3.66).

CDC42BPB is a downstream effector of CDC42. Mutations of the latter cause Takenouchi-Kosaki syndrome with DD/ID and some further overlapping features (with CDC42BPB-associated phenotypes).

Homozygous Cdc42bpb KO in mouse appears to be nonviable (MGI:2136459). Loss of gek in the eyes of Drosophila results in disrupted growth cone targeting to the lamina (gek is the fly CDC42BPB ortholog).
Sources: Literature
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger changed review comment from: Comment on list classification: 2 Families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.; to: Comment on list classification: Added to panel and rated Amber by Zornitza Stark. 2 families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Classified gene: ADAM22 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Added comment: Comment on list classification: 2 Families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Gene: adam22 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.46 ADAM22 Rebecca Foulger Publications for gene: ADAM22 were set to 27066583; 30237576
Early onset or syndromic epilepsy v2.45 ADAM22 Rebecca Foulger commented on gene: ADAM22: Mouse model: Adam22-/- mice develop lethal seizures during the first postnatal weeks (e.g. PMID:15876356).
Early onset or syndromic epilepsy v2.45 ADAM22 Rebecca Foulger Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, 617933 to ?Epileptic encephalopathy, early infantile, 61, 617933
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:30237576 (Maddirevula et al., 2019) searched their database of clinical exomes for homozygous variants and report an 18 year old male with an Arg860* variant in ADAM22. Seizures started age 5 months with a focal seizure, and continued with generalized tonic clonic seizures and status epilepticus (Supplementary Table). His development was normal until 5 months when he had a slower gain of milestones. He has ID with severely delayed speech. Family history revealed ID and epilepsy in his old brother and in wider family.
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger commented on gene: ADAM22
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, MIM# 617933 to Epileptic encephalopathy, early infantile, 61, 617933
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Classified gene: CTU2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Added comment: Comment on list classification: Added to panel as Amber: Sufficient cases of seizures but 1 patient shows febrile seizures, and phenotype is variable. Plus just one study so far. Therefore Amber is appropriate, awaiting further evidence.
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Gene: ctu2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.42 CTU2 Rebecca Foulger gene: CTU2 was added
gene: CTU2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 31301155
Phenotypes for gene: CTU2 were set to seizures; DREAM‐PL syndrome; Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142
Added comment: Added to panel based on PMID:31301155 (Shaheen et al., 2019) who characterise the phenotype of 5 patients with DREAM-PL syndrome (Dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly) and summarise 4 Founder patients from previous studies (PMID:27480277, PMID:26633546). In total 6/10 patients had seizures including Generalized epilepsy, atypical absence seizures, complex febriles seizures and focal epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v2.41 CACNA1H Sarah Leigh Publications for gene: CACNA1H were set to 12891677; 32227660
Early onset or syndromic epilepsy v2.40 SAMD12 Zornitza Stark gene: SAMD12 was added
gene: SAMD12 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SAMD12 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SAMD12 were set to 30194086; 29507423
Phenotypes for gene: SAMD12 were set to Epilepsy, familial adult myoclonic, 1, MIM# 601068
Mode of pathogenicity for gene: SAMD12 was set to Other
Review for gene: SAMD12 was set to GREEN
gene: SAMD12 was marked as current diagnostic
Added comment: Repeat expansions of intronic TTTCA and TTTTA motifs within SAMD12 have been identified in over 50 Japanese and Chinese families. Most families with affected individuals were heterozygous however 4 patients from 3 families had homozygous repeat expansions, which was associated with a more severe phenotype. Western blot analysis showed decreased levels of the protein in patient brains. Note these were identified on long-read sequencing and may not be detectable by all assays.
Sources: Literature
Early onset or syndromic epilepsy v2.40 CACNA1H Sarah Leigh Phenotypes for gene: CACNA1H were changed from to Hyperaldosteronism, familial, type IV 617027; {Epilepsy, childhood absence, susceptibility to, 6} 611942; {Epilepsy, idiopathic generalized, susceptibility to, 6} 611942
Early onset or syndromic epilepsy v2.39 CACNA1H Sarah Leigh Added comment: Comment on publications: PMID 32227660 presents further evidence refuting a monogenic contribution of this gene to epilepsy.
Early onset or syndromic epilepsy v2.39 CACNA1H Sarah Leigh Publications for gene: CACNA1H were set to 12891677
Early onset or syndromic epilepsy v2.38 SEMA6B Zornitza Stark gene: SEMA6B was added
gene: SEMA6B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SEMA6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA6B were set to 32169168
Phenotypes for gene: SEMA6B were set to Progressive myoclonic epilepsy
Review for gene: SEMA6B was set to GREEN
Added comment: Five individuals from unrelated families reported with de novo variants in the last exon, escaping NMD.
Sources: Literature
Early onset or syndromic epilepsy v2.38 GAD1 Sarah Leigh Phenotypes for gene: GAD1 were changed from Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele to ?Cerebral palsy, spastic quadriplegic, 1 603513; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Early onset or syndromic epilepsy v2.37 GAD1 Sarah Leigh Publications for gene: GAD1 were set to https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Early onset or syndromic epilepsy v2.36 GAD1 Sarah Leigh Classified gene: GAD1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.36 GAD1 Sarah Leigh Gene: gad1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.35 GAD1 Sarah Leigh gene: GAD1 was added
gene: GAD1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GAD1 were set to https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Phenotypes for gene: GAD1 were set to Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Review for gene: GAD1 was set to GREEN
Added comment: Five biallelic loss of function variants reported in 11 cases in 6 unrelated families. All cases had epilepsy syndrome, 10 profound intellectual disabilty (1 case died at day 9 of life) and other nuerological and developement features. Supportive functional studies were also presented.
Sources: Literature
Early onset or syndromic epilepsy v2.34 SETD1B Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases (PMID29322246; 31440728 31685013). Strucutral variants have also been reported that encompass SETD1B (PMID 20648245; 27106595; 25428890; 22369279).; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases who displayed epilepsy (PMID29322246; 31440728 31685013). Strucutral variants have also been reported that encompass SETD1B (PMID 20648245; 27106595; 25428890; 22369279).
Early onset or syndromic epilepsy v2.34 SETD1B Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases. Strucutral variants have also been reported that encompass SETD1B.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases (PMID29322246; 31440728 31685013). Strucutral variants have also been reported that encompass SETD1B (PMID 20648245; 27106595; 25428890; 22369279).
Early onset or syndromic epilepsy v2.34 SETD1B Sarah Leigh Publications for gene: SETD1B were set to 29322246; 31440728; 31685013
Early onset or syndromic epilepsy v2.33 SETD1B Sarah Leigh Classified gene: SETD1B as Green List (high evidence)
Early onset or syndromic epilepsy v2.33 SETD1B Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for SETD1B associated intellectual disability, epilepsy and autism. At least 3 variants reported in at least 3 unrelated cases. Strucutral variants have also been reported that encompass SETD1B.
Early onset or syndromic epilepsy v2.33 SETD1B Sarah Leigh Gene: setd1b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.32 SETD1B Sarah Leigh Phenotypes for gene: SETD1B were changed from to Epilepsy with myoclonic absences; intellectual disability
Early onset or syndromic epilepsy v2.31 SETD1B Sarah Leigh Added comment: Comment on mode of inheritance: Mode of inheritance obtained from Gen2Phen
Early onset or syndromic epilepsy v2.31 SETD1B Sarah Leigh Mode of inheritance for gene: SETD1B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.30 SETD1B Sarah Leigh Publications for gene: SETD1B were set to
Early onset or syndromic epilepsy v2.29 SETD1A Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for intellectual disability. At least 4 variants reported, 3 de novo and 1 segrating in a family.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for intellectual disability. At least 4 variants reported, 3 de novo and 1 segregating in a family.
Early onset or syndromic epilepsy v2.29 SETD1A Sarah Leigh Classified gene: SETD1A as Green List (high evidence)
Early onset or syndromic epilepsy v2.29 SETD1A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for intellectual disability. At least 4 variants reported, 3 de novo and 1 segrating in a family.
Early onset or syndromic epilepsy v2.29 SETD1A Sarah Leigh Gene: setd1a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.28 SERPINI1 Sarah Leigh Classified gene: SERPINI1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.28 SERPINI1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 5 variants reported in unrelated cases.
Early onset or syndromic epilepsy v2.28 SERPINI1 Sarah Leigh Gene: serpini1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.27 SERPINI1 Sarah Leigh Phenotypes for gene: SERPINI1 were changed from Encephalopathy, familial, with neuroserpin inclusion bodies MIM#604218 to Encephalopathy, familial, with neuroserpin inclusion bodies 604218
Early onset or syndromic epilepsy v2.26 RNF13 Sarah Leigh Classified gene: RNF13 as Green List (high evidence)
Early onset or syndromic epilepsy v2.26 RNF13 Sarah Leigh Gene: rnf13 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.25 RNF13 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies.; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies. Gain-of-function mechanism has been reported, therefore the mutational spectrum may be limited and is still to be determined through further cases or further functional studies (view of Helen Britain, GeL Clincial Fellow).
Early onset or syndromic epilepsy v2.25 SCAMP5 Sarah Leigh Tag watchlist tag was added to gene: SCAMP5.
Early onset or syndromic epilepsy v2.25 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered. ; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Early onset or syndromic epilepsy v2.25 PTEN Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote AKT1 from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote PTEN from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.
Early onset or syndromic epilepsy v2.25 SCN8A Sarah Leigh Added comment: Comment on mode of pathogenicity: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy. This differs from the previosly reported gain of function, monoallelic variants (PMID 24194747;22365152).
Early onset or syndromic epilepsy v2.25 SCN8A Sarah Leigh Mode of pathogenicity for gene: SCN8A was changed from Other to Other
Early onset or syndromic epilepsy v2.24 SCN8A Sarah Leigh Added comment: Comment on mode of pathogenicity: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy.
Early onset or syndromic epilepsy v2.24 SCN8A Sarah Leigh Mode of pathogenicity for gene: SCN8A was changed from None to Other
Early onset or syndromic epilepsy v2.23 SCN8A Sarah Leigh Added comment: Comment on mode of inheritance: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy.
Early onset or syndromic epilepsy v2.23 SCN8A Sarah Leigh Mode of inheritance for gene: SCN8A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.22 SCN8A Sarah Leigh Phenotypes for gene: SCN8A were changed from Cognitive impairment with or without cerebellar ataxia; Intellectual disability; Epileptic encephalopathy, early infantile, 13 to ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080
Early onset or syndromic epilepsy v2.21 SCN8A Sarah Leigh Publications for gene: SCN8A were set to Trudeau et al (2004) J Med Genet 43: 527_530; O'Brien and Meisler (2013) Frontiers in Genet 4(213): 1-9; Veeramah et al (2012) Am J Hum Genet 90: 502_510
Early onset or syndromic epilepsy v2.20 SCAMP5 Sarah Leigh Added comment: Comment on mode of pathogenicity: Heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease.
Early onset or syndromic epilepsy v2.20 SCAMP5 Sarah Leigh Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.19 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh commented on gene: SCAMP5: PMID 32020363 reports a homozygous variant (NM_001178111:c.271C>T, p.R91W rs747966691) in two sibs of a Chinese consanguienious family, with early onset epilepsy and Parkinson’s disease (the heterozygous parents had a normal phenotype). The p.R91W knock-in mouse showed typical early-onset epilepsy and functional studies showed dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain. The patients with this variant did not show signs of autism, intellectual disability, or other growth and developmental disorders.
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Green List (high evidence)
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
Early onset or syndromic epilepsy v2.18 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
Early onset or syndromic epilepsy v2.17 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.16 SCAMP5 Sarah Leigh Added comment: Comment on mode of inheritance: Based on the reporting of a de novo heterozygous varaiant (NM_001178111.1:c.538G>T) in two unrelated cases (PMID: 31439720) and a homozygous variant (NM_001178111:c.271C>T, rs747966691) in two members of a Chinese consanguienious family (PMID: 32020363).
Early onset or syndromic epilepsy v2.16 SCAMP5 Sarah Leigh Mode of inheritance for gene: SCAMP5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.15 SCAMP5 Sarah Leigh Mode of inheritance for gene: SCAMP5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.14 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347
Early onset or syndromic epilepsy v2.13 RNF13 Sarah Leigh reviewed gene: RNF13: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.13 RNF113A Sarah Leigh Classified gene: RNF113A as Green List (high evidence)
Early onset or syndromic epilepsy v2.13 RNF113A Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for X-linked trichothiodystrophy. At least 3 terminating variants reported in unrelated cases. Supportive functional studies also reported.
Early onset or syndromic epilepsy v2.13 RNF113A Sarah Leigh Gene: rnf113a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.12 RARS Sarah Leigh Classified gene: RARS as Green List (high evidence)
Early onset or syndromic epilepsy v2.12 RARS Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported in at least 9 cases of Hypomyelinating Leukodystrophy exhibinting epilepsy. Supportive functional studies were also reported.
Early onset or syndromic epilepsy v2.12 RARS Sarah Leigh Gene: rars has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.11 RARS Sarah Leigh commented on gene: RARS
Early onset or syndromic epilepsy v2.11 RARS Sarah Leigh Tag new-gene-name tag was added to gene: RARS.
Early onset or syndromic epilepsy v2.11 RALGAPA1 Sarah Leigh Classified gene: RALGAPA1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.11 RALGAPA1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for RALGAPA1-related neurodevelopmental disorder. At least 5 variants reported in at least 4 unrelated cases.
Early onset or syndromic epilepsy v2.11 RALGAPA1 Sarah Leigh Gene: ralgapa1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.10 RALGAPA1 Sarah Leigh Added comment: Comment on phenotypes: Intellectual disability;hypotonia;infantile spasms
Early onset or syndromic epilepsy v2.10 RALGAPA1 Sarah Leigh Phenotypes for gene: RALGAPA1 were changed from Intellectual disability; hypotonia; infantile spasms. to .Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation 618797
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Classified gene: PUM1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 SNVs in at least 5 unrelated cases and CNVs spanning PUM1 in 9 cases. Supportive functional studies also reported.
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Gene: pum1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.8 PUM1 Sarah Leigh Added comment: Comment on phenotypes: Global developmental delay;Intellectual disability;Seizures;Abnormality of the face;Ataxia;Cryptorchidism
Early onset or syndromic epilepsy v2.8 PUM1 Sarah Leigh Phenotypes for gene: PUM1 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism to Spinocerebellar ataxia 47 617931
Early onset or syndromic epilepsy v2.7 PUM1 Sarah Leigh Publications for gene: PUM1 were set to 29474920; 30903679; 31859446
Early onset or syndromic epilepsy v2.6 PIGP Sarah Leigh Classified gene: PIGP as Green List (high evidence)
Early onset or syndromic epilepsy v2.6 PIGP Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 2 variants reported (rs768633670, rs778481061). rs768633670 were reported as a compound heterozygotes in one case and was present in at least two geographically separated consanguineous European families; suggesting a founder effect in the European population (PMID 32042915).
Supportive functional studies are also presented.
Early onset or syndromic epilepsy v2.6 PIGP Sarah Leigh Gene: pigp has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.5 PIGP Sarah Leigh Phenotypes for gene: PIGP were changed from ?Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Early onset or syndromic epilepsy v2.4 PIGP Sarah Leigh Publications for gene: PIGP were set to 28334793; 31139695
Early onset or syndromic epilepsy v2.3 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
Early onset or syndromic epilepsy v2.3 SNIP1 Zornitza Stark reviewed gene: SNIP1: Rating: RED; Mode of pathogenicity: None; Publications: 22279524; Phenotypes: Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.3 DDC Lothar Schlueter gene: DDC was added
gene: DDC was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDC were set to 28100251; 30952622; 20505134; 19172410
Phenotypes for gene: DDC were set to Aromatic L-amino acid decarboxylase deficiency 608643; floppy child; dystonia; hypotonia; developmental delay; oculogyric crisis
Review for gene: DDC was set to GREEN
Added comment: Seizures are not a key symptom for aromatic L-amino acid decarboxylase deficiency (AADCD). However, some patients have seizures. Oculogyric crises, which are a key symptom, could be mistaken for epileptic seizures. In the review paper of Wassenberg et al. (2017) about 8% of AADCD patients suffer from seizures (9/117). Manegold et al. (2009) found 3 patients with seizures and corresponding EEG abnormalities in a cohort of 9 patients. They also point out, that it was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. Another review by Brun et al. (2010) mentions abnormal EEG in 10 out of 78 patients without further detail about seizures.
Sources: Literature
Early onset or syndromic epilepsy v2.3 Rebecca Foulger Panel version has been signed off
Early onset or syndromic epilepsy v2.0 TRAPPC4 Zornitza Stark reviewed gene: TRAPPC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31794024; Phenotypes: intellectual disability, epilepsy, spasticity, microcephaly; Mode of inheritance: None
Early onset or syndromic epilepsy v2.0 TMX2 Zornitza Stark reviewed gene: TMX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31735293, 31586943; Phenotypes: Microcephaly, ID, brain malformations, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 SNX27 Zornitza Stark reviewed gene: SNX27: Rating: GREEN; Mode of pathogenicity: None; Publications: 25894286, 31721175, 21300787, 23524343; Phenotypes: intellectual disability, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 PUM1 Zornitza Stark reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474920, 25768905, 30903679, 31859446; Phenotypes: intellectual disability, epilepsy, Spinocerebellar ataxia 47, MIM# 617931; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 PMPCB Zornitza Stark reviewed gene: PMPCB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29576218; Phenotypes: Multiple mitochondrial dysfunctions syndrome 6, MIM# 617954; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 OXR1 Zornitza Stark reviewed gene: OXR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31785787, 22028674; Phenotypes: Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay, MIM# 213000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 NSF Zornitza Stark reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: 31675180; Phenotypes: Seizures, EEG with burst suppression, Global developmental delay, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 KAT8 Zornitza Stark reviewed gene: KAT8: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31794431; Phenotypes: Intellectual disability, seizures, autism, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 SERPINI1 Zornitza Stark gene: SERPINI1 was added
gene: SERPINI1 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: SERPINI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SERPINI1 were set to 28631894; 25401298; 12103288
Phenotypes for gene: SERPINI1 were set to Encephalopathy, familial, with neuroserpin inclusion bodies MIM#604218
Review for gene: SERPINI1 was set to GREEN
gene: SERPINI1 was marked as current diagnostic
Added comment: >3 unrelated families with progressive myoclonus epilepsy
Sources: Expert list
Early onset or syndromic epilepsy v2.0 CERS1 Zornitza Stark reviewed gene: CERS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30800706, 21625621; Phenotypes: Epilepsy, progressive myoclonic, 8 MIM#616230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 RALGAPA1 Zornitza Stark gene: RALGAPA1 was added
gene: RALGAPA1 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: RALGAPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RALGAPA1 were set to 32004447
Phenotypes for gene: RALGAPA1 were set to Intellectual disability; hypotonia; infantile spasms.
Review for gene: RALGAPA1 was set to GREEN
gene: RALGAPA1 was marked as current diagnostic
Added comment: Four unrelated individuals reported.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 ALKBH8 Zornitza Stark reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079898; Phenotypes: Intellectual developmental disorder, autosomal recessive 71, MIM# 618504; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 SLC39A8 Zornitza Stark gene: SLC39A8 was added
gene: SLC39A8 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: SLC39A8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A8 were set to 26637978; 26637979
Phenotypes for gene: SLC39A8 were set to Congenital disorder of glycosylation, type IIn , MIM#16721
Review for gene: SLC39A8 was set to GREEN
gene: SLC39A8 was marked as current diagnostic
Added comment: 6 individuals from Hutterite descent and two other unrelated families reported. Seizures reported in 2 Hutterite individuals and also in the other two unrelated families.
Sources: Expert Review
Early onset or syndromic epilepsy v2.0 PIGS Zornitza Stark gene: PIGS was added
gene: PIGS was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: PIGS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGS were set to 30269814
Phenotypes for gene: PIGS were set to Glycosylphosphatidylinositol biosynthesis defect 18, MIM# 618143
Review for gene: PIGS was set to GREEN
gene: PIGS was marked as current diagnostic
Added comment: Three unrelated families reported. Severe neurological phenotype ranging from fetal akinesia (one family) to ID/EE (two families). Although pregnancies were terminated in one family, features observed in the affected fetuses suggest a severe neurological phenotype and hence we have rated this gene Green on our Epilepsy and our ID panels. I have added the gene to your CDG panel.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 WDR45B Zornitza Stark reviewed gene: WDR45B: Rating: GREEN; Mode of pathogenicity: None; Publications: 21937992, 28503735, 27431290; Phenotypes: Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, MIM# 617977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 UGP2 Zornitza Stark reviewed gene: UGP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31820119; Phenotypes: Epileptic encephalopathy, intellectual disability, microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 TUBA8 Zornitza Stark edited their review of gene: TUBA8: Added comment: Another affected individual reported as part of a bigger brain malformations cohort.; Changed publications: 31481326
Early onset or syndromic epilepsy v2.0 TRPM3 Zornitza Stark reviewed gene: TRPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31278393; Phenotypes: Intellectual disability, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 TIMM50 Zornitza Stark Deleted their comment
Early onset or syndromic epilepsy v2.0 TIMM50 Zornitza Stark commented on gene: TIMM50: At least 4 families reported, seizures in all reported individuals.
Early onset or syndromic epilepsy v2.0 TIMM50 Zornitza Stark edited their review of gene: TIMM50: Added comment: More families reported, supporting gene-disease association; note seizures reported in all.; Changed rating: GREEN; Changed publications: 27573165, 30190335, 31058414
Early onset or syndromic epilepsy v2.0 ST3GAL3 Zornitza Stark edited their review of gene: ST3GAL3: Added comment: Additional family reported recently with seizure phenotype.; Changed rating: AMBER; Changed publications: 23252400, 31584066
Early onset or syndromic epilepsy v2.0 SLC5A6 Zornitza Stark gene: SLC5A6 was added
gene: SLC5A6 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A6 were set to 31754459; 27904971
Phenotypes for gene: SLC5A6 were set to Developmental delay; epilepsy; neurodegeneration
Review for gene: SLC5A6 was set to GREEN
gene: SLC5A6 was marked as current diagnostic
Added comment: Two unrelated families reported, functional data and some evidence of response to treatment.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 SETD5 Zornitza Stark reviewed gene: SETD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29484850; Phenotypes: Intellectual disability, autosomal dominant 23 (MIM # 615761); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 SETD1B Zornitza Stark edited their review of gene: SETD1B: Added comment: Another individual with a de novo variant in this gene and epilepsy reported in 31440728 bringing the total to three, and possibly two more in 31685013.; Changed rating: GREEN; Changed publications: 29322246, 31440728, 31685013; Changed phenotypes: Epilepsy with myoclonic absences, intellectual disability; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 SETD1A Zornitza Stark gene: SETD1A was added
gene: SETD1A was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: SETD1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD1A were set to 31197650
Phenotypes for gene: SETD1A were set to Epilepsy
Review for gene: SETD1A was set to GREEN
gene: SETD1A was marked as current diagnostic
Added comment: Four unrelated families reported: in three, the variants occurred de novo, and in the fourth, it segregated with disease. Some functional data.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 RNF13 Zornitza Stark reviewed gene: RNF13: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30595371; Phenotypes: Epileptic encephalopathy, early infantile, 73, MIM# 618379; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 PTEN Zornitza Stark commented on gene: PTEN: Cowden and BRRS are germline PTEN-related conditions and can present with macrocephaly/neurodevelopmental phenotype in childhood, including ID/autism and sometimes seizures as outlined in the previous reviews. The associated cancer risk makes the condition important to diagnose.

There are also somatic PTEN-related conditions such as Proteus, but these are not under consideration for this panel. One of the reviews below refers to AKT1, which is confusing.
Early onset or syndromic epilepsy v2.0 NUP214 Zornitza Stark gene: NUP214 was added
gene: NUP214 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP214 were set to 31178128; 30758658
Phenotypes for gene: NUP214 were set to Encephalopathy, acute, infection-induced, susceptibility to, 9, MIM# 618426; epileptic encephalopathy; developmental regression; microcephaly
Review for gene: NUP214 was set to GREEN
gene: NUP214 was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 NEDD4L Zornitza Stark edited their review of gene: NEDD4L: Added comment: Seizures are a frequently reported feature in this brain development disorder.; Changed publications: 28515470, 23934111, 28212375, 27694961
Early onset or syndromic epilepsy v2.0 NEUROD2 Zornitza Stark gene: NEUROD2 was added
gene: NEUROD2 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: NEUROD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NEUROD2 were set to 30323019; 16504944
Phenotypes for gene: NEUROD2 were set to Epileptic encephalopathy, early infantile, 72, MIM# 618374
Review for gene: NEUROD2 was set to GREEN
gene: NEUROD2 was marked as current diagnostic
Added comment: Two unrelated individuals with de novo missense variants in this gene, two animal models.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 MTHFS Zornitza Stark reviewed gene: MTHFS: Rating: GREEN; Mode of pathogenicity: None; Publications: 30031689, 31844630, 22303332; Phenotypes: Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 MED17 Zornitza Stark reviewed gene: MED17: Rating: GREEN; Mode of pathogenicity: None; Publications: 30345598; Phenotypes: Microcephaly postnatal progressive with seizures and brain atrophy, 613668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 MAGI2 Zornitza Stark reviewed gene: MAGI2: Rating: RED; Mode of pathogenicity: None; Publications: 31056551; Phenotypes: Epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 GRIA2 Zornitza Stark reviewed gene: GRIA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31300657; Phenotypes: Intellectual disability, autism, Rett-like features, epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 GLS Zornitza Stark gene: GLS was added
gene: GLS was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: GLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLS were set to 30575854
Phenotypes for gene: GLS were set to Epileptic encephalopathy, early infantile, 71, MIM# 618328
Review for gene: GLS was set to AMBER
Added comment: Three individuals from two unrelated families reported with early neonatal refractory seizures, structural brain abnormalities and oedema; significantly increased glutamine levels.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 GABRB1 Zornitza Stark reviewed gene: GABRB1: Rating: ; Mode of pathogenicity: None; Publications: 23934111, 27273810, 31618474; Phenotypes: Epileptic encephalopathy, early infantile, 45, MIM# 617153; Mode of inheritance: None; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 FOXRED1 Zornitza Stark edited their review of gene: FOXRED1: Added comment: A couple more cases reported in the literature in 2019 bringing the total to 6, including another one with seizures are part of the phenotype (31434271).; Changed rating: GREEN; Changed publications: 20858599, 20818383, 31434271
Early onset or syndromic epilepsy v2.0 FGFR3 Zornitza Stark edited their review of gene: FGFR3: Added comment: This condition is well documented as being associated with epilepsy. It can be difficult to recognise clinically, particularly in infancy and therefore we consider this gene merits as much inclusion in an Epilepsy panel as other syndromic diagnoses (e.g. EFTUD2 etc).; Changed publications: 24630288, 27485793, 23649205, 12794698
Early onset or syndromic epilepsy v2.0 FDFT1 Zornitza Stark reviewed gene: FDFT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29909962; Phenotypes: Squalene synthase deficiency, MIM# 618156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 EXT2 Zornitza Stark reviewed gene: EXT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26246518, 30288735, 30997052; Phenotypes: Seizures, scoliosis, and macrocephaly syndrome, MIM# 616682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 DOLK Zornitza Stark edited their review of gene: DOLK: Added comment: Early presentation with seizures and demise reported in some individuals. Transferrin isoforms are not a reliable test in the newborn period to guide appropriate genomic analysis towards a CDG/metabolic panel; we also note the 25% recurrence risk, and hence we have included this gene as Green on our panel.; Changed publications: 23890587, 28816422, 24144945
Early onset or syndromic epilepsy v2.0 DMXL2 Zornitza Stark reviewed gene: DMXL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31688942, 30237576; Phenotypes: Epileptic encephalopathy, early infantile, 81, MIM# 618663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 DLL1 Zornitza Stark reviewed gene: DLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31353024; Phenotypes: Intellectual disability, autism, seizures, variable brain abnormalities, scoliosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 DEAF1 Zornitza Stark reviewed gene: DEAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30923367; Phenotypes: Dyskinesia, seizures, and intellectual developmental disorder 617171, autosomal dominant mental retardation 24, MIM# 615828; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.0 SCN8A Zornitza Stark reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31625145; Phenotypes: Epileptic encephalopathy, early infantile, 13, MIM# 614558, dominant and recessive; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 STXBP1 Zornitza Stark reviewed gene: STXBP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31855252; Phenotypes: Epileptic encephalopathy, early infantile, 4, MIM#612164; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 CPLX1 Zornitza Stark gene: CPLX1 was added
gene: CPLX1 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: CPLX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPLX1 were set to 26539891; 28422131
Phenotypes for gene: CPLX1 were set to Epileptic encephalopathy, early infantile, 63, MIM# 617976
Review for gene: CPLX1 was set to GREEN
gene: CPLX1 was marked as current diagnostic
Added comment: Five individuals from three unrelated families reported in larger neurodevelopmental cohorts.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 AGMO Zornitza Stark gene: AGMO was added
gene: AGMO was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: AGMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGMO were set to 31555905; 27000257
Phenotypes for gene: AGMO were set to microcephaly; intellectual disability; epilepsy
Review for gene: AGMO was set to AMBER
Added comment: Three unrelated families reported, though epilepsy not an invariable feature.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 NPRL2 Louise Daugherty Tag watchlist was removed from gene: NPRL2.
Early onset or syndromic epilepsy v2.0 NPRL2 Louise Daugherty commented on gene: NPRL2
Early onset or syndromic epilepsy v2.0 KIAA1109 Louise Daugherty Tag watchlist was removed from gene: KIAA1109.
Early onset or syndromic epilepsy v2.0 KIAA1109 Louise Daugherty commented on gene: KIAA1109
Early onset or syndromic epilepsy v2.0 KCNQ5 Louise Daugherty Tag watchlist was removed from gene: KCNQ5.
Early onset or syndromic epilepsy v2.0 KCNQ5 Louise Daugherty commented on gene: KCNQ5
Early onset or syndromic epilepsy v2.0 HNRNPR Louise Daugherty Tag watchlist was removed from gene: HNRNPR.
Early onset or syndromic epilepsy v2.0 HNRNPR Louise Daugherty commented on gene: HNRNPR
Early onset or syndromic epilepsy v2.0 GOT2 Louise Daugherty commented on gene: GOT2
Early onset or syndromic epilepsy v2.0 GOT2 Louise Daugherty Tag watchlist was removed from gene: GOT2.
Early onset or syndromic epilepsy v2.0 EIF2B3 Louise Daugherty Tag watchlist was removed from gene: EIF2B3.
Early onset or syndromic epilepsy v2.0 EIF2B3 Louise Daugherty commented on gene: EIF2B3
Early onset or syndromic epilepsy v2.0 EIF2B1 Louise Daugherty Tag watchlist was removed from gene: EIF2B1.
Early onset or syndromic epilepsy v2.0 EIF2B1 Louise Daugherty commented on gene: EIF2B1
Early onset or syndromic epilepsy v2.0 CSNK2B Louise Daugherty Tag watchlist was removed from gene: CSNK2B.
Early onset or syndromic epilepsy v2.0 CSNK2B Louise Daugherty commented on gene: CSNK2B
Early onset or syndromic epilepsy v2.0 CNPY3 Louise Daugherty Tag watchlist was removed from gene: CNPY3.
Early onset or syndromic epilepsy v2.0 CNPY3 Louise Daugherty commented on gene: CNPY3
Early onset or syndromic epilepsy v2.0 ARV1 Louise Daugherty Tag watchlist was removed from gene: ARV1.
Early onset or syndromic epilepsy v2.0 ARV1 Louise Daugherty commented on gene: ARV1
Early onset or syndromic epilepsy v2.0 AFF3 Louise Daugherty changed review comment from: As a result of watchlist tag audit the watchlist tag was removed from AFF3- this is now a green gene. Preprint information is now available Voisin et al, 2019; to: As a result of watchlist tag audit the watchlist tag was removed from AFF3- this is now a green gene. Preprint information is now available Voisin et al, 2019 https://www.biorxiv.org/content/10.1101/693937v1
Early onset or syndromic epilepsy v2.0 AFF3 Louise Daugherty Tag watchlist was removed from gene: AFF3.
Early onset or syndromic epilepsy v2.0 AFF3 Louise Daugherty commented on gene: AFF3
Early onset or syndromic epilepsy v2.0 TET3 Konstantinos Varvagiannis gene: TET3 was added
gene: TET3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TET3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007
Phenotypes for gene: TET3 were set to Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face
Penetrance for gene: TET3 were set to Complete
Review for gene: TET3 was set to AMBER
Added comment: Beck et al (2020 - DOI: https://doi.org/10.1016/j.ajhg.2019.12.007) report on individuals with monoallelic de novo or biallelic pathogenic TET3 variants.

For both inheritance modes (AR/AD) DD/ID were among the observed features (mild-severe - individuals from families 2, 4 and 6 for whom presence of ID was not commented, relevance to the current panel is suggested from the developmental milestones in the supplement. One individual presented DD without ID). Other features included hypotonia (in 8), ASD/autistic features (in 5), seizures (2 unrelated subjects for each inheritance mode). Postnatal growth abnormalities were observed in many, in most cases involving head size (with/without abnormal stature) and few presented abnormal prenatal growth. Variable movement disorders were observed in some. Some facial features appeared to be more common (eg. long face, tall forehead, etc).

Most were referred for their DD. Extensive prior genetic investigations had (mostly) come out normal (with possible contribution of a 16p11.2 dup in an individual with monoallelic variant or a 16q22 dup in another with biallelic TET3 variants). Monoallelic / biallelic variants in all subjects were identified following exome sequencing.

TET3 encodes a methylcytosine dioxygenase (the TET family consisting of 3 enzymes, TET1, TET2, TET3). These enzymes are involved in DNA demethylation through a series of reactions beginning with the conversion of 5-methyl cytosine [5mc] to 5-hydromethylcytosine [5hmC].

5 individuals from 3 families (1/3 consanguineous) harbored biallelic missense variants. 5 different missense variants were observed. Heterozygous parents appeared to be mildly affected (eg. having learning difficulties, etc).

6 individuals from 5 families harbored monoallelic variants [3 truncating (of which 2 localizing in the last exon), 2 missense SNVs]. In one family the variant was inherited from a similarly affected parent. In all other cases the variant had occured de novo. No additional TET3 variants were identified, with the limitations of WES.

All missense mutations, whether observed in individuals with biallelic or monoallelic variants, were located within the catalytic domain or - for a single variant (NM_001287491.1:c.2254C>T / p.Arg752Cys) - adjacent to it.

Functional studies were carried out only for (all) missense variants observed in individuals with biallelic variants. Conversion of 5mC to 5hmC is the first step in DNA demethylation. In HEK293 cells overexpressing either wt or variants, production of 5hmc was measured. 4/5 missense variants evaluated demonstrated a defect in converting 5mC to 5hmC, Arg752Cys being an exception (as also predicted by its localization).

DD/ID and abnormal growth are also features of disorders of the epigenetic machinery (DNA methylation machinery, histone machinery, chromatin remodelers, other chromatin-associated proteins). Similarly to TET3, both monoallelic and biallelic variants in KDM5B, encoding for another component of the epigenetic machinery, have been identified in individuals with ID.

Mouse models discussed by the authors [several Refs provided though not here reviewed] : The gene has been shown to be highly expressed in oocytes, zygotes and neurons and to play a role in demethylation of the paternal genome after fertilization. (From the MGI: 'mice inheriting a null allele from a germ cell conditional null mother display impaired reprogramming of the paternal genome resulting in reduced embryo viability'). Beck et al also note that Tet3 inhibition or depletion in differentiated neurons can impact synaptic function [PMIDs cited: 25915473, 24757058, 26711116].
Sources: Literature
Early onset or syndromic epilepsy v2.0 PIGP Konstantinos Varvagiannis edited their review of gene: PIGP: Added comment: Please consider upgrading this gene to Green.

In a recent study, Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.; Changed publications: 28334793, 31139695, https://doi.org/10.1212/NXG.0000000000000387
Early onset or syndromic epilepsy v2.0 CACNA2D2 Louise Daugherty commented on gene: CACNA2D2
Early onset or syndromic epilepsy v2.0 CACNA2D2 Louise Daugherty Tag watchlist was removed from gene: CACNA2D2.
Early onset or syndromic epilepsy v2.0 ASTN1 Zornitza Stark gene: ASTN1 was added
gene: ASTN1 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: ASTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASTN1 were set to 29706646; 27431290; 26539891
Phenotypes for gene: ASTN1 were set to Intellectual disability; epilepsy; cortical malformations
Review for gene: ASTN1 was set to GREEN
gene: ASTN1 was marked as current diagnostic
Added comment: Three families reported as part of large cohorts albeit proposing multiple novel candidate genes with minimal detail and no functional validation.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 ASNS Zornitza Stark gene: ASNS was added
gene: ASNS was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: ASNS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ASNS were set to Asparagine synthetase deficiency, MIM# 615574
Review for gene: ASNS was set to GREEN
Added comment: Encephalopathy, including seizures is a feature of this metabolic condition.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 APC2 Zornitza Stark reviewed gene: APC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31585108; Phenotypes: Cortical dysplasia, complex, with other brain malformations 10, MIM#618677; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.0 ADRA2B Zornitza Stark reviewed gene: ADRA2B: Rating: RED; Mode of pathogenicity: None; Publications: 24114805, 21937992; Phenotypes: Cortical myoclonus and epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 ADAM22 Zornitza Stark gene: ADAM22 was added
gene: ADAM22 was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: ADAM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAM22 were set to 27066583; 30237576
Phenotypes for gene: ADAM22 were set to Epileptic encephalopathy, early infantile, 61, MIM# 617933
Review for gene: ADAM22 was set to AMBER
Added comment: Two families reported; the second one as part of a large consanguineous cohort.
Sources: Expert list
Early onset or syndromic epilepsy v2.0 RNF113A Konstantinos Varvagiannis gene: RNF113A was added
gene: RNF113A was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RNF113A 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: RNF113A were set to 25612912; 31880405; 31793730; 29133357; 30506991; 15256591; 24026126; 23555887
Phenotypes for gene: RNF113A were set to ?Trichothiodystrophy 5, nonphotosensitive, 300953
Penetrance for gene: RNF113A were set to Complete
Review for gene: RNF113A was set to GREEN
Added comment: The gene has been reviewed for the ID panel. Seizures have been reported in 4 affected males from 3 families.

From the ID panel:
Nonphotosensitive trichothiodystrophy-5 (TTD5 - #300953) is caused by mutation in the RNF113A gene on Xq24. DD, ID and seizures are part of the phenotype in males. (Several) heterozygous females have not been reported to exhibit these features (DD/ID/seizures) although a single female in the first report had speech/motor delay and learning difficulties.

Corbett et al (2015 - PMID: 25612912) reported on 2 cousins with profound ID and epilepsy among other principal features of the disorder. Linkage analysis (probably low(?) LOD score) localized the gene to a 7.75 Mb region on Xq and subsequent Sanger and exome sequencing identified an RNF113A stopgain variant in both (NM_006978.2:c.901C>T / p.Q301*). Other X-chr variants did not segregate with the disorder. Previously sequencing of other trichothiodystrophy genes (in both) and CMA (X-chromosome BAC array / ISCA CMA) were non-diagnostic. The variant in this family was identified in a previous study (Tarpey et al 2009 - PMID: 19377476) but was 'incorrectly' discarded at the time due to a sequencing error in a control DNA sample (analysis repeated by Corbett et al). The same variant was also reported in 2 fetuses in a later report (PMID: 31793730).

Mendelsohn et al (2019 - PMID: 31880405) reported on 2 unrelated affected males. The 1st presented with severe DD/ID (independent walking at 7y, single words/non-verbal with with special educational needs at 11y), seizures as well as typical features of the disorder. Metabolic work-up (incl. 7-DHCR) and genetic testing (Allagile, PFIC genes, CMA) were non-diagnostic. Duo WES revealed a frameshift variant [c.903_910delGCAGACCCA / p.(Gln302fs*12)] inherited from the mother. Maternal XCI was completely skewed (100:0). The 2nd individual (briefly reported as REQ18-0616 by Monies et al - PMID: 31130284) presented global DD and seizures along with all other core features of the disorder at the age of 16m. Karyotype was normal. Exome revealed a frameshift variant [NM_006978.3:c.897_898delTG / p.(Cys299*)].

Further evidence is based on the role of the RNA113A, being involved in mRNA splicing (/spiceosome function) [Gatti da Silva et al 2018 - PMID: 30506991 & many other Refs] as well in DNA repair (E3 ubiquitin-protein ligase in a mechanism for sensing DNA damage induced by alkylation) [Brickner et al 2017 - PMID: 29133357]. In the latter study, LCLs from individuals harboring Q301* were shown to be hypersensitive to an alkylating agent (MMS) which was also the case for an RNF113A knockdown cell line. The cells had reduced ASCC alkylation repair complex foci formation, which was rescued upon reconstitution of patient cells with wt RNF113A.

Animal models :
Disruption of rnf113a in zebrafish resulted among others in small head and underdeveloped gut (PMID cited : 15256591 - Amsterdam et al) similar to the microcephaly observed in several individuals and/or abnormal gut development/diarrhoea reported in few.
Knockdown of the Drosophila ortholog (mdlc) led to reduced proliferation of neuroblasts. Neuronal differentiation was initiated but not completed. Expression of the full-length human gene rescued the CNS defects (discussed by Mendelsohn et al citing PMID: 24026126 - Carney et al). RNA-seq data from the same study were analyzed by Corbett et al, and differentialy expressed genes were enriched for genes involved in DNA damage response and repair.
Knockdown of RNF-113 in C.elegans sensitises cells to UVA-induced DNA damage. RNF-113 was shown to be involved in interstrand DNA crosslink repair and interact with a RAD51C homolog (PMID cited: 23555887 - Lee et al).

[Please consider upgrade/inclusion in other relevant panels eg. the 'Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome panel' where the gene has red rating].
Sources: Literature
Early onset or syndromic epilepsy v2.0 MTHFS Konstantinos Varvagiannis gene: MTHFS was added
gene: MTHFS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFS were set to 30031689; 31844630; 22303332; https://doi.org/10.1007/978-3-642-40337-8_10
Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367
Penetrance for gene: MTHFS were set to Complete
Review for gene: MTHFS was set to GREEN
Added comment: Biallelic pathogenic MTHFS variants cause Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (# 618367).

The gene encodes 5,10-Methenyltetrahydrofolate synthetase which catalyzes conversion of 5-formyltetrahydrofolate (5-FTHF or folinic acid) to 5,10-methenyltetrahydrofolate (5,10-MTHF).

At least 3 unrelated individuals have been reported. The phenotype appears to be relevant to both epilepsy and ID gene panels and the role of variants/the gene supported by enzymatic activity studies, 5-FTHF accumulation, 5,10-MTHF levels (low/low-normal), the role of folate metabolism pathway overall and some supporting (metabolic) evidence from the mouse model.
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Rodan et al (2018 - PMID: 30031689) reported on 2 individuals both presenting with microcephaly, severe global DD, epilepsy, progressive spasticity and cerebral hypomyelination upon MRI imaging. Short stature was also feature in both.

The 1st patient was an 8-year-old male who following exome sequencing was found to harbor 2 missense variants each inherited from a carrier parent. (NM_006441.3:c.434G>A / p.R145Q and c.107T>C / p.L36P). A further AFG3L2 indel was not felt to fit with his phenotype (and the onset of the related disorder appears to occur later).

Previous investigations included extensive metabolic testing, CMA, Angelman syndrome methylation analysis, GFAP, POLG1, TYMP sequencing, mitochondrial genome analysis and an XL-ID gene panel (further suggesting relevance of this gene to the current panel) were all non-diagnostic.

CSF 5-MTHF levels were initially on the low-normal range, subsequently found to be decreased (upon folinic acid supplementation) and later normalized upon use of another regimen.

MTHFS activity was measured in control fibroblasts as well as fibroblasts from this individual, with the latter demonstrating no enzyme activity. Accumulation (30x elevation) of 5-FTHF (the substrate of MTHFS) was demonstrated in patient fibroblasts.

The 2nd patient was a 11-year-old male with similar features incl. global DD (standing/walking/single words at/after 4 years of age, limited vocabulary and articulation upon last examination).

Extensive metabolic work-up as well as genetic testing for an epilepsy panel, vanishing white matter disease gene panel, mitochondrial genome as well as specific gene sequencing (LAMA2, POLR3A, POLR3B) were all non-diagnostic. Trio exome revealed 2 MTHFS variants in trans configuration (c.484C>T / p.Q162X and c.434G>A / p.R145Q).
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Romero et al (2019 - PMID: 31844630) reported on a 4-year-old female with congenital microcephaly, severe global DD (nonverbal/nonambulatory at the age of 4), spasticity, epilepsy and cerebral hypomyelination.

Extensive investigations prior to exome sequencing revealed macrocytic anemia, decreased CSF 5-MTHF and elevated neopterin, 2 CNVs of uncertain significance upon CMA with additional long ROH on chr15. Methylation studies were negative. The child was homozygous for c.220C>T / p.R74X (RefSeq is probably NM_006441.3. MTHFS lies on chr15. The parents were unrelated but came from the same town). There were no other candidate variants from the exome analysis.

Both articles discuss extensively the role of the folate metabolism pathway overall in nucleic acid synthesis, AA metabolism, neurotransmitter synthesis, methylation as well as 5-FTHF / 5,10-MTHF in particular in myelin stabilization and DNA synthesis (eg. according to Romero et al. a defect in MTHFS would impair myelin production and also lead to decreased myelin stability).
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A book chapter cited by Rodan et al (in N. Blau et al. (eds.), Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases - DOI: 10.1007/978-3-642-40337-8_10) included limited details on a patient with 'MTHFS gene mutation'. This individual had early speech delay, seizures beginning in infancy, ID, autistic features, recurrent infections and was found to have very low CSF 5-MTHF levels. [Details in p169 and table 10.6 - p173].
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In a mouse model reported by Field et al (2011 - PMID: 22303332), Mthfs was disrupted through insertion of a gene trap vector between the first 2 exons. Heterozygous [Mthfs(gt/+)] mice were fertile and viable. Mthfs protein levels were slightly but not statistically significantly reduced in tissues measured. No homozygous embryos were recovered following intercrosses of heterozygous mice, suggesting that Mthfs is an essential gene. Mouse embryonic fibroblasts from heterozygous mice [Mthfs (gt/+)] exhibited reduced de novo purine biosynthesis, but did not exhibit altered de novo thymidylate biosynthesis. Plasma folate levels were altered in heterozygous mice on a standard (/control) diet.

[Please consider inclusion in other possibly relevant panels e.g. for metabolic disorders]
Sources: Literature
Early onset or syndromic epilepsy v2.0 PUM1 Konstantinos Varvagiannis gene: PUM1 was added
gene: PUM1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PUM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PUM1 were set to 29474920; 30903679; 31859446
Phenotypes for gene: PUM1 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism
Penetrance for gene: PUM1 were set to unknown
Review for gene: PUM1 was set to GREEN
Added comment: 5 unrelated individuals with de novo pathogenic PUM1 variants have been reported in the literature. DD (5/5), ID (4/5 - relevant severity to the current panel), seizures (4/4 - absence/tonic-clonic, abnormal EEG) and variable other features (incl. facial dysmorphism, ataxia, cryptorchidism) appear to be part of the phenotype. 9 individuals with deletions spanning PUM1 and proximal genes presented similar features.

[1] PMID: 29474920 - Gennarino et al (2018)
[2] PMID: 30903679 - Bonnemason-Carrere et al (2019)
[3] PMID: 31859446 - Voet et al (2019) [with review of the literature]

SNVs in relevant individuals were identified by exome sequencing and were in all cases de novo.

Arg1147Trp was a recurrent variant reported in 3 unrelated subjects with ID and seizures (Refs 1,2,3 / NM_001020658.1:c.3439C>T). A nonsense variant was reported in an additional one with DD, ID, seizures and additional features (c.2509C>T / p.Arg837* - Ref3). One individual with a de novo missense variant (c.3416G>A / p.Arg1139Trp) with DD and ataxia, though without ID was reported in Ref1.

Details on 9 individuals with 0.3 - 5.6 Mb deletions spanning PUM1 and other genes are provided in Ref1. Features also included DD, ID, seizures, ataxia, etc.

Extensive initial investigations were reported for individuals in Refs 2 and 3 (various investigations incl. karyotype, SNP-array, targeted sequencing of OPHN1, KANSL1 or of a small panel of ID genes, biopsies and/or metabolic work-up) to rule out alternative causes. These only revealed a likely benign CNV and a GRIA3 SNV of uncertain significance in the case of an individual harboring the recurrent Arg1147Trp variant [Ref2].

Role of the gene (from OMIM):
Pumilio proteins, such as PUM1, negatively regulate gene expression by repressing translation of mRNAs to which they bind (Lee et al., 2016). A clinically significant PUM1 target is ataxin (ATXN1; 601556), mutation in which causes spinocerebellar ataxia-1 (SCA1; 601556).

Variant studies:
- Arg1147Trp was shown to be associated with normal PUM1 mRNA levels, but reduced (to ~43%) PUM1 protein levels in patient fibroblasts. ATXN1 mRNA and protein levels, as well as protein and/or mRNA levels of other PUM1 targets were shown to be increased (Ref1).
- In Ref1, in vitro transfection assays with wt or mt PUM1 were performed in HEK293T cells to evaluate repression of ATXN1 and E2F3. While overexpression of wt and Arg1147Trp were able to reduce ATXN1 and E2F3 levels, Arg1139Trp was not able to repress ATXN1 or E2F3.
- Upon overexpression in mouse hippocampal neurons, PUM1 missense mutations (among others Arg1139Trp and Arg1147Trp) were shown to alter neuronal morphology.

Overall haploinsufficiency is the proposed mechanism for the disorder for which the acronym PADDAS is used (Pumilio1-associated developmental disability, ataxia and seizure).

Milder mutations reducing PUM1 levels by 25% are associated with adult-onset ataxia without ID (PRCA or Pumilio1-related cerebellar ataxia) [Ref1].

Mouse models:
The role of PUM1 was first suggested in mouse models where Pum1 mutations were shown to lead to a SCA1-like phenotype (PMID cited : 12086639 - Watase et al 2002) further shown to be caused by increased Atxn1 mRNA and protein levels (PMID cited : 25768905 - Gennarino et al 2015).
The mouse model seems to recapitulate several of the features observed in affected individuals : Pum1 homozygous ko mice display among others hyperactivity, progressive cerebellar signs, spontaneous seizures as also observed in affected individuals (PMID cited : 25768905 - Gennarino et al 2015). Cryptorchidism was observed in 2 patients similar to testicular hypoplasia reported in Pum1 ko mice (PMID cited : 22342750 - Chen et al 2012).
- Heterozygous mice were evaluated in Ref1 with 69% or 75% exhibiting spontaneous seizures by the end of 30 or 35 wks respectively, with abnormal EEG activity already by 16 wks.

Additional individuals with PUM1 variants and a relevant phenotype of ID with or without seizures have been reported as part of the DDD study or as external submissions to Decipher and ClinVar :

https://decipher.sanger.ac.uk/search?q=PUM1#research-variants/results [ DDD4K.01387 participant ]
https://decipher.sanger.ac.uk/search?q=pum1#consented-patients/results [ external submission(s) ]
https://www.ncbi.nlm.nih.gov/clinvar/variation/431110/ [ splice-site variant in an individual with ID submitted prior to the 1st publication on the disorder ]
Sources: Literature
Early onset or syndromic epilepsy v2.0 DLL1 Konstantinos Varvagiannis gene: DLL1 was added
gene: DLL1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLL1 were set to 31353024
Phenotypes for gene: DLL1 were set to Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis
Penetrance for gene: DLL1 were set to unknown
Review for gene: DLL1 was set to AMBER
Added comment: Gene added to the ID panel. Epilepsy has been reported in 6 unrelated individuals. Please consider inclusion with amber/green rating.

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Heterozygous DLL1 pathogenic variants cause Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (# 618709).

Fischer-Zirnsak et al (2019 - PMID: 31353024) reported on 15 affected individuals from 12 unrelated families.

Most common features included DD/ID (12/14), ASD (6/14 - belonging to 6 families) or other behavioral abnormalities, seizures (6/14 - from 6 unrelated families) and various brain MRI abnromalities. As commented by OMIM (based on the same ref) "Cognitive function ranges from severely impaired to the ability to attend schools with special assistance". Among other features, scoliosis was observed in 4. The authors could not identify a distinctive facial gestalt.

Variable initial investigations (where discussed/performed - also suggesting relevance to the current panel) included CMA, FMR1, FLNA, mitochondrial DNA analysis and metabolic work-up but had not revealed an alternative cause.

The DLL1 variants were identified by WES (with the exception of a 122-kb microdeletion spanning DLL1 and FAM120B detected by CMA). Nonsense, frame-shift, splice-site variants in positions predicted to result to NMD were identified in most. One individual was found to harbor a missense variant (NM_005618.3:c.536G>T / p.Cys179Phe) and another the aforementioned microdeletion.

The variant in several individuals had occurred as a de novo event. In 2 families, it was inherited from an also affected parent (an unaffected sib was non-carrier) while in 3 families parental studies were not possible/complete.

In frame insertion of 4 residues was demonstrated for a splice site variant, from LCLs of the corresponding individual. For another individual, material was unavailable for mRNA studies. The missense variant affected a cysteine (of the DSL domain) conserved in all Notch ligands while AA changes affecting the same position of JAG1 (another Notch ligand) have been described in patients with Alagille s.

Based on the variants identified and reports of deletions spanning DLL1 in the literature, haploinsufficiency is the proposed underlying mechanism. The gene has also a pLI of 1 and %HI of 4.65.

DLL1 encodes the Delta-like canonical Notch ligand 1. Notch signaling is an established pathway for brain morphogenesis. Previous in vivo and in vitro studies have demonstrated the role of DLL1 in CNS. The gene is highly expressed in neuronal precursor cells during embryogenesis. Expression of Dll1 (and other molecules of the Notch signalling pathway) in an oscillatory/sustained pattern and cell-cell interactions important for this pathway have been demonstrated to play a role in neuronal differentiation. [Most discussed by Fischer-Zirnsak et al with several refs provided / also Gray et al., 1999 - PMID: 10079256 & OMIM].

Animal models as summarized by the authors:
[Mouse] Loss of Dll1 in mice has been shown to increase neuronal differentiation, cause CNS hyperplasia and increased number of neurons (PMIDs cited: 9109488, 12397111, 20081190). Reduced Dll1 expression was associated with scoliosis and mild vertebral defects (cited PMIDs: 19562077, 14960495, 22484060 / among others Dll1 haploinsufficiency and dominant negative models studied). Scoliosis and vertebral segmentation defects were features in 4 and 1 individual, respectively in the cohort of 15.
[Zebrafish] Homozygous mutations in dlA, the zebrafish ortholog, disrupted the Delta-Notch signaling and led to patterning defects in the hindbrain and overproduction of neurons (cited: 15366005).
Sources: Literature
Early onset or syndromic epilepsy v2.0 TFE3 Konstantinos Varvagiannis reviewed gene: TFE3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30595499, 31833172, https://doi.org/10.1126/scisignal.aax0926; Phenotypes: Global developmental delay, Intellectual disability, Abnormality of skin pigmentation, Coarse facial features, Seizures; Mode of inheritance: Other
Early onset or syndromic epilepsy v2.0 UGP2 Konstantinos Varvagiannis gene: UGP2 was added
gene: UGP2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UGP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGP2 were set to 31820119
Phenotypes for gene: UGP2 were set to Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face
Penetrance for gene: UGP2 were set to Complete
Review for gene: UGP2 was set to GREEN
Added comment: Perenthaler et al. (2019 - PMID: 31820119) provide evidence that homozygosity for a variant abolishing the start codon of the UGP2 transcript (NM_001001521.1) encoding the predominant (short) protein isoform in brain, leads to a severe epileptic encephalopathy.

This variant (chr2:64083454A>G / NM_001001521.1:c.1A>G - p.?) is also predicted to result in a substitution of a methionine at position 12 by a valine of the longer UGP2 transcript (NM_006759.3:c.34A>G - p.Met12Val).

The 2 isoforms differ only by 11 amino acids at the N-terminal and are otherwise expected to be functionally equivalent.

The authors provide details on 22 individuals from 15 families (some of which consanguineous).

Features included intractable seizures (in all), absence of developmental milestones (in all), progressive microcephaly, visual impairment. The authors reported also presence of somewhat similar facial features. Some of these individuals passed away early.

Previous work-up in several of them (incl. SNP-array, gene panel testing and metabolic investigations) had not revealed any abnormality, apart from ROH in some individuals. In all cases, the homozygous UGP2 SNV was the only P/LP variant for the neurodevelopmental phenotype following exome/genome sequencing. Segregation studies in affected/unaffected family members were compatible.

Families came from the Netherlands (but mostly from) India, Pakistan and Iran. Presence of a region of homozygosity shared between individuals from different families suggested that the variant might represent a mutation that originated several generations ago (in the area of Balochistan). The variant is present 15x in gnomAD, only in heterozygous state (in Asian mostly, reported once in Ashkenazi Jewish or Europeans) [ https://gnomad.broadinstitute.org/variant/2-64083454-A-G ].

UGP2 encodes UDP-glucose pyrophosphorylase which is an essential enzyme in sugar metabolism, catalyzing conversion of glucose-1-phosphate to UDP-glucose. UDP-glucose, in turn, serves as precursor for production of glycogen by glycogen synthase.

The authors provide several lines of evidence for a the role of the gene in the CNS as well as for the deleterious effect of the specific variant :
- In patient fibroblasts total UGP2 levels were not signifficantly different compared to parent / control fibroblasts, the longer isoform being upregulated (and stable) when the shorter is missing. Immunocytochemistry demonstrated similar localization of UGP2 in the case of mutant or wt cells. Enzymatic activity (/capacity to produce UDP-glucose) was similar between homozygous mut, heterozygous and wt fibroblasts.
- In H9-derived neural stem cells, Western Blot, RT-PCR and qRT-PCR suggested that the short isoform is the predominant one. (In embryonic stem cells, or fibroblasts the ratio between short and long isoform was lower).
- Analysis of RNA-seq data from human fetal tissues suggested that the short isoform is the predominant in brain.
- UGP2 was detected upon immunohistochemistry in fetal brain tissues from first to third trimester of pregnancy while Western Blot confirmed preferential expression of the shorter isoform.
- Homozygous embryonic (ESC) or neural stem cells (NSC) for the variant (knock-in/KI) or for a frameshift variant (knock-out/KO) were generated. Study of NSCs demonstrated reduced total UGP2 protein expression upon Western Blot in the case of KI cells and depleted in KO ones. Transcriptome analysis did not show major transcriptome alterations in KI/KO ESCs compared to wt. In NSC KI/KO cells transcriptome alterations were observed compared to wt with upregulation among others of genes for synaptic processes and genes implicated in epilepsy.
- The absence of UGP2 was shown to result in reduced ability of KO/KI NSCs to produce UDP-glucose, reduced capacity to synthesize glycogen under hypoxia (rescued in the case of KO cells by overexpression of wt or long isoform), defects of protein glycosylation as well as in increased unfolded protein response (/susceptibility to ER stress). These alterations are commented to be possibly implicated in pathogenesis of epilepsy, progressive microcephaly, etc.
- A CRISPR-Cas9 zebrafish model leading with loss of ugp2a and hypomorphic ugp2b (the zebrafish homologs of UGP2) demonstrated abnormal behavior, reduced eye movements and increased frequency/duration of movements upon stimulation with a potent convulsant (suggestive of increased seizure susceptibility).
- UGP knockout in drosophila is lethal while flies compound heterozygous for hypomorphic alleles are viable but show a movement defects due to altered synaptogenesis secondary to glycosylation defects (cited PMID: 27466186).
- The authors make speculations as for the occurrence of a single variant (and not others) eg. absence of UGP2 (in the case of LoF variants affecting both isoforms) would possibly be incompatible with life, Met12Val being tolerable for the long transcript not affecting stability/enzymatic activity (which may not be the case for other substitutions affecting Met12), etc.
Sources: Literature
Early onset or syndromic epilepsy v2.0 ADPRHL2 Louise Daugherty Tag new-gene-name tag was added to gene: ADPRHL2.
Early onset or syndromic epilepsy v2.0 ADPRHL2 Louise Daugherty commented on gene: ADPRHL2
Early onset or syndromic epilepsy v2.0 KAT8 Konstantinos Varvagiannis gene: KAT8 was added
gene: KAT8 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KAT8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KAT8 were set to 31794431
Phenotypes for gene: KAT8 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Penetrance for gene: KAT8 were set to unknown
Review for gene: KAT8 was set to GREEN
Added comment: Heterozygous pathogenic missense KAT8 variants have been reported in individuals with DD, ID and epilepsy. Variants occurred as de novo events within the chromobarrel or the acetyltransferase domain and were all shown to affect H4K16 acetylation, as would be predicted by the gene's function (lysine acetyltransferase). Evidence from brain specific Kat8 knockout in mouse, supports the role of the gene in brain development. One similarly affected individual compound heterozygous for a nonsense and a missense variant (the former affecting subnuclear localization and the latter H4K16ac) was also reported, with carrier relatives being unaffected. Mutations in genes of the MSL/NSL complexes (with which KAT8 forms multisubunit complexes) or genes in other acetyltransferases of the same subfamily (MYST) as KAT8 cause neurodevelopmental disorders [Details provided below].
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Li et al. (2019 - PMID: 31794431) report on 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants, as well as an additional one compound heterozygous for a nonsense and a missense one.

Overlapping phenotype consisted of DD/ID (8/8), seizures/epilepsy (6/8), brain MRI anomalies as well as presence of variable facial dysmorphic features. Less frequent features included abnormal vision (5/8), feeding difficulties (3/8), cardiac anomalies (3/8), autism (in 1).

The (9th) individual with biallelic variants had similar phenotype of DD/ID, epilepsy, autism and dysmorphic facial features. Heterozygous parents and sister, the latter carrier for the missense variant, were all unaffected.

All individuals had undergone exome sequencing, while extensive other investigations for at least 7/9 had only revealed variants of uncertain significance/contribution to the phenotype or were normal.

KAT8 encodes lysine acetyltransferase 8, which acetylates histone H4 at lysine 16 (H4K16). It belongs to the MYST subfamily of lysine acetyltransferases, the other members of which include KAT6A, KAT6B (both involved in neurodevelopmental disorders) and KAT5.

KAT8 forms two stoichiometric multisubunitcomplexes, one with the MSL complex and the other with the NSL. Mutations in genes encoding for subunits of the NSL or MSL complex (eg. KANSL1 and MSL3) are associated with neurodevelopmental disorders.

Overall 6 missense SNVs were reported among the heterozygous patients, p.Tyr90Cys (NM_032188.2:c.269A>G) being a recurrent one seen in 3. The compound heterozygous patient had a missense (c.973C>T / p.Arg325Cys) and a nonsense variant (c.523A>T / p.Lys175*). All missense variants lied either in the chromobarrel domain or the acetyltransferase domain. Variants in the latter domain localized within the KAT8/Mof-specific region or - in the case of the compound heterozygous individual - within the acetyl-CoA binding motif.

FLAG-tagged KAT8 (either wt or for all missense SNVs) was transfected in HEK293 cells with vectors for HA-tagged MSL proteins. While the nonsense variant was difficult to express, missense SNVs were expressed to similar levels to wt, promoted expression of MSL proteins but resulted in defective H4K16 acetylation and to a lesser extent H4K5 acetylation. As a result all missense variants impaired acetylation. This was also the case for chromobarrel domain variants, while expression of a KAT8 lacking the chromobarrel domain confirmed its ability to form complex with the MSL proteins and the impairment of H4K16 acetylation.

The nonsense variant demonstrated abnormal subnuclear localization.

The mouse model provides extensive evidence for the involvement of KAT8 in cerebral development. Cerebrum-specific Kat8 knockout mice presented postnatal growth retardation, hyperactivity/irritability, pre-weaning lethality, and cerebral hypoplasia upon autopsy. Loss of Kat8 reduced the number of neural stem and progenitor cells available for embryonic cerebrocortical development, impaired cell proliferation and stimulated apoptosis. The article also provides additional evidence from mouse model.
Sources: Literature
Early onset or syndromic epilepsy v2.0 RARS Konstantinos Varvagiannis gene: RARS was added
gene: RARS was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RARS were set to 31814314; 28905880; 24777941
Phenotypes for gene: RARS were set to Leukodystrophy, hypomyelinating, 9 616140
Penetrance for gene: RARS were set to Complete
Review for gene: RARS was set to GREEN
Added comment: Biallelic pathogenic RARS1 variants cause Leukodystrophy, hypomyelinating, 9 (# 616140).

The current review was based primarily on PMID: 31814314 (Mendes et al, 2019) providing details on 20 affected individuals from 15 families. 5 of these patients were included in a previous publication (Wolf et al, 2014 - PMID: 24777941) sharing authors with this study.

Clinical presentation and severity can be highly variable. However, among the 15 patients of relevant age (5/20 deceased at an early age), ID was observed in 13 (in 6/13 mild-moderate, in 7/13 severe/profound). Epilepsy was reported in half (10/20) with seizures being refractory to treatment in most and the phenotype corresponding to an infantile epileptic encephalopathy. DD and seizures were the presenting feature in 7 and 5 patients respectively, while in other cases presenting features were less specific (eg. failure to thrive in 1/20, irritabilty in 2/20). As a result the gene appears to be relevant to both DD/ID and epilepsy panels.

RARS1 encodes the cytoplasmic arginyl-tRNA synthetase 1, which is a component of the aminoacyl-tRNA synthetase complex (OMIM and Wolf et al, 2014 - PMID: 24777941). Aminoacyl-tRNA synthetases catalyze the aminoacylation ('charging') of tRNA by (with) their cognate amino acid.

Utilisation of alternative initiation codons, from a single mRNA transcript, results in translation of a long and a short protein isoform (Zheng et al 2006 - PMID: 16430231). The long isoform is needed for the formation of the multi-synthetase complex (MSC), while the short is free in the cytoplasm and does not have any interaction with the MSC. The long isoform appears to be essential for protein synthesis (discussed with several refs provided in PMID: 28905880 - Nafisinia et al, 2017).

The role of variants has been supported in several patients by additional studies - among others :
[PMID 31814314] Impaired Arginyl-tRNA synthetase activity was demonstrated in fibroblasts from 3 patients. Activity was normal in one additional individual compound heterozygous for a variant affecting initiation codon and a missense one. Western blot however demonstrated presence mainly of the short protein isoform. The authors suggest that this isoform possibly contributed to enzymatic activity. The long isoform which is needed for the MSC complex was only represented by a faint band in the Western Blot of the same individual.
[PMID: 28905880] Using fibroblasts from an affected subject homozygous for a missense variant (NM_002887.3:c.5A>G / p.Asp2Gly) and controls, a 75% reduction of the long isoform was shown upon WB. The short isoform was present at similar levels. As the N-terminus (of the long isoform) mediates interaction with the MSC (and AIMP1), assembly of the latter was 99% reduced in patient fibroblasts. Proliferation of patient fibroblasts was significantly reduced when cultured in a medium with limited arginine, a finding which was thought to reflect inefficient protein synthesis.

Mutations in other genes encoding for aminoacyl-tRNA synthetases (eg. AARS1, VARS1) or scaffolding proteins of the multisynthetase complex (eg. AIMP1 and AIMP2) lead to neurodevelopmental disorders with overlapping phenotype [most genes rated green in both the ID and epilepsy panel].
Sources: Literature
Early onset or syndromic epilepsy v2.0 AFF3 Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
----
As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature

---------------

Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb deletion affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
----
As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature

---------------

Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
Early onset or syndromic epilepsy v2.0 Rebecca Foulger promoted panel to version 2.0
Early onset or syndromic epilepsy v1.498 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Early onset or syndromic epilepsy v1.497 TRAPPC4 Konstantinos Varvagiannis gene: TRAPPC4 was added
gene: TRAPPC4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC4 were set to 31794024
Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment
Penetrance for gene: TRAPPC4 were set to Complete
Review for gene: TRAPPC4 was set to GREEN
Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant.

Overlapping features included feeding difficulties, progressive microcephaly, severe to profound developmental disability (7/7 - DD also prior to the onset of seizures / regression also reported in 3), epilepsy (7/7 - onset in the first year), spastic quadriparesis. Other findings in some/few incl. scoliosis, cortical visual and hearing impairment. Some facial features were shared (eg. bitemporal narrowing, long philtrum, open mouth with thin tented upper lip, pointed chin, etc). Brain imaging demonstrated abnormalities in those performed (among others cerebral with/without cerebellar atrophy).

Work-up prior to exome sequencing was normal (highly variable incl. metabolic testing, CMA, MECP2, CDKL5, mitochondrial depletion studies, etc).

Exome of affected individuals (and parents +/- affected sibs in some families) revealed a homozygous TRAPPC4 splicing variant [NM_016146.5:c.454+3A>G / chr11:g.118890966A>G (hg19)]. Sanger sequencing confirmed variant in affecteds, heterozygosity in parents and compatible genotypes with disease status in sibs/other members.

Families were of Caucasian/Turkish and French-Canadian ethnicities. SNP array to compare haplotypes between affecteds in 2 families did not reveal a shared haplotype (/founder effect) and the variant is present in gnomAD (68/281054 - no hmz) in many populations (European/Asian/African/Latino) [https://gnomad.broadinstitute.org/variant/11-118890966-A-G].

mRNA studies in fibroblasts from an affected individual confirmed the splicing defect (2 RT-PCR products corresponding to wt and a shorter due to skipping of exon 3, the latter further confirmed by Sanger sequencing. The shorter transcript is not present in controls). qPCR revealed that the normal transript in patient fibroblasts was present at 6% of the level observed in control fibroblasts (or 54% in the case of a heterozygote parent compared to controls).

Western blot in patient fibroblasts, revealed presence of full-length protein in significantly reduced levels compared to fibroblasts from carrier parents or controls. There was no band using an antibody targeting the N-terminal region of the protein prior to exon 3, suggesting that NMD applies (skipping of ex3 is also predicted to lead to frameshift).

TRAPPC4 encodes one of the core proteins of the TRAPP complex. Use of different accessory proteins leads to formation of 2 distinct complexes (TRAPPII / III). The complex has an important role in intracellular trafficking. Both TRAPPII & TRAPPIII have a function in the secretory pathway, while complex III has a role also in autophagy. Core proteins are important for the complex stability. The TRAPP complex serves as a GEF for Ypt/Rab GTPases [several refs in article].

Mutations in genes for other proteins of the complex lead to neurodevelopmental disorders with associated ID ('TRAPPopathies' used by the authors / TRAPPC12, C6B, C9 green in the current panel).

Western blot suggested that levels of other TRAPP subunits (TRAPPC2 or C12) under denaturing conditions, although PAGE/size exclusion chromatography suggested that the levels of fully-assembled TRAPP complexes were lower in affected individuals.

Studies in patient fibroblasts showed a secretory defect (between ER, Golgi and the plasma membrane) which was restored upon lentiviral transduction with wt TRAPPC4 construct. Basal and starvation-induced autophagy were also impaired in patient fibroblasts (increased LC3 marker and LC3-positive structures / impaired co-localization with lysosomes) partly due to defective autophagosome formation (/sealing).

TRAPPC4 is the human orthologue of the yeast Trs23. In a yeast model of reduced Trs23 (due to temperature instability) the authors demonstrated impaired assembly of the TRAPP core. The yeast model recapitulated the autophagy as well as well as the secretory defect observed in patient fibroblasts.
Sources: Literature
Early onset or syndromic epilepsy v1.497 SNX27 Konstantinos Varvagiannis gene: SNX27 was added
gene: SNX27 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SNX27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNX27 were set to 25894286; 31721175; 21300787; 23524343
Phenotypes for gene: SNX27 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: SNX27 were set to Complete
Review for gene: SNX27 was set to AMBER
Added comment: (From the ID panel)

Evidence from 2 publications suggests that DD, ID and seizures are part of the phenotype of individuals with biallelic SNX27 pathogenic variants :
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Damseh, Danson et al (2015 - PMID: 25894286) first reported on a consanguineous family with 4 affected sibs, homozygous for an SNX27 pathogenic variant. Features incl. hypotonia soon after birth, failure to thrive, severely delayed psychomotor development with no milestone acquisition, occurrence of myoclonic seizures with 3 individuals deceased early. Exome sequencing in one revealed a few candidate variants, with an SNX27 frameshift one [NM_030918.6:c.515_516del - p.(His172Argfs*6) / absent from ExAC] being the only retained following Sanger segregation studies. Using fibroblasts from an affected individual, Western blot with an antibody which would also bind prior to the truncation site, was consistent with dramatically reduced/absent SNX27 truncated mutant protein. Protein levels of VPS35, a component of the retromer responsible for direct cargo binding (not mediated by a cargo adaptor as SNX27), were normal.
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Parente et al (2019 - PMID: 31721175) reported on a 13-year-old male with motor and language delay, ADHD, ID (kindergarten academic level at the age of 13) and seizures with onset at the age of 9 years (GTC, with abnormal EEG and postical SV tachycardia). Variable physical findings were reported. White matter hyperintesities were noted upon initial brain MRI (but were less marked in subsequent ones). Initial genetic testing (Alexander's disease, CMA, FMR1) was normal. Exome revealed compound heterozygosity for 2 SNX27 variants (NM_030918.5/NM_001330723.1 both apply c.510C>G - p.Tyr170* and c.1295G>A - p.Cys432Tyr) each inherited from healthy carrier parents. There were no other potentially causative variants. A parental history of - isolated - late onset seizures was reported (so this individual may not be considered for the seizure phenotype here).

The authors also reported on a further 31-year old affected male. This individual had infantile hypotonia, poor eye contact with subsequent significant DD, seizures (febrile/afebrile T-C with onset at the age of 14m) and ID estimated in the severe range. Variable - though somewhat different - physical findings were reported. Initial work-up included basic metabolic testing, standard karyotype, FISH for 15q11 and subtelomeric regions and PHF6 genetic testing - all normal. Exome (and subsequent Sanger confirmation/parental studies) revealed compound heterozygosity for a missense and a frameshift variant (c.989G>A / p.Arg330His and c.782dupT / p.Leu262Profs*6 same in NM_001330723.1, NM_030918.6).
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SNX27 encodes sorting nexin 27, a cargo adaptor for the retromer. The latter is a multi-protein complex essential for regulating the retrieval and recycling of transmembrane cargos from endosomes to the trans-Golgi network or the plasma membrane [Lucas et al 2016 - PMID: 27889239 / McNally et al 2018 - PMID: 30072228].

As summarized by Parente et al, the encoded protein by regulating composition of the cell surface influences several processes eg. neuronal excitability, synaptic plasticity, Wnt signaling etc. It has been shown to interact with surface receptors and their ligands including GIRK channels, 5-HT4, ionotropic glutamate receptors (incl. NMDA- and AMPA-type receptors) and mGluR5 [several refs. provided].

Knockout of Snx27 in mice resulted in embryonic lethality (16% hmz of the 25% expected), severe postnatal growth retardation and death within the first 3 weeks. Snx27(+/-) mice have normal neuroanatomy but exhibit cognitive deficits (in learning and memory) and defects in synaptic function/plasticity with reduced amounts of NMDA and AMPA receptors (Cai et al - PMID: 21300787, Wang et al - PMID: 23524343).
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There is no associated phenotype in OMIM/G2P.
Sources: Literature
Early onset or syndromic epilepsy v1.497 OXR1 Konstantinos Varvagiannis gene: OXR1 was added
gene: OXR1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002
Phenotypes for gene: OXR1 were set to Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum
Penetrance for gene: OXR1 were set to Complete
Review for gene: OXR1 was set to GREEN
Added comment: Wang et al (2019 - https://doi.org/10.1016/j.ajhg.2019.11.002 ) report on 5 individuals (from 3 families) with biallelic OXR1 LoF variants.

Common features included hypotonia (4/5), severe global DD (5/5) and speech delay (5/5), ID (5/5), epilepsy (5/5) with cerebellar dysplasia/atrophy (5/5) and in some scoliosis.

All were investigated by exome sequencing and were found to harbor biallelic loss-of-function variants (2 splice-site, a stopgain and a frameshift one) either in homozygosity (2 consanguineous families) or in compound heterozygosity. In all cases parental segregation studies were compatible and in one family, an unaffected sib shown to be carrier.

Althouhgh OXR1 has been shown to affect several processes (among others DNA lesions induced by oxidative stress in E.coli, neuronal maintenance, mitochondrial morphology and DNA maintenance, etc), its mechanism of action is still not well defined. There are 6 RefSeq transcripts, the longest (NM_018002.3) encoding 3 protein domains (LysM, GRAM, TLDc). The TLDc domain is encoded by all transcripts.

Identified variants affected (probably all - fig1D) transcripts expressed in the CNS, namely NM_018002.3, NM_001198532.1, NM_181354.4. The 3 transcripts not expressed in the CNS are NM_001198533.1, NM_001198534.1 and NM_001198535.1.

Western blot with 2 different antibodies which would bind upstream of the truncation site failed to detect presence of truncated proteins in 2 affected individuals from 2 families.

The Drosophila homolog of OXR is mustard (mtd). The authors provide evidence that loss of mtd is lethal. This was however rescued by expression of an 80kb fly BAC clone covering mtd, or the fly mtd-RH isoform cDNA, or a short human OXR1 cDNA containing only the TLDc domain or a human NCOA7 cDNA. The latter is another human mtd homolog which also contains the TLDc domain. As a result the TLDc domain compensated sufficiently for loss of mtd.

Flies that survived displayed bang sensitivity and climbing defects the former assay being suggestive of susceptibility to seizures and the latter of impaired neurological/muscular function.

The authors provided evidence that mtd is broadly expressed in the fly CNS. RNAi mediated mtd knockdown specific to neurons (elav/nSyb-GAL4 expression of mtd RNAi) led to lethal eclosion defects for RNAis targeting most (18)/all(23) mtd isoforms. Lifespan was increased upon expression of human OXR1 cDNA. Neuronal loss and vacuolization was demonstrated and additional experiments in R7 photoreceptors showed presence of aberrant lysosomal structures (autolysosomes, autophagosomes and/or endolysosomes).

Aberrant lysosomal structures were also observed in fibroblasts from affected individuals (accumulation of lysosomes and/or presence of highly aberrant compartments with content typical of lysosomal dysfunction).

Overall the data presented suggest a critical role for OXR1 in lysosomal biology.

Although previous reports suggested that OXR1 is involved in oxidative stress resistance, studies performed by the authors suggested that oxidative stress is probably not the driver of the mutant fly defects.
Sources: Literature
Early onset or syndromic epilepsy v1.497 PCYT2 Ellen McDonagh reviewed gene: PCYT2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.497 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Early onset or syndromic epilepsy v1.496 WWOX Rebecca Foulger Publications for gene: WWOX were set to Tabarki (2015) Ben-Salam (2015) Mignot (2015)
Early onset or syndromic epilepsy v1.495 WWOX Rebecca Foulger Phenotypes for gene: WWOX were changed from to Epileptic encephalopathy, early infantile, 28, 616211
Early onset or syndromic epilepsy v1.494 WDR45 Rebecca Foulger Phenotypes for gene: WDR45 were changed from to Neurodegeneration with brain iron accumulation 5, 300894
Early onset or syndromic epilepsy v1.493 WDR45 Rebecca Foulger Publications for gene: WDR45 were set to Saitsu et al (2013) Nat Genet. 45(4):445-9
Early onset or syndromic epilepsy v1.492 STX1B Rebecca Foulger Phenotypes for gene: STX1B were changed from to Generalized epilepsy with febrile seizures plus, type 9, 616172
Early onset or syndromic epilepsy v1.491 STX1B Rebecca Foulger Mode of inheritance for gene: STX1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.490 SLC6A1 Rebecca Foulger Phenotypes for gene: SLC6A1 were changed from to Myoclonic-atonic epilepsy, 616421
Early onset or syndromic epilepsy v1.489 SLC6A1 Rebecca Foulger Publications for gene: SLC6A1 were set to Carvill et al (2015) Am J Hum Genet 96(5): 808-15
Early onset or syndromic epilepsy v1.488 PNPO Rebecca Foulger Phenotypes for gene: PNPO were changed from to Pyridoxamine 5'-phosphate oxidase deficiency, 610090
Early onset or syndromic epilepsy v1.487 NDUFS8 Rebecca Foulger Phenotypes for gene: NDUFS8 were changed from Mitochondrial complex I deficiency, nuclear type 2, 618222 to Mitochondrial complex I deficiency, nuclear type 2, 618222; Leigh syndrome due to mitochondrial complex I deficiency
Early onset or syndromic epilepsy v1.486 NDUFS8 Rebecca Foulger Phenotypes for gene: NDUFS8 were changed from to Mitochondrial complex I deficiency, nuclear type 2, 618222
Early onset or syndromic epilepsy v1.485 DNM1 Rebecca Foulger Mode of inheritance for gene: DNM1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.484 DNM1 Rebecca Foulger Publications for gene: DNM1 were set to EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11
Early onset or syndromic epilepsy v1.483 DNM1 Rebecca Foulger Phenotypes for gene: DNM1 were changed from to Epileptic encephalopathy, early infantile, 31, 616346
Early onset or syndromic epilepsy v1.482 CYFIP2 Rebecca Foulger Mode of pathogenicity for gene: CYFIP2 was changed from None to Other
Early onset or syndromic epilepsy v1.481 CYFIP2 Rebecca Foulger Publications for gene: CYFIP2 were set to 29534297
Early onset or syndromic epilepsy v1.480 CYFIP2 Rebecca Foulger Phenotypes for gene: CYFIP2 were changed from to Epileptic encephalopathy, early infantile, 65, 618008
Early onset or syndromic epilepsy v1.479 CSTB Rebecca Foulger Publications for gene: CSTB were set to
Early onset or syndromic epilepsy v1.478 CSTB Rebecca Foulger Phenotypes for gene: CSTB were changed from to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800
Early onset or syndromic epilepsy v1.477 PNPT1 Konstantinos Varvagiannis gene: PNPT1 was added
gene: PNPT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PNPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPT1 were set to 31752325
Phenotypes for gene: PNPT1 were set to Combined oxidative phosphorylation deficiency 13, MIM 614932
Penetrance for gene: PNPT1 were set to Complete
Review for gene: PNPT1 was set to GREEN
Added comment: Reviewed for the intellectual disability panel. Seizures may be observed in affected individuals (details below). Please consider inclusion with amber / green rating.

---

Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.
Sources: Literature
Early onset or syndromic epilepsy v1.477 SCAMP5 Ellen McDonagh Added comment: Comment on mode of pathogenicity: A dominant negative effect is predicted.
Early onset or syndromic epilepsy v1.477 SCAMP5 Ellen McDonagh Mode of pathogenicity for gene: SCAMP5 was changed from Other to Other
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Classified gene: SCAMP5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Added comment: Comment on list classification: Gene added by external Reviewer, and promoted to Amber due to review and overall evidence.
Early onset or syndromic epilepsy v1.476 SCAMP5 Ellen McDonagh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.475 TMX2 Konstantinos Varvagiannis gene: TMX2 was added
gene: TMX2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31735293; 31270415
Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration
Penetrance for gene: TMX2 were set to Complete
Review for gene: TMX2 was set to GREEN
Added comment: This gene was reviewed for the intellectual disability panel. Epilepsy is part of the phenotype. Therefore green rating should be considered.

From the ID panel :
A recent report by Vandervore, Schot et al. following the previous review (Am J Hum Genet. 2019 Nov 12 - PMID: 31735293), provides further evidence that biallelic TMX2 mutations cause malformations of cortical development, microcephaly, DD and ID and epilepsy.

As a result this gene should probably be considered for inclusion in the ID/epilepsy panels with green rating.

Overall, 14 affected subjects from 10 unrelated families are reported in the aforementioned study. The majority had severe DD/ID (failure to achieve milestones, absent speech/ambulation and signs of cerebral palsy) with few having a somewhat milder impairment. 12 (of the 14) presented with epilepsy (spasms, myoclonic seizures, focal seizures with/without generalization or generalized tonic-clonic seizures) with onset most often in early infancy. Upon brain MRI (in 12 individuals), 5 presented polymicrogyria, 2 others pachygyria, 4 with brain atrophy, etc.

All individuals were found to harbor biallelic TMX2 mutations by exome sequencing while previous investigations in several had ruled out alternative causes (infections, metabolic or chromosomal anomalies). Missense variants, an in-frame deletion as well as pLoF (stopgain/frameshift) variants were reported. [NM_015959.3 used as ref below].

The effect of variants was supported by mRNA studies, eg. RT-qPCR/allele specific RT-qPCR. The latter proved reduced expression for a frameshift variant (c.391dup / p.Leu131Profs*6) most likely due to NMD. Total mRNA levels were also 23% lower in an individual compound htz for a missense variant and a stopgain one localized in the last exon (c.757C>T / p.Arg253*). As for the previously reported c.614G>A (p.Arg205Gln), affecting the last nucleotide of exon 6, total mRNA in skin fibroblasts from a homozygous individual was not significantly decreased. RNA-Seq however demonstrated the presence of 4 different transcripts (roughly 25% each), one representing the regular mRNA, one with intron 6 retention (also present at low levels in healthy individuals), one with loss of 11 nucleotides within exon 6 and a fourth one due to in-frame skipping of exon 6.

*To the best of my understanding :

Thioredoxin (TRX)-related transmembrane proteins (TMX) belong to the broader family of oxidoreductases of protein disulfide isomerase (PDI) having an important role in protein folding.

Study of the data from the Allen Human Brain Atlas suggest relevant fetal expression also increasing during postnatal life.

As RNA-seq was carried out for 2 individuals, GO analysis suggested that the most deregulated clusters of genes are implicated in post-translational protein modifications (as would be expected for PDIs), membranes and synapse while pathway analysis suggested that relevant categories were inhibited eg. nervous system development/function and cell growth/proliferation/survival.

Upon transfection of HEK293T cells, exogenous TMX2 was shown to co-localize with calnexin (CNX) to the (ER) mitochondria-associated-membrane. Mass-spectrometry based analysis of co-immunoprecipitated proteins confirmed interaction with CNX but also other regulators of calcium homeostasis, mitochondrial membrane components and respiratory chain NADH dehydrogenase.

Study of the mitochondrial activity of TMX2-deficient fibroblasts suggested reduced respiratory reserve capacity, compensated by increased glycolytic activity.

TMX2 occurs in both reduced and oxidized monomeric form. It also forms (homo)dimers with the ratio of dimers/monomers increasing under conditions of oxidative stress. Variant TMX2 increased propensity to form dimers, thus mimicking increased oxidative state. This was observed under stress but also under native conditions.

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Created: 26 Nov 2019, 11:21 p.m. | Last Modified: 26 Nov 2019, 11:21 p.m.
Panel Version: 2.1122

[Previous review]

PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI.

All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones.

Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families).

Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks.

The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals).

This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven.

TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article.

As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging).
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Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism).
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There is no associated phenotype in OMIM/G2P/SysID.
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Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence.
Sources: Literature
Sources: Literature
Early onset or syndromic epilepsy v1.475 IDH2 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green.Refers to glioma patients: not a seizure disorder. Demoted from Green to RED.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Refers to glioma patients- not a seizure disorder. Demoted from Green to RED.
Early onset or syndromic epilepsy v1.475 CYP27A1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.475 SCN9A Rebecca Foulger Publications for gene: SCN9A were set to 19763161; 29500686
Early onset or syndromic epilepsy v1.474 FLNA Rebecca Foulger changed review comment from: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was notes that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.; to: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was noted that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.
Early onset or syndromic epilepsy v1.474 PEX6 Rebecca Foulger Classified gene: PEX6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.474 PEX6 Rebecca Foulger Gene: pex6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.473 PEX6 Rebecca Foulger commented on gene: PEX6: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.473 PEX3 Rebecca Foulger Classified gene: PEX3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.473 PEX3 Rebecca Foulger Gene: pex3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.472 PEX3 Rebecca Foulger commented on gene: PEX3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.472 PEX2 Rebecca Foulger Classified gene: PEX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.472 PEX2 Rebecca Foulger Gene: pex2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.471 PEX2 Rebecca Foulger commented on gene: PEX2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.471 PEX19 Rebecca Foulger Classified gene: PEX19 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.471 PEX19 Rebecca Foulger Gene: pex19 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.470 PEX19 Rebecca Foulger commented on gene: PEX19: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.470 PEX13 Rebecca Foulger Classified gene: PEX13 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.470 PEX13 Rebecca Foulger Gene: pex13 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.469 PEX13 Rebecca Foulger commented on gene: PEX13: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that PEX genes are better tested through the metabolic panel, and should be demoted to Amber.
Early onset or syndromic epilepsy v1.469 BSCL2 Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should change from 'BOTH monoallelic and biallelic' to 'BIALLELIC': just one monoallelic case so far, which could be a false positive.
Early onset or syndromic epilepsy v1.469 BSCL2 Rebecca Foulger Mode of inheritance for gene: BSCL2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.468 NDUFA1 Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should be updated from XLR to XLD.
Early onset or syndromic epilepsy v1.468 NDUFA1 Rebecca Foulger Mode of inheritance for gene: NDUFA1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.467 NSDHL Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should remain as XLR.
Early onset or syndromic epilepsy v1.467 NSDHL Rebecca Foulger Mode of inheritance for gene: NSDHL was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.466 ADAR Rebecca Foulger Added comment: Comment on mode of inheritance: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that MOI should remain as BIALLELIC: No current evidence for seizures in monoallelic cases.
Early onset or syndromic epilepsy v1.466 ADAR Rebecca Foulger Mode of inheritance for gene: ADAR was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.465 DNAJC5 Rebecca Foulger Classified gene: DNAJC5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.465 DNAJC5 Rebecca Foulger Gene: dnajc5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.464 DNAJC5 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures present later. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.464 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.464 SGSH Rebecca Foulger commented on gene: SGSH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.464 EXT2 Rebecca Foulger Classified gene: EXT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.464 EXT2 Rebecca Foulger Gene: ext2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.463 EXT2 Rebecca Foulger commented on gene: EXT2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures not a presenting feature. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.463 CLPB Rebecca Foulger Classified gene: CLPB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.463 CLPB Rebecca Foulger Gene: clpb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.462 CLPB Rebecca Foulger commented on gene: CLPB: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Although there are three cases, most patients don't have seizures. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.462 TMEM70 Rebecca Foulger Classified gene: TMEM70 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.462 TMEM70 Rebecca Foulger Gene: tmem70 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.461 TMEM70 Rebecca Foulger commented on gene: TMEM70: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Insufficient seizure evidence. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.461 SLC6A19 Rebecca Foulger Classified gene: SLC6A19 as Red List (low evidence)
Early onset or syndromic epilepsy v1.461 SLC6A19 Rebecca Foulger Gene: slc6a19 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.460 SLC6A19 Rebecca Foulger commented on gene: SLC6A19: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Epilepsy is not a key feature. Demoted from Green to Red.
Early onset or syndromic epilepsy v1.460 SLC35A1 Rebecca Foulger Publications for gene: SLC35A1 were set to 23873973; 15576474; 28856833; 30115659
Early onset or syndromic epilepsy v1.459 SLC35A1 Rebecca Foulger Classified gene: SLC35A1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.459 SLC35A1 Rebecca Foulger Gene: slc35a1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.458 SLC35A1 Rebecca Foulger commented on gene: SLC35A1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.458 SCO2 Rebecca Foulger Publications for gene: SCO2 were set to 10545952; 10749987; 18924171
Early onset or syndromic epilepsy v1.457 SCO2 Rebecca Foulger Classified gene: SCO2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.457 SCO2 Rebecca Foulger Gene: sco2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.456 SCO2 Rebecca Foulger commented on gene: SCO2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.456 SCO1 Rebecca Foulger Classified gene: SCO1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.456 SCO1 Rebecca Foulger Gene: sco1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.455 SCO1 Rebecca Foulger commented on gene: SCO1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.455 QDPR Rebecca Foulger Classified gene: QDPR as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.455 QDPR Rebecca Foulger Gene: qdpr has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.454 QDPR Rebecca Foulger commented on gene: QDPR: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.454 PRODH Rebecca Foulger Classified gene: PRODH as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.454 PRODH Rebecca Foulger Gene: prodh has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.453 PRODH Rebecca Foulger commented on gene: PRODH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.453 PEX7 Rebecca Foulger Classified gene: PEX7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.453 PEX7 Rebecca Foulger Gene: pex7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.452 PEX7 Rebecca Foulger commented on gene: PEX7: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.452 PEX12 Rebecca Foulger Classified gene: PEX12 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.452 PEX12 Rebecca Foulger Gene: pex12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.451 PEX12 Rebecca Foulger commented on gene: PEX12: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted all PEX genes from Green to Amber.
Early onset or syndromic epilepsy v1.451 PEX10 Rebecca Foulger Publications for gene: PEX10 were set to 20695019
Early onset or syndromic epilepsy v1.450 PEX10 Rebecca Foulger Classified gene: PEX10 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.450 PEX10 Rebecca Foulger Gene: pex10 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.449 PEX10 Rebecca Foulger commented on gene: PEX10: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted all PEX genes from Green to Amber.
Early onset or syndromic epilepsy v1.449 PEX1 Rebecca Foulger Classified gene: PEX1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.449 PEX1 Rebecca Foulger Gene: pex1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.448 PEX1 Rebecca Foulger commented on gene: PEX1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted all PEX genes from Green to Amber.
Early onset or syndromic epilepsy v1.448 MTR Rebecca Foulger Classified gene: MTR as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.448 MTR Rebecca Foulger Gene: mtr has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.447 MTR Rebecca Foulger commented on gene: MTR: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Metabolic phenotype with failure to thrive, with seizures presenting later. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.447 IDH2 Rebecca Foulger Classified gene: IDH2 as Red List (low evidence)
Early onset or syndromic epilepsy v1.447 IDH2 Rebecca Foulger Gene: idh2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.446 IDH2 Rebecca Foulger commented on gene: IDH2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green.Refers to glioma patients: not a seizure disorder. Demoted from Green to RED.
Early onset or syndromic epilepsy v1.446 HLCS Rebecca Foulger Classified gene: HLCS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.446 HLCS Rebecca Foulger Gene: hlcs has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.445 HLCS Rebecca Foulger commented on gene: HLCS: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.445 GSS Rebecca Foulger Classified gene: GSS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.445 GSS Rebecca Foulger Gene: gss has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.444 GSS Rebecca Foulger commented on gene: GSS: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.444 GLYCTK Rebecca Foulger Classified gene: GLYCTK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.444 GLYCTK Rebecca Foulger Gene: glyctk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.443 GLYCTK Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Bordeline cases from literature, variable phenotype and needs better genotype:phenotype correlation. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.443 GLYCTK Rebecca Foulger commented on gene: GLYCTK: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.443 GFM1 Rebecca Foulger Classified gene: GFM1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.443 GFM1 Rebecca Foulger Gene: gfm1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.442 GFM1 Rebecca Foulger commented on gene: GFM1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.442 GCH1 Rebecca Foulger Classified gene: GCH1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.442 GCH1 Rebecca Foulger Gene: gch1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.441 GCH1 Rebecca Foulger commented on gene: GCH1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.441 FH Rebecca Foulger Classified gene: FH as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.441 FH Rebecca Foulger Gene: fh has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.440 FH Rebecca Foulger commented on gene: FH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.440 FAR1 Rebecca Foulger Classified gene: FAR1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.440 FAR1 Rebecca Foulger Gene: far1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.439 FAR1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Borderline evidence and variable phenotype. Requires better genotype:phenotype correlation. Demoted from Green to Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.439 FAR1 Rebecca Foulger commented on gene: FAR1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Borderline evidence and variable phenotype. Requires better genotype:phenotype correlation. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.439 DOLK Rebecca Foulger Classified gene: DOLK as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.439 DOLK Rebecca Foulger Gene: dolk has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.438 DOLK Rebecca Foulger commented on gene: DOLK: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.438 CYP27A1 Rebecca Foulger Classified gene: CYP27A1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.438 CYP27A1 Rebecca Foulger Gene: cyp27a1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.437 CYP27A1 Rebecca Foulger commented on gene: CYP27A1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.437 PTS Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Seizures may present before 9 months, and could be the primary presentation in these cases. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Seizures may present before 9 months, and could be the primary presentation in these cases. Since the last group review, PTS has also been promoted to Green on the 'Inborn errors of metabolism' panel (v 1.407). Promoted PTS from Amber to Green on the epilepsy panel.
Early onset or syndromic epilepsy v1.437 PTS Rebecca Foulger Classified gene: PTS as Green List (high evidence)
Early onset or syndromic epilepsy v1.437 PTS Rebecca Foulger Gene: pts has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.436 PTS Rebecca Foulger commented on gene: PTS: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Seizures may present before 9 months, and could be the primary presentation in these cases. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.436 RRM2B Rebecca Foulger commented on gene: RRM2B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Kept rating as Amber.
Early onset or syndromic epilepsy v1.436 PEX5 Rebecca Foulger commented on gene: PEX5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Kept rating as Amber.
Early onset or syndromic epilepsy v1.436 GTPBP3 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Kept rating as Amber.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Kept rating as Amber.
Early onset or syndromic epilepsy v1.436 GTPBP3 Rebecca Foulger commented on gene: GTPBP3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Kept rating as Amber.
Early onset or syndromic epilepsy v1.436 DPM2 Rebecca Foulger commented on gene: DPM2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Kept rating as Amber.
Early onset or syndromic epilepsy v1.436 SCN9A Rebecca Foulger Classified gene: SCN9A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.436 SCN9A Rebecca Foulger Gene: scn9a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.435 SCN9A Rebecca Foulger commented on gene: SCN9A: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted SCN9A from Green to Amber.
Early onset or syndromic epilepsy v1.435 KCNA1 Rebecca Foulger Classified gene: KCNA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.435 KCNA1 Rebecca Foulger Gene: kcna1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.434 KCNA1 Rebecca Foulger commented on gene: KCNA1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted KCNA1 from Green to Amber.
Early onset or syndromic epilepsy v1.434 FLNA Rebecca Foulger Added comment: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was notes that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.
Early onset or syndromic epilepsy v1.434 FLNA Rebecca Foulger Mode of inheritance for gene: FLNA was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.433 FLNA Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy, and following Green ratings by Alisdair McNeill and Alison Callaway: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.
Early onset or syndromic epilepsy v1.433 FLNA Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.
Early onset or syndromic epilepsy v1.433 FLNA Rebecca Foulger commented on gene: FLNA: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.433 CACNA2D2 Rebecca Foulger Phenotypes for gene: CACNA2D2 were changed from Absence epilepsy to Absence epilepsy; Cerebellar atrophy with seizures and variable developmental delay, 618501
Early onset or syndromic epilepsy v1.432 CACNA2D2 Rebecca Foulger Classified gene: CACNA2D2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.432 CACNA2D2 Rebecca Foulger Gene: cacna2d2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.431 CACNA2D2 Rebecca Foulger commented on gene: CACNA2D2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.431 ALG8 Rebecca Foulger commented on gene: ALG8: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Although there is inconsistency amongst patients, there are sufficient cases for a Green rating. Kept rating as Green.
Early onset or syndromic epilepsy v1.431 TDP2 Rebecca Foulger commented on gene: TDP2
Early onset or syndromic epilepsy v1.431 GOT2 Rebecca Foulger Classified gene: GOT2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.431 GOT2 Rebecca Foulger Gene: got2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.430 GOT2 Rebecca Foulger commented on gene: GOT2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.430 HNRNPR Rebecca Foulger Mode of inheritance for gene: HNRNPR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.429 HNRNPR Rebecca Foulger Classified gene: HNRNPR as Green List (high evidence)
Early onset or syndromic epilepsy v1.429 HNRNPR Rebecca Foulger Gene: hnrnpr has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.428 HNRNPR Rebecca Foulger commented on gene: HNRNPR: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Although obvious dysmoprhism is associated with the phenotype, it meets the criteria for a Green rating. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.428 ZNF142 Rebecca Foulger Classified gene: ZNF142 as Green List (high evidence)
Early onset or syndromic epilepsy v1.428 ZNF142 Rebecca Foulger Gene: znf142 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.427 ZNF142 Rebecca Foulger commented on gene: ZNF142: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Sufficient cases for inclusion. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.427 TRRAP Rebecca Foulger commented on gene: TRRAP: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Seizures aren't a prominent feature. Kept rating as Amber.
Early onset or syndromic epilepsy v1.427 NPRL2 Rebecca Foulger Classified gene: NPRL2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.427 NPRL2 Rebecca Foulger Gene: nprl2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.426 NPRL2 Rebecca Foulger commented on gene: NPRL2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Sufficient cases to support gene:disease association, although unaffected carriers/incomplete penetrance may make variant interpretation difficult. Promoted from Amber to Green with the option to review on subsequent versions.
Early onset or syndromic epilepsy v1.426 HCN2 Rebecca Foulger Marked gene: HCN2 as ready
Early onset or syndromic epilepsy v1.426 HCN2 Rebecca Foulger Gene: hcn2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.426 HCN2 Rebecca Foulger commented on gene: HCN2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Although this is a borderline case with questions over phenotype segregation, there are sufficient cases to support inclusion. Although seizures aren’t one of the cardinal phenotypes, most cases will be trios and therefore there will be less issues in being inclusive. Kept rating of HCN2 as Green with the option of review on subsequent panel versions.
Early onset or syndromic epilepsy v1.426 AFF3 Rebecca Foulger Classified gene: AFF3 as Green List (high evidence)
Early onset or syndromic epilepsy v1.426 AFF3 Rebecca Foulger Gene: aff3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.425 AFF3 Rebecca Foulger commented on gene: AFF3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green: Sufficient evidence in pre-print Voisin et al., 2019 article. Promoted AFF3 from Amber to Green.
Early onset or syndromic epilepsy v1.425 SCN9A Alison Callaway reviewed gene: SCN9A: Rating: AMBER; Mode of pathogenicity: None; Publications: 30834459, 29500686; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.425 ALG8 Rebecca Foulger changed review comment from: 26066342 (Hock et al., 2015) describe 3 new patients with ALG8-CDG, provide an update on 2 previous patients and summarise 10 previous patients. The 15 patients total included 4 pairs of siblings. Brain involvement (psychomotor disability or seizures or ataxia or structural anomalies) were seen in 12/13 patients.; to: 26066342 (Hock et al., 2015) describe 3 new patients with ALG8-CDG, provide an update on 2 previous patients and summarise 10 previous patients. The 15 patients total included 4 pairs of siblings. Brain involvement (psychomotor disability or seizures or ataxia or structural anomalies) was seen in 12/13 patients.
Early onset or syndromic epilepsy v1.425 DMXL2 Konstantinos Varvagiannis changed review comment from: This gene can be considered for inclusion in both ID and epilepsy panels probably with green (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc) or amber rating.

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be constant features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1).
This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Sources: Literature; to: This gene can be considered for inclusion in both ID and epilepsy panels probably with green (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc) or amber rating.

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be constant features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AR) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1).
This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Sources: Literature
Early onset or syndromic epilepsy v1.425 DMXL2 Konstantinos Varvagiannis gene: DMXL2 was added
gene: DMXL2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DMXL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DMXL2 were set to 25248098; 30237576; 31688942; 30732576
Phenotypes for gene: DMXL2 were set to Epileptic encephalopathy, early infantile, 81, MIM 618663; ?Polyendocrine-polyneuropathy syndrome, MIM 616113
Penetrance for gene: DMXL2 were set to unknown
Review for gene: DMXL2 was set to GREEN
Added comment: This gene can be considered for inclusion in both ID and epilepsy panels probably with green (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc) or amber rating.

Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.

DD, ID and (probably) epilepsy appear however to be constant features in several individuals with biallelic pathogenic variants as summarized in the studies below.

OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]

DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1).
This gene is included in some gene panels for ID.

[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
-----------
[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
-----------
[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.

All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.

Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A

Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].

In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.

DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).

The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).

As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).

In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.

shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.

The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.

Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Sources: Literature
Early onset or syndromic epilepsy v1.425 ALG8 Rebecca Foulger commented on gene: ALG8: PMID:19688606 (Vesela et al., 2009) present a girl with neonatal onset of CDG. Seizures were present from the first day and the girl died age 2 months from progressive oedema, bleeding and cardio-respiratory insufficiency. She had compound het variants in ALG8 (p.T47P and p.R364X).
Early onset or syndromic epilepsy v1.425 ALG8 Rebecca Foulger commented on gene: ALG8: PMID:23430830 (Millon et al., 2011) report 2 siblings with a congenital glycosylation disorder. Their clinical presentation included seizures. The authors could not identify the genetic deficiency in these patients yet.
Early onset or syndromic epilepsy v1.425 ALG8 Rebecca Foulger commented on gene: ALG8: 26066342 (Hock et al., 2015) describe 3 new patients with ALG8-CDG, provide an update on 2 previous patients and summarise 10 previous patients. The 15 patients total included 4 pairs of siblings. Brain involvement (psychomotor disability or seizures or ataxia or structural anomalies) were seen in 12/13 patients.
Early onset or syndromic epilepsy v1.425 FLNA Alison Callaway reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.425 CACNA2D2 Zerin Hyder reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30410802, PMID: 31402629, PMID: 24358150, PMID: 23339110, PMID: 29997391; Phenotypes: epilepsy, ataxia, developmental delay, cerebellar atrophy; Mode of inheritance: None
Early onset or syndromic epilepsy v1.425 SLC6A19 Rebecca Foulger Phenotypes for gene: SLC6A19 were changed from to Hartnup disorder, 234500
Early onset or syndromic epilepsy v1.424 SLC6A19 Rebecca Foulger Publications for gene: SLC6A19 were set to
Early onset or syndromic epilepsy v1.423 SLC6A19 Rebecca Foulger commented on gene: SLC6A19: PMID:20399395 (Cheon et al 2010) report a Korean boy age 8 years and 5 months with Hartnup disorder. He had seizures, ADHD and mental retardation. Genetic analysis revealed novel compound het variants in SLC6A19: p.Thr596fsX73 and p.Ser303Leu.
Early onset or syndromic epilepsy v1.423 SCO2 Rebecca Foulger commented on gene: SCO2: PMID:18924171 (Verdijk et al, 2008) report compound het SOC2 variants (E140K and W36X) in 2 siblings with fatal infantile cardioencephalomyopathy. The index patient had convulsions age 1 day and died of heart failure age 25 days. The sibling fetus was terminated at 23 weeks following genetic testing.
Early onset or syndromic epilepsy v1.423 SCO2 Rebecca Foulger commented on gene: SCO2: PMID:10749987 (Jaksch et al., 2000) report 10 patients with fatal hypertrophic cardiomyopathy from 9 families. Mutations in SCO2 (E140K, R171W) were found in 3 patients (2 unrelated families) all of whom had seizures: Table 1.
Early onset or syndromic epilepsy v1.423 SCO2 Rebecca Foulger commented on gene: SCO2: PMID:10545952 (Papadopoulou et al 1999) identified variants in SCO2 in 3 unrelated infants with fatal cardioencephalomyopathy and COX deficiency. Patient 2 had focal epileptiform discharges on an EEG.
Early onset or syndromic epilepsy v1.423 SCO1 Rebecca Foulger commented on gene: SCO1: PMID:22231385 (Honzik et al., 2012) summarise 461 patients with mitochondrial disorders. One patient had a variant in SCO1: seizures were not a feature (Table 2, Stiburek et al., 2009).
Early onset or syndromic epilepsy v1.423 SCO1 Rebecca Foulger changed review comment from: PMID:15023375 report an 8-week old infant who presented with neonatal seizures and limb malformations. There were multiple seizure types, including multifocal myoclonus, complex partial events and generalised tonic–clonic episodes. Treatment of seizures was of limited success. The specific defect seen in the patient was a complex IV deficiency. Although no known variants were identified, the clinical picture overlaps with the SCO1 presentation.; to: PMID:15023375 (Kurian et al., 2004) report an 8-week old infant who presented with neonatal seizures and limb malformations. There were multiple seizure types, including multifocal myoclonus, complex partial events and generalised tonic–clonic episodes. Treatment of seizures was of limited success. The specific defect seen in the patient was a complex IV deficiency. Although no known variants were identified, the clinical picture overlaps with the SCO1 presentation.
Early onset or syndromic epilepsy v1.423 SCO1 Rebecca Foulger Publications for gene: SCO1 were set to 23878101; 11013136; 19295170
Early onset or syndromic epilepsy v1.422 SCO1 Rebecca Foulger changed review comment from: PMID:23878101 (Leary et al., 2013) report compound het variants in SCO1 in a patient with fatal encephalopathy. The patient developed seizures age 4 months which were difficult to control. He died age 5 months (Supporting information).; to: PMID:23878101 (Leary et al., 2013) report compound het variants in SCO1 in a patient with fatal encephalopathy. The patient developed seizures age 4 months which were difficult to control. He died age 5 months (seizure information and extended clinical phenotype is the supporting information).
Early onset or syndromic epilepsy v1.422 SCO1 Rebecca Foulger commented on gene: SCO1: PMID:15023375 report an 8-week old infant who presented with neonatal seizures and limb malformations. There were multiple seizure types, including multifocal myoclonus, complex partial events and generalised tonic–clonic episodes. Treatment of seizures was of limited success. The specific defect seen in the patient was a complex IV deficiency. Although no known variants were identified, the clinical picture overlaps with the SCO1 presentation.
Early onset or syndromic epilepsy v1.422 SCO1 Rebecca Foulger commented on gene: SCO1: PMID:23878101 (Leary et al., 2013) report compound het variants in SCO1 in a patient with fatal encephalopathy. The patient developed seizures age 4 months which were difficult to control. He died age 5 months (Supporting information).
Early onset or syndromic epilepsy v1.422 QDPR Rebecca Foulger Phenotypes for gene: QDPR were changed from Hyperphenylalaninemia, BH4-deficient, C, 261630 to Hyperphenylalaninemia, BH4-deficient, C, 261630; DHPR deficiency
Early onset or syndromic epilepsy v1.421 QDPR Rebecca Foulger Publications for gene: QDPR were set to 9341885; 26006720
Early onset or syndromic epilepsy v1.420 QDPR Rebecca Foulger commented on gene: QDPR: Seizures listed in the OMIM Clinical synopsis for 'Hyperphenylalaninemia, BH4-deficient, C' (MIM:261630).
Early onset or syndromic epilepsy v1.420 QDPR Rebecca Foulger commented on gene: QDPR: Ikeda et al. (1997, PMID:9341885) report a Japanese boy with hyperphenylalaninemia and a splicing error variant in QDPR. He was the offspring of first-cousin parents. The patient showed intractable seizures and developmental delay.
Early onset or syndromic epilepsy v1.420 PRODH Rebecca Foulger Publications for gene: PRODH were set to 12217952
Early onset or syndromic epilepsy v1.419 PRODH Rebecca Foulger commented on gene: PRODH: PMID:17412540 (Afenjar et al 2007) report 4 unrelated children and biallelic variants in PRODH. The authors note that 4 previous patients had been reported (Jacquet et al, 2002, 2003 and Raux et al 2007) and of the 8 total patients, 5 had epilepsy (plus febrile case), often severe with status epilepticus.
Early onset or syndromic epilepsy v1.419 PRODH Rebecca Foulger commented on gene: PRODH: PMID:18197084 (Di Rosa et al., 2008) screened 4 unrelated Italian children all of whom presented with epilepsy and ID, and compound het/homozygous variants in PRODH. Functional tests to confirm the pathogenicity were not performed.
Early onset or syndromic epilepsy v1.419 PRODH Rebecca Foulger Publications for gene: PRODH were set to
Early onset or syndromic epilepsy v1.418 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:16141001 (Rosewich et al 2005) studied 33 patients with PEX1 variants. Seizures are a feature in Table 3 for 6 patients.
Early onset or syndromic epilepsy v1.418 PEX1 Rebecca Foulger Publications for gene: PEX1 were set to 12402331; 26387595; 9398847
Early onset or syndromic epilepsy v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:15098231 (Poll-The BT et al 2004) surveyed 31 patients with a generalized peroxisomal disorder from 27 families. 7/31 patients (23%) developed seizures from 0 - 2.7 years. Most patients (60-70%) had variants in the PEX1 gene. Most frequent variants include G843D and frameshift c.2097insT.
Early onset or syndromic epilepsy v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:15301838 (Michelakakis et al, 2004) decribe a female patient of healthy unrelated patients. Her diagnosis of Leber congenital amaurosis was subsequently demonstrated to be a PEX1 defect. Myoclonic seizures began age 2. The patient is heterozygous for G843D variant and an additional second variant that is not yet identified.
Early onset or syndromic epilepsy v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:28432012 (Ge et al., 2017) report 2 Chinese newborns with Zellweger phenotypes and compound het variants in PEX1 (Arg577Thrfs*15 and Asn830Thrfx*61). Although the authors note that seizures are in the clinical spectrum of ZS patients, seizures were not reported for the Chinese newborns.
Early onset or syndromic epilepsy v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:21844578 (Cho et al., 2011) report a Korean patient who was compound het for variants in the PEX1 gene (p.H678QfsX3 and p.R949W) inherited from the parents. He had typical features of ZS including seizures (starting 4 days old), dysmorphic face and a poor suck.
Early onset or syndromic epilepsy v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:28666289 (Komulainen-Ebrahim et al., 2017) describe a homozygous MTR p.P1173L variant in a patient with drug-resistant seizures associated with hyperhomocysteinemia and hypomethioninemia.
Early onset or syndromic epilepsy v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:9683607 (Wilson et al., 1998) report 3 cblG patients, including 2 siblings who presented with neonatal seizures.
Early onset or syndromic epilepsy v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:25526710 (Huemer et al., 2015) summarise clinical features of 13 patients with the cblG defect (caused by defects in MTR): 5/13 had seizures.
Early onset or syndromic epilepsy v1.417 IDH2 Rebecca Foulger commented on gene: IDH2: A number of papers note that IDH1 and IDH2 variants have an established association with preoperative seizures in patients with grade II-IV diffuse gliomas (PMID:29172136, 29288860, 22217666).
Early onset or syndromic epilepsy v1.417 IDH2 Rebecca Foulger Publications for gene: IDH2 were set to 20847235
Early onset or syndromic epilepsy v1.416 IDH2 Rebecca Foulger commented on gene: IDH2: PMID:24049096 (Nota et al., 2013) report 3 cases, with seizures reported in 2/3. Case 2 was a 9 year old Caucasian girl with tonic-clonic seizures and mosaic IDH2 variants. Case 3 was a Caucasian girl with seizures age 3 months- her seizures responded well to anticonvulsants. The patient died from sudden cardiac arrest age 8, and was found to have a heterozygous IDH2 c.419G>A variant. Germline mosaicism in the mother was suggested to explain the inheritance pattern in this family.
Early onset or syndromic epilepsy v1.416 HLCS Rebecca Foulger commented on gene: HLCS: PMID:27114915 (Donti et al., 2016) describe a cohort of 5 patients. Case 5 had focal seizures age 5 months which have continued since. He has compound het variants in HLCS (N570K and c.1519+5G>A). The authors note that the phenotypic spectrum of HCLS is broad, from intractable seizures and ID to normal growth and development.
Early onset or syndromic epilepsy v1.416 GSS Rebecca Foulger Publications for gene: GSS were set to 26984560
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:26669244 (Gunduz et al., 2016) report 4 patients with GS deficiency. Case I and Case IV had seizures noted together with homozygous variants (splicing variant in I and p.R125H in IV): Table 1.
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: Seizures are recorded in OMIM Clinical synopsis for MIM:266130 based on Marstein et al., 1976 (no PubMed).
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:15990954 (Njallson et al 2005) summarise the phenotypes of patients with glutathione synthetase deficiency, but don't mention seizures or epilepsy (as noted in review by Tracy Lester).
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:11445798 (Ristoff et al,. 2001) examined 28 patients with Glutathione synthetase deficiency (GSSD). Diagnosis was based on metabolic tests. 16/28 had neurological symptoms such as seizures/psychomotor retardation. In 16 patients with severe GS deficiency, 7 had seizures.
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:26984560 (Atwal et al. 2016) present a 19 year old female with Glutathione synthetase deficiency (GSSD). She was diagnosed with a mild seizure disorder age 10, and treated with the antiepileptic lamotrigine, which was discontinued once she was seizure free for 5 years. The authors note it is possible her seizures were unrelated to the underlying GSSD.
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger Publications for gene: GSS were set to
Early onset or syndromic epilepsy v1.414 GLYCTK Rebecca Foulger Publications for gene: GLYCTK were set to 3588091; 30637540; 28462797; 20949620
Early onset or syndromic epilepsy v1.413 GLYCTK Rebecca Foulger Publications for gene: GLYCTK were set to 3588091
Early onset or syndromic epilepsy v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:30637540 (Zehavi et al., 2019) report a male from a consanguineous Arab family with intractable seizures and a homozygous missense pathogenic variant in GLYCTK (p.Leu152Pro).
Early onset or syndromic epilepsy v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:28462797 (Swanson et al., 2017) reviewed the Serbian patient from Sass et al., 2010. In addition to p.Phe483SerfsX2 variant in GLYCTK, the patient had an additional Ser117Leu variant in AMT highlighting the co-occurence of two metabolic conditions (D-glyceric aciduria and nonketotic hyperglycinemia).
Early onset or syndromic epilepsy v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:20949620 (Sass et al., 2010) report 3 patients of Serbian, Mexican and Turkish origin, including the original 1974 (Serbian) patient. All had homozygous variant in GLYTCK:
Patient A was a Serbian boy with generalized seizures beginning age 8 weeks (p.Phe483SerfsX2 variant).
Patient B was a Mexican girl with focal clonic seizures and a Phe493Cys variant.
Patient C was a Turkish boy where seizures were not noted (p.Leu520CysfsX108 variant).
Early onset or syndromic epilepsy v1.412 GFM1 Rebecca Foulger Publications for gene: GFM1 were set to 25852744; 26937387; 28216230; 23430926; 21986555
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:28216230 (Simon et al., 2017) report 2 brothers with compound het variants in GFM1 (maternally-inherited p.Arg250Trp and paternally-inherited p.Gly230_231Glnins19). The younger brother (P1) developed seizures by 4.5 months, characterised as infantile spasms. He has remained seizure free on treatment with topiramate. No seizures were noted for the brother who died age 10 months from multiple organ failure. The authors suggest additional modifier genes may be responsible for the different in severity between the brothers.
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:26937387 (Ravn et al., 2015) describe 3 patients with novel GFM1 variants. Patient 3 (a girl of non-consanguineous parents) had epileptic seizures beginning at 2 months old. She died at 3 months during a febrile episode.
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:21986555. Galmiche et al., 2012 report two unrelated patients with homozygous GFM1 variants (R671C). The parents were both heterozygous for this variant For the first patient (an Algerian boy from consanguineous parents), no clinical seizures were noted but EEG showed burst of multifocal spikes.
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:25852744. Brito et al., 2015 report an infant born to unrelated Caucasian parents with seizures amongst her phenotype (starting age 7 months) and compound het variants in GFM1 (Gly469Valfs*84 and Arg671Cys). The authors summarise clinical features of previous GFM1-deficient patients and note seizures in 5/12 patients.
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:21119709. In a girl, born of consanguineous parents, with combined oxidative phosphorylation deficiency, Smits et al. (2011) identified a homozygous R250W variant in GFM1. The patient had refractory seizures amongst her phenotypes. This paper is referred to in the review by Tracy Lester.
Early onset or syndromic epilepsy v1.411 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057; 7730309; 31202265
Early onset or syndromic epilepsy v1.410 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057; 7730309
Early onset or syndromic epilepsy v1.409 GCH1 Rebecca Foulger commented on gene: GCH1: Additional evidence for seizures being part of the metabolic disorder comes from PMID:31202265 (Dayasiri et al, 2019) who report a S. Asian child with AR GTPCH (GCH1) deficiency, diagnosed from metabolic testing and family consanguinity. Features included recurrent seizures since 3 months old.
Early onset or syndromic epilepsy v1.409 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057
Early onset or syndromic epilepsy v1.408 HCN2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept MOI as 'BOTH monoallelic and biallelic' as supported by reviews from Helen Lord and Alison Callaway, and literature (PMID:22131395).
Early onset or syndromic epilepsy v1.408 HCN2 Rebecca Foulger Mode of inheritance for gene: HCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.407 Ellen McDonagh Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS Rare Disease Virtual
Early onset or syndromic epilepsy v1.406 Ellen McDonagh List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; R59
Early onset or syndromic epilepsy v1.405 NSF Konstantinos Varvagiannis gene: NSF was added
gene: NSF was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NSF were set to 31675180
Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Penetrance for gene: NSF were set to unknown
Review for gene: NSF was set to AMBER
Added comment: Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed).
Sources: Literature
Early onset or syndromic epilepsy v1.405 SCAMP5 Konstantinos Varvagiannis gene: SCAMP5 was added
gene: SCAMP5 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAMP5 were set to 31439720; 20071347
Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Penetrance for gene: SCAMP5 were set to unknown
Mode of pathogenicity for gene: SCAMP5 was set to Other
Review for gene: SCAMP5 was set to AMBER
Added comment: PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures, behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
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PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
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SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
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Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature
Early onset or syndromic epilepsy v1.405 PCYT2 Konstantinos Varvagiannis gene: PCYT2 was added
gene: PCYT2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy
Penetrance for gene: PCYT2 were set to Complete
Review for gene: PCYT2 was set to GREEN
Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations.

The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy.

Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below):
- P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu
- P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one.

Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID).

For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive.

All variants were absent from / had extremely low AF in public databases, with no homozygotes.

Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway.

In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability.

Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied:
- Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant.
- RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls.
- Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls.

The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping.

CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish.

Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088).

Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life.

PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.

As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating.

[Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc].
Sources: Literature
Early onset or syndromic epilepsy v1.405 FDFT1 Konstantinos Varvagiannis gene: FDFT1 was added
gene: FDFT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDFT1 were set to 29909962
Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face
Penetrance for gene: FDFT1 were set to Complete
Review for gene: FDFT1 was set to AMBER
Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below].
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Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias).

FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis.

A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites.

Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis).

WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included:
- Minigene splice assay demonstrating retention of 22 bp in intron 8.
- Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts)
- Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot.
Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected).

As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant :
- cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect.
- Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity.

Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure.

In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories.
Sources: Literature
Early onset or syndromic epilepsy v1.405 GOT2 Rebecca Foulger commented on gene: GOT2
Early onset or syndromic epilepsy v1.405 HNRNPR Rebecca Foulger commented on gene: HNRNPR
Early onset or syndromic epilepsy v1.405 HLCS Rebecca Foulger Publications for gene: HLCS were set to
Early onset or syndromic epilepsy v1.404 HLCS Rebecca Foulger Phenotypes for gene: HLCS were changed from to Holocarboxylase synthetase deficiency, 253270
Early onset or syndromic epilepsy v1.403 PLA2G6 Rebecca Foulger Classified gene: PLA2G6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.403 PLA2G6 Rebecca Foulger Added comment: Comment on list classification: Although PLA2G6 is Green on the 'Inborn errors of metabolism' panel, have added to the Epilepsy panel as Amber as unclear if seizures are a consistent feature. Requires clinical review (and review of the MOI in PMID:27513994) before promotion to Green.
Early onset or syndromic epilepsy v1.403 PLA2G6 Rebecca Foulger Gene: pla2g6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.402 PLA2G6 Rebecca Foulger Added comment: Comment on mode of inheritance: Selected 'BIALLELIC' inheritance to match the metabolism PanelApp panels (including Inborn errors of metabolism, V1.392), all OMIM disorders and both G2P disorders. However, PMID:27513994 report autosomal dominant inheritance for Familial cortical myoclonic tremor with epilepsy (FCMTE).
Early onset or syndromic epilepsy v1.402 PLA2G6 Rebecca Foulger Mode of inheritance for gene: PLA2G6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:27513994 (Gao et al., 2016) report a family (41 members) which included 6 individuals affected with Familial cortical myoclonic tremor with epilepsy (FCMTE). All 6 individuals had tremors while 5 individuals had seizures. Genomic sequencing was performed on 3 affected and 2 unaffected individuals. A novel missense variant c.475C>T (p.A159T) in PLA2G6 with AD inheritance was identified in this family which segregated with the disease. Note that a variant in SNRNP200 gene also segregated with the disease but is within the untranslated region and the functional effect is unclear.
Early onset or syndromic epilepsy v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:30772976. Ma et al., 2019 analyse a Chinese Han pedigree with seizures amongst the phenotype. Compound het variants in PLA2G6 were found (p.A80T and p.D331Y) (full English text not available).
Early onset or syndromic epilepsy v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:30340910. Darling et al., 2019 investigated 16 patients from 13 families with PLA2G6-associated neurodegeneration (an autosomal recessive disorder). Epilepsy was observed in 8/16 patients (7 families, 2 patients had been previously reported, Table 1). All patients harboured missense, nonsense and frameshift variants in PLA2G6.
Early onset or syndromic epilepsy v1.401 PLA2G6 Rebecca Foulger gene: PLA2G6 was added
gene: PLA2G6 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: PLA2G6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLA2G6 were set to 30340910; 27513994; 30772976
Phenotypes for gene: PLA2G6 were set to PLA2G6-associated neurodegeneration (PLAN); Familial cortical myoclonic tremor with epilepsy (FCMTE); Infantile neuroaxonal dystrophy 1, 256600; Neurodegeneration with brain iron accumulation 2B, 610217
Added comment: Added to epilepsy panel based on a Green rating on the 'Inborn errors of metabolism panel'- seizures are a reported feature of MIM:256600 and MIM:610217.
Sources: Literature, Other
Early onset or syndromic epilepsy v1.400 DNAJC5 Rebecca Foulger Classified gene: DNAJC5 as Green List (high evidence)
Early onset or syndromic epilepsy v1.400 DNAJC5 Rebecca Foulger Added comment: Comment on list classification: Added to panel as a Green gene as seizures are a symptom of the metabolic disorder, and sufficient epilepsy cases from literature.
Early onset or syndromic epilepsy v1.400 DNAJC5 Rebecca Foulger Gene: dnajc5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:22235333: Velinov et al., 2012. The authors previously described the Parry family in the 1970s. All affected individuals from the family had a history of progressive seizure disorder. They identified a pLeu116del variant in DNAJC5 which segregated with the disease. 8 additional families were studied for this paper, with seizures amongst the phenotypes. In one affected individual, pLeu115Arg was identified (proband BD-319) who had seizures and gradual dementia beginning in the mid 30s.
Early onset or syndromic epilepsy v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:29506599: Jarrett et al., 2018 report a family with Kufs disease in which the proband and 3/4 children presented with cognitive impariment, seizures and myoclonus. Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) variant in the DNAJC5 gene. EEG on the asymptomatic fourth child showed moderatley severe slowing. The proband's father was deceased but had a history of epileptic seizures.
Early onset or syndromic epilepsy v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:22978711: Cadieux-Dion et al., 2013. report a p.L116del variant in DNAJC5 in two distinct American families, and a p.L115R variant in an additional family. All individuals showed generalized tonic-clonic seizures.
Early onset or syndromic epilepsy v1.399 DNAJC5 Rebecca Foulger gene: DNAJC5 was added
gene: DNAJC5 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: DNAJC5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DNAJC5 were set to 22978711; 29506599; 22235333
Phenotypes for gene: DNAJC5 were set to Ceroid lipofuscinosis, neuronal, 4, Parry type, 162350; autosomal dominant Kufs disease; generalized tonic–clonic seizures
Added comment: Added DNAJC5 to the Epilepsy panel based on a Green rating on the 'Inborn errors of metabolism' panel: seizures are listed as a symptom of MIM:162350 in OMIM.
Sources: Literature, Other
Early onset or syndromic epilepsy v1.398 CLN6 Rebecca Foulger commented on gene: CLN6: PMID:30561534. Berkovic et al., 2019 report phenotypes of patients with CLN6 pathogenic variants from 13 unrelated families (homozygous in 4 families and compound het in 9 families). The typical presentation was progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures.
Early onset or syndromic epilepsy v1.398 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341; 31029456; 31216804
Early onset or syndromic epilepsy v1.397 SETD5 Rebecca Foulger Phenotypes for gene: SETD5 were changed from Mental retardation, autosomal dominant 23 to Mental retardation, autosomal dominant 23, 615761
Early onset or syndromic epilepsy v1.396 SETD5 Rebecca Foulger Publications for gene: SETD5 were set to
Early onset or syndromic epilepsy v1.395 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341; 31029456
Early onset or syndromic epilepsy v1.394 CLN6 Rebecca Foulger changed review comment from: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not avaialble).; to: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not available).
Early onset or syndromic epilepsy v1.394 CLN6 Rebecca Foulger commented on gene: CLN6: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not avaialble).
Early onset or syndromic epilepsy v1.394 CLN6 Rebecca Foulger commented on gene: CLN6: Additional case in PMID:31029456 (Matsumoto et al., 2019) of Japanese boy with a homozygous C.794_976del variant p. (Ser265del) in CLN6. Symptoms include focal seizures.
Early onset or syndromic epilepsy v1.394 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341
Early onset or syndromic epilepsy v1.393 SGSH Rebecca Foulger Classified gene: SGSH as Green List (high evidence)
Early onset or syndromic epilepsy v1.393 SGSH Rebecca Foulger Added comment: Comment on list classification: Added SGSH to the panel with a Green rating: Green on the 'Inborn errors of metabolism' panel, and seizures are part of the MPS IIIA phenotype. Sufficient cases from the literature for inclusion on the panel.
Early onset or syndromic epilepsy v1.393 SGSH Rebecca Foulger Gene: sgsh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.392 SGSH Rebecca Foulger commented on gene: SGSH: PMID: 30593151 (Li et al., 2018) report an 8 year old female with developmental regression and seizures amongst her symptoms. She was diagnosed with autosomal recessive (AR) MPS IIIA with compound het variants in SGSH (c.1298G>A p.Arg433Gln and c.630 G>T p.Trp210Cys), inherited from each parent. The pathogenicity of c.630G>T has not been reported yet. c.1298G>A has been associated with MPS-IIIA previously.
Early onset or syndromic epilepsy v1.392 SGSH Rebecca Foulger commented on gene: SGSH: PMID:21061399: Valstar et al. 2010 retrospectively reviewed the clinical features of 92 patients with MPS IIIA, including 32 living and 60 deceased individuals. There was wide phenotypic variability but Epilepsy was reported in 53/80 patients with a median seizure age of 11 years (range, 1-43 years). Patients with a severe MPS IIIA phenotype developed epilepsy at a significantly earlier age compared to patients suffering from a more attenuated form of the disease.
Early onset or syndromic epilepsy v1.392 SGSH Rebecca Foulger gene: SGSH was added
gene: SGSH was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: SGSH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGSH were set to 21061399; 30593151
Phenotypes for gene: SGSH were set to Mucopolysaccharidosis type IIIA (Sanfilippo A), 252900; seizures
Review for gene: SGSH was set to GREEN
Added comment: Added SGSH to the panel based on Green rating on the 'Inborn errors of metabolism' panel: seizures are a part of the Mucopolysaccharidosis phenotype.
Sources: Literature, Other
Early onset or syndromic epilepsy v1.391 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease
Early onset or syndromic epilepsy v1.389 Rebecca Foulger List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy
Early onset or syndromic epilepsy v1.388 APC2 Catherine Snow reviewed gene: APC2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.388 BSCL2 Rebecca Foulger Phenotypes for gene: BSCL2 were changed from Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685 to Intractable epilepsy and neurological regression; Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685
Early onset or syndromic epilepsy v1.387 BSCL2 Rebecca Foulger Publications for gene: BSCL2 were set to 24896178; 26503795; 23564749; 15181077; 30767895; 23564749
Early onset or syndromic epilepsy v1.386 BSCL2 Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:31369919 (Fernandez-Marmiesse et al., 2019) report 2 siblings with profound refractory epilepsy and neurological regression. A de novo Met189Lys variant in BSCL2 was detected that was absent in the parents and unaffected sibling. This is the first evidence of an association between a heterozygous BSCL2 variant and EIEE, and supports an AD+AR Mode of inheritance.
Early onset or syndromic epilepsy v1.386 BSCL2 Rebecca Foulger Mode of inheritance for gene: BSCL2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.385 BSCL2 Rebecca Foulger Publications for gene: BSCL2 were set to 24896178; 26503795; 23564749; 15181077; 30767895
Early onset or syndromic epilepsy v1.384 CYP27A1 Rebecca Foulger Publications for gene: CYP27A1 were set to 18227423; 22336472; 24442603; 29484516
Early onset or syndromic epilepsy v1.383 EXT2 Rebecca Foulger changed review comment from: Comment on list classification: Added CLPB to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).; to: Comment on list classification: Added EXT2 to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Early onset or syndromic epilepsy v1.383 EMX2 Rebecca Foulger Classified gene: EMX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.383 EMX2 Rebecca Foulger Gene: emx2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.382 EMX2 Rebecca Foulger Classified gene: EMX2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.382 EMX2 Rebecca Foulger Added comment: Comment on list classification: Demoted EMX2 from Green to Amber based on the Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy, and the post-Webex review by Helen Lord. The Schizencephaly phenotype is more appropriate for the ID/Cortical malformations panel, and EMX2 has now been added as a Green gene to 'Malformations of cortical development' (#96) panel.
Early onset or syndromic epilepsy v1.382 EMX2 Rebecca Foulger Gene: emx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.381 TDP2 Catherine Snow changed review comment from: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green; to: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. All individuals reported to have seizures, although age of onset varied from 2 months to 12 years. There are sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green.
Early onset or syndromic epilepsy v1.381 TDP2 Catherine Snow Classified gene: TDP2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.381 TDP2 Catherine Snow Added comment: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green
Early onset or syndromic epilepsy v1.381 TDP2 Catherine Snow Gene: tdp2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.380 TDP2 Catherine Snow Mode of inheritance for gene: TDP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.379 TANC2 Rebecca Foulger Classified gene: TANC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.379 TANC2 Rebecca Foulger Added comment: Comment on list classification: Set rating of TANC2 to Amber. Not yet associated with a disorder in OMIM or Gene2Phenotype. One 2019 paper linking TANC2 with epilepsy in 11/20 cases: sufficient unrelated cases in PMID:31616000 but the pathogenicity of the variants has not been confirmed.
Early onset or syndromic epilepsy v1.379 TANC2 Rebecca Foulger Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.378 TANC2 Rebecca Foulger gene: TANC2 was added
gene: TANC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TANC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TANC2 were set to 31616000
Phenotypes for gene: TANC2 were set to NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Seizures; Epilepsy
Added comment: Added TANC2 to panel following curation of TANC2 on the Intellectual disability panel. PMID:31616000 (Guo et al, 2019) report 11/20 individuals with a TANC2 variant who had a formal diagnosis of epilepsy (n=9) or who suffered recurrent seizures (n=2).
Sources: Literature
Early onset or syndromic epilepsy v1.377 CLN6 Rebecca Foulger Classified gene: CLN6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.377 CLN6 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on Amber review by Tracy Lester and PMID:21549341 (Arsov et al., 2011) where seizures are a consistent feature across families.
Early onset or syndromic epilepsy v1.377 CLN6 Rebecca Foulger Gene: cln6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.376 NDUFS7 Rebecca Foulger Phenotypes for gene: NDUFS7 were changed from to Mitochondrial complex I deficiency, nuclear type 3, 618224
Early onset or syndromic epilepsy v1.375 CLN6 Rebecca Foulger Mode of inheritance for gene: CLN6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.374 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to
Early onset or syndromic epilepsy v1.373 ALG2 Rebecca Foulger Phenotypes for gene: ALG2 were changed from to ?Congenital disorder of glycosylation type Ii, 607906; Myasthenic syndrome congenital 14 with tubular aggregates, 616228
Early onset or syndromic epilepsy v1.372 ALG2 Rebecca Foulger Mode of inheritance for gene: ALG2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.371 EXT2 Rebecca Foulger changed review comment from: Comment on list classification: Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).; to: Comment on list classification: Added CLPB to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Early onset or syndromic epilepsy v1.371 TXN2 Rebecca Foulger commented on gene: TXN2
Early onset or syndromic epilepsy v1.371 MT-CO3 Rebecca Foulger commented on gene: MT-CO3
Early onset or syndromic epilepsy v1.371 EXT2 Rebecca Foulger Classified gene: EXT2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.371 EXT2 Rebecca Foulger Added comment: Comment on list classification: Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Early onset or syndromic epilepsy v1.371 EXT2 Rebecca Foulger Gene: ext2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.370 CLPB Rebecca Foulger commented on gene: CLPB
Early onset or syndromic epilepsy v1.370 TXN2 Rebecca Foulger gene: TXN2 was added
gene: TXN2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Red
Mode of inheritance for gene: TXN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TXN2 were set to 26626369
Phenotypes for gene: TXN2 were set to ?Combined oxidative phosphorylation deficiency 29, 616811; infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy
Early onset or syndromic epilepsy v1.370 MT-CO3 Rebecca Foulger gene: MT-CO3 was added
gene: MT-CO3 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Red
Mode of inheritance for gene gene: MT-CO3 was set to MITOCHONDRIAL
Publications for gene: MT-CO3 were set to 8739943; 12915481
Phenotypes for gene: MT-CO3 were set to seizures
Early onset or syndromic epilepsy v1.370 EXT2 Rebecca Foulger gene: EXT2 was added
gene: EXT2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green
Mode of inheritance for gene: EXT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXT2 were set to 26246518; 30997052; 30288735; 30075207
Phenotypes for gene: EXT2 were set to Seizures, scoliosis, and macrocephaly syndrome, 616682
Early onset or syndromic epilepsy v1.370 CLPB Rebecca Foulger gene: CLPB was added
gene: CLPB was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green
Mode of inheritance for gene: CLPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPB were set to 26916670; 25597510; 25597511
Phenotypes for gene: CLPB were set to Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271
Early onset or syndromic epilepsy v1.369 GPHN Rebecca Foulger Publications for gene: GPHN were set to 26613940; 12684523; 11095995; 22040219; 24561070
Early onset or syndromic epilepsy v1.368 GPHN Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from BIALLELIC to BOTH monoallelic and biallelic. Although OMIM records AR inheritance, a review by Tracy Lester notes PMIDs:24561070, 23393157 who report the association of hemizygous GPHN microdeletions with an epilepsy phenotype. The biallelic and monoallelic MOI matches the MOI of GPHN on the metabolism panels.
Early onset or syndromic epilepsy v1.368 GPHN Rebecca Foulger Mode of inheritance for gene: GPHN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.367 GPHN Rebecca Foulger Publications for gene: GPHN were set to 26613940; 12684523; 11095995
Early onset or syndromic epilepsy v1.366 ABAT Rebecca Foulger Publications for gene: ABAT were set to 20052547; 27376954
Early onset or syndromic epilepsy v1.365 ADAR Rebecca Foulger Publications for gene: ADAR were set to
Early onset or syndromic epilepsy v1.364 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plu review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.; to: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plus review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.
Early onset or syndromic epilepsy v1.364 ISCA-37446-Loss Rebecca Foulger commented on Region: ISCA-37446-Loss: PMID:30977115: Eaton et al., 2019: Overall, 11% (12/108) of deletion carriers had an epilepsy diagnosis. 57/96 remaining deletion carriers (59.4%) had seizures or seizure-like symptoms (including febrile seizures). Most patients with 22q11.2 deletion syndrome had either deletion type A-D (ISCA-37446 75.9%) or deletion type A-B (ISCA-37433 6.5% 7/108 patients)- see Table 1.
Early onset or syndromic epilepsy v1.364 ISCA-37446-Loss Rebecca Foulger commented on Region: ISCA-37446-Loss: Added CNV to panel on recommendation from Alisdair McNeill (SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST) who notes that "Multiple case series demonstrate 22q11.2 deletion syndrome is associated with epilepsy, e.g. PubMed:30977115" (personal communication via email, October 7th 2019).
Early onset or syndromic epilepsy v1.364 ISCA-37433-Loss Rebecca Foulger commented on Region: ISCA-37433-Loss: PMID:30977115: Eaton et al., 2019: Overall, 11% (12/108) of deletion carriers had an epilepsy diagnosis. 57/96 remaining deletion carriers (59.4%) had seizures or seizure-like symptoms (including febrile seizures). Most patients with 22q11.2 deletion syndrome had either deletion type A-D (ISCA-37446 75.9%) or deletion type A-B (ISCA-37433 6.5% 7/108 patients)- see Table 1.
Early onset or syndromic epilepsy v1.364 ISCA-37433-Loss Rebecca Foulger commented on Region: ISCA-37433-Loss: Added CNV to panel on recommendation from Alisdair McNeill (SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST) who notes that "Multiple case series demonstrate 22q11.2 deletion syndrome is associated with epilepsy, e.g. PubMed:30977115" (personal communication via email, October 7th 2019).
Early onset or syndromic epilepsy v1.364 ISCA-37433-Loss Rebecca Foulger reviewed Region: ISCA-37433-Loss: Rating: ; Mode of pathogenicity: None; Publications: 30977115; Phenotypes: Epilepsy, seizures, seizure-like symptoms; Mode of inheritance: None
Early onset or syndromic epilepsy v1.364 ISCA-37446-Loss Rebecca Foulger reviewed Region: ISCA-37446-Loss: Rating: ; Mode of pathogenicity: None; Publications: 30977115; Phenotypes: Epilepsy, seizures, seizure-like symptoms; Mode of inheritance: None
Early onset or syndromic epilepsy v1.364 ISCA-37433-Loss Rebecca Foulger Region: ISCA-37433-Loss was added
Region: ISCA-37433-Loss was added to Genetic epilepsy syndromes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37433-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37433-Loss were set to 15545748; 15889418; 20301696
Phenotypes for Region: ISCA-37433-Loss were set to Learning difficulties; immune deficiency; renal anomalies; cleft palate, polydactyly; 22q11.2 deletion syndrome; diaphragmatic hernia; 192430; polyhydramnios; DiGeorge syndrome; Velocardiofacial syndrome; 188400; facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; congenital heart disease
Early onset or syndromic epilepsy v1.364 ISCA-37446-Loss Rebecca Foulger Region: ISCA-37446-Loss was added
Region: ISCA-37446-Loss was added to Genetic epilepsy syndromes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37446-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37446-Loss were set to micrognathia; neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells; clefting; DiGeorge syndrome; Velocardiofacial syndrome; 188400; cardiac malformations; Hearing deficits
Early onset or syndromic epilepsy v1.363 NDUFAF4 Rebecca Foulger commented on gene: NDUFAF4: Amber ratings from Tracy Lester and Zornitza Stark support the current Amber rating of NDUFAF4.
Early onset or syndromic epilepsy v1.363 NDUFAF4 Rebecca Foulger Publications for gene: NDUFAF4 were set to
Early onset or syndromic epilepsy v1.362 NDUFAF4 Rebecca Foulger Phenotypes for gene: NDUFAF4 were changed from to Mitochondrial complex I deficiency, nuclear type 15, 618237
Early onset or syndromic epilepsy v1.361 NDUFAF4 Rebecca Foulger Mode of inheritance for gene: NDUFAF4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Marked gene: CCND2 as ready
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Gene: ccnd2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Classified gene: CCND2 as Red List (low evidence)
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Added comment: Comment on list classification: Demoted CCND2 from Amber to Red following Red reviews by Zornitza Stark and Tracy Lester- as noted previously by Sarah Leigh: epilepsy is not a reported feature of the disorder.
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Gene: ccnd2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.359 CCND2 Rebecca Foulger Mode of inheritance for gene: CCND2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.358 CCND2 Rebecca Foulger Publications for gene: CCND2 were set to
Early onset or syndromic epilepsy v1.357 CCND2 Rebecca Foulger Phenotypes for gene: CCND2 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, 615938
Early onset or syndromic epilepsy v1.356 ARID1B Rebecca Foulger Marked gene: ARID1B as ready
Early onset or syndromic epilepsy v1.356 ARID1B Rebecca Foulger Gene: arid1b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.356 ARID1B Rebecca Foulger commented on gene: ARID1B: The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ARID1B.
Early onset or syndromic epilepsy v1.356 ARID1B Rebecca Foulger Publications for gene: ARID1B were set to
Early onset or syndromic epilepsy v1.355 ASAH1 Rebecca Foulger Marked gene: ASAH1 as ready
Early onset or syndromic epilepsy v1.355 ASAH1 Rebecca Foulger Gene: asah1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.355 ASAH1 Rebecca Foulger commented on gene: ASAH1: The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ASAH1.
Early onset or syndromic epilepsy v1.355 ASAH1 Rebecca Foulger Phenotypes for gene: ASAH1 were changed from Spinal muscular atrophy with progressive myoclonic epilepsy, 159950 to Spinal muscular atrophy with progressive myoclonic epilepsy, 159950; SMA with myoclonic epilepsy
Early onset or syndromic epilepsy v1.354 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 8955159; 22703880; 29169047; 24164096; 30291339; 27026573; 29169047; 30291339; 27026573; 26526000; 25578555; 31216804; 27723502
Early onset or syndromic epilepsy v1.354 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 29169047; 22703880; 24164096; 30291339; 27026573; 29169047; 30291339; 27026573; 26526000; 25578555; 31216804; 27723502
Early onset or syndromic epilepsy v1.353 ISCA-37429-Loss Rebecca Foulger changed review comment from: The Green rating by Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.; to: The Green rating by Alisdair McNeill (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.
Early onset or syndromic epilepsy v1.353 CREBBP Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'imprinted status unknown' to 'NOT imprinted' to match reviews from GLH experts Tracy Lester and Alisdair McNeill.
Early onset or syndromic epilepsy v1.353 CREBBP Rebecca Foulger Mode of inheritance for gene: CREBBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 CREBBP Rebecca Foulger commented on gene: CREBBP: The Green rating by Dr Alisdair McNeill (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of CREBBP.
Early onset or syndromic epilepsy v1.352 ISCA-37429-Loss Rebecca Foulger Marked Region: ISCA-37429-Loss as ready
Early onset or syndromic epilepsy v1.352 ISCA-37429-Loss Rebecca Foulger Region: isca-37429-loss has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.352 ISCA-37429-Loss Rebecca Foulger commented on Region: ISCA-37429-Loss: The Green rating by Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.
Early onset or syndromic epilepsy v1.352 ISCA-37429-Loss alisdair mcneill reviewed Region: ISCA-37429-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 FLNA alisdair mcneill reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 CREBBP alisdair mcneill reviewed gene: CREBBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29460469; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 ASAH1 alisdair mcneill reviewed gene: ASAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: SMA with myoclonic epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.352 ARID1B alisdair mcneill reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 KCNA1 Rebecca Foulger Publications for gene: KCNA1 were set to 29056246; 11026449; 9581771
Early onset or syndromic epilepsy v1.351 KCNA1 Rebecca Foulger edited their review of gene: KCNA1: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Early onset or syndromic epilepsy v1.351 SCN9A Rebecca Foulger edited their review of gene: SCN9A: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Early onset or syndromic epilepsy v1.351 FLNA Rebecca Foulger edited their review of gene: FLNA: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Early onset or syndromic epilepsy v1.351 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
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[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature
Early onset or syndromic epilepsy v1.351 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to AMBER
Added comment: This gene was reviewed for the ID panel (details below).

It could be also be considered for inclusion in the epilepsy panel as amber/green.

[Seizures in 8/14 individuals (generalized tonic-clonic/myoclonic, onset 3m - 6yrs) although some individuals were too young when last examined (eg. 8m) and sibs in one family (F7) were discordant for this feature at the ages of 4y7m (+) and 6y (-). Lissencephaly is often associated with seizures which have occasionally been observed in Apc2-deficient mice (PMID cited: 22573669)].

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Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
Sources: Literature
Early onset or syndromic epilepsy v1.351 AP2M1 Rebecca Foulger Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior
Early onset or syndromic epilepsy v1.350 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Early onset or syndromic epilepsy v1.349 PIGQ Rebecca Foulger Phenotypes for gene: PIGQ were changed from Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome to Epileptic encephalopathy, early infantile, 77, 618548; Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome
Early onset or syndromic epilepsy v1.348 PIGB Rebecca Foulger Phenotypes for gene: PIGB were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot
Early onset or syndromic epilepsy v1.347 ACTL6B Rebecca Foulger commented on gene: ACTL6B: ACTL6B now has a 'confirmed' rating for 'EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE' in the DD panel of Gene2Phenotype (DDG2P update, 18/09/2019), supporting the Green rating of ACTL6B on this panel.
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Classified gene: ALKBH8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Added comment: Comment on list classification: Demoted ALKBH8 from Green to Amber following review from Helen Lord on behalf of West Midlands, Oxford and Wessex GLH, and agreement from Richard Scott (Genomics England clinical team).
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.346 POLG2 Rebecca Foulger Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528; Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
Early onset or syndromic epilepsy v1.345 POLG2 Rebecca Foulger Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia to Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
Early onset or syndromic epilepsy v1.344 POLG2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept rating as Amber to match Helen Lord's review, but changed MOI from biallelic to 'BOTH biallelic and monoallelic' since (as Helen Lord notes) Young et al 2011 (PMID:21555342) report 4/11 patients with seizures as part of their phenotype and heterozygous variants in POLG2.
Early onset or syndromic epilepsy v1.344 POLG2 Rebecca Foulger Mode of inheritance for gene: POLG2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.343 PIGP Rebecca Foulger Tag watchlist tag was added to gene: PIGP.
Early onset or syndromic epilepsy v1.343 PIGP Rebecca Foulger Classified gene: PIGP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.343 PIGP Rebecca Foulger Added comment: Comment on list classification: PIGP was added to the panel and rated Green by Konstantinos Varvagiannis. Upgraded rating from Grey to Amber, and added watchlist tag, following review of literature and GLH-review by Helen Lord. Not yet associated with a disorder in Gene2Phenotype. 2 unrelated cases from the literature plus a third case from LOVD. Therefore Amber rating is appropriate.
Early onset or syndromic epilepsy v1.343 PIGP Rebecca Foulger Gene: pigp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.342 KATNB1 Rebecca Foulger Tag watchlist tag was added to gene: KATNB1.
Early onset or syndromic epilepsy v1.342 PMPCB Konstantinos Varvagiannis changed review comment from: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature; to: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.342 POLG2 Rebecca Foulger Publications for gene: POLG2 were set to 31286721; 27592148; 30157269
Early onset or syndromic epilepsy v1.341 SPATA5 Rebecca Foulger Classified gene: SPATA5 as Green List (high evidence)
Early onset or syndromic epilepsy v1.341 SPATA5 Rebecca Foulger Added comment: Comment on list classification: The Green review by Helen Lord (September 23rd 2019) supports the existing Green rating of SPATA5.
Early onset or syndromic epilepsy v1.341 SPATA5 Rebecca Foulger Gene: spata5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.340 KATNB1 Rebecca Foulger Classified gene: KATNB1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.340 KATNB1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber, and added watchlist tag: KATNB1 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype. Linked to lissencephaly with microcephaly in OMIM. There are sufficient cases from from the literature to support inclusion on the epilepsy panel (PMIDs:25521378, 25521379, 26640080) but epilepsy is not a feature in all cases and a Red recent review was left by Helen Lord. Therefore rated Amber as other panels may be more appropriate.
Early onset or syndromic epilepsy v1.340 KATNB1 Rebecca Foulger Gene: katnb1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.339 GABRA5 Rebecca Foulger Classified gene: GABRA5 as Green List (high evidence)
Early onset or syndromic epilepsy v1.339 GABRA5 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: GABRA5 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-70 in OMIM, and there are three cases from 2 publications (PMIDs 29961870 and 31056671) of GABRA5 variants associated with early infantile epileptic encephalopathy for a diagnostic rating. A Green rating is supported by a recent review by Helen Lord.
Early onset or syndromic epilepsy v1.339 GABRA5 Rebecca Foulger Gene: gabra5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.338 GABRA2 Rebecca Foulger Classified gene: GABRA2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.338 GABRA2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: GABRA2 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-78 in OMIM, and there are sufficient cases from from the literature (PMIDs:29422393, 29961870, 31032849, https://doi.org/10.1101/678219) of GABRA2 variants associated with early infantile epileptic encephalopathy for a diagnostic rating. A Green rating is supported by a recent review by Helen Lord.
Early onset or syndromic epilepsy v1.338 GABRA2 Rebecca Foulger Gene: gabra2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Marked gene: PAK1 as ready
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Gene: pak1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Classified gene: PAK1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Added comment: Comment on list classification: Updated PAK1 from Amber to Green: Subsequent to the 8th August Webex, Konstantinos Varvagiannis left a Green review of PAK1 on the Epilepsy panel based on an additional 2019 paper (Horn et al, PMID:31504246). Green rating is supported by a new review by Helen Lord.
Early onset or syndromic epilepsy v1.337 PAK1 Rebecca Foulger Gene: pak1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.336 GABRA2 Rebecca Foulger changed review comment from: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girls with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.; to: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girl with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.
Early onset or syndromic epilepsy v1.336 KATNB1 Rebecca Foulger changed review comment from: KATNB1 was added to the panel and rated Grey by Konstantinos Varvagiannis. Summary of evidence is as follows (see Konstantinos Varvagiannis' review for details): 3 publications reporting patients with biallelic KATNB1 variants. The phenotype includes seizures in some, but not all cases:

PMID:25521378. Mishra-Gorur et al. 2014 report 5 families with malformations of cortical development and homozygous KATNB1 variants. In many families homozygous variants in additional genes were also reported. Epilepsy was reported in 3/7 individuals (from 2 families): Supplementary Table S1).

PMID:25521379. Hu et al., 2014 report 3 Middle Eastern families with microcephaly, Global DD and seizures, and 3 different homozygous variants in KATNB1.

PMID:26640080. Yigit el al. 2016 report a homozygous acceptor splice-site intronic KATNB1 variant in a 5 year old Turkish girl born to consanguineous cousins, who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, dental abnormalities and developmental delay. She developed seizures age 6 months.; to: KATNB1 was added to the panel and rated Green by Konstantinos Varvagiannis. Summary of evidence is as follows (see Konstantinos Varvagiannis' review for details): 3 publications reporting patients with biallelic KATNB1 variants. The phenotype includes seizures in some, but not all cases:

PMID:25521378. Mishra-Gorur et al. 2014 report 5 families with malformations of cortical development and homozygous KATNB1 variants. In many families homozygous variants in additional genes were also reported. Epilepsy was reported in 3/7 individuals (from 2 families): Supplementary Table S1).

PMID:25521379. Hu et al., 2014 report 3 Middle Eastern families with microcephaly, Global DD and seizures, and 3 different homozygous variants in KATNB1.

PMID:26640080. Yigit el al. 2016 report a homozygous acceptor splice-site intronic KATNB1 variant in a 5 year old Turkish girl born to consanguineous cousins, who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, dental abnormalities and developmental delay. She developed seizures age 6 months.
Early onset or syndromic epilepsy v1.336 PMPCB Konstantinos Varvagiannis gene: PMPCB was added
gene: PMPCB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMPCB were set to 29576218
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954
Penetrance for gene: PMPCB were set to Complete
Review for gene: PMPCB was set to GREEN
Added comment: Review from the ID panel:

Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954).

5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218).

Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset.

Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2):
- c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B]
- c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C]
- c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs]

The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel).

Extensive studies demonstrated (perhaps a better summary provided by OMIM):
- Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells.
- Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity.
- Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters.
- Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue.

Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested).

PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable).

As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.336 PAK1 Helen Lord edited their review of gene: PAK1: Added comment: Horn et al paper 2019 (31504246). 4 unrelated patients with intellectual disability, macrocephaly and seizures had de novo het missense variants in the PAK1 gene using trio exome sequencing. 3/4 of the patients reported as having seizures/focal epilepsy. 1/4 had one typical febrile seizure (age not known). All 4 variants located in important domains and are likely to lead to a gain of function.; Changed rating: GREEN; Changed publications: 31504246
Early onset or syndromic epilepsy v1.336 POLG2 Helen Lord reviewed gene: POLG2: Rating: AMBER; Mode of pathogenicity: None; Publications: 21555342, 27592148, 30157269, 31286721; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.336 SPATA5 Helen Lord reviewed gene: SPATA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 26299366, 29343804; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.336 GOT2 Helen Lord reviewed gene: GOT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.336 GABRA2 Helen Lord reviewed gene: GABRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29422393, 31032849; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.336 GABRA5 Helen Lord reviewed gene: GABRA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961870, 31056671, 30033060; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.336 HNRNPR Helen Lord reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 26795593, 31079900; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.336 KATNB1 Helen Lord reviewed gene: KATNB1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.336 PIGP Helen Lord reviewed gene: PIGP: Rating: AMBER; Mode of pathogenicity: None; Publications: 28334793, 31139695; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.336 TIMM50 Konstantinos Varvagiannis reviewed gene: TIMM50: Rating: GREEN; Mode of pathogenicity: None; Publications: 27573165, 30190335, 31058414, Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T); Phenotypes: 3-methylglutaconic aciduria, type IX (MIM 617698); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.336 SLC25A12 Rebecca Foulger Publications for gene: SLC25A12 were set to 24515575; 19641205; 27290639; 26633542
Early onset or syndromic epilepsy v1.335 GABRA5 Rebecca Foulger commented on gene: GABRA5: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): 3 literature cases from 2 papers of patients with epileptic encephalopathy and GABRA5 missense variants:

PMID:29961870, Butler et al. 2018 report a 2 year old boy with EIEE (seizure onset age 4 months) and a p.V294L variant in GABRA5. Cognitive and motor development slowed at the time of seizure onset. A de novo variant in MIA2 was also detected but was considered unlikely to contribute to the patients phenotypes due to allele frequencies in the gnomAD database.

PMID:31056671, Hernandez et al. 2019 screened a cohort of patients with epilepsy and ID and report 2 individuals with EIEE and GABRA5 missense variants (V294F and S413F). Seizures included focal, febrile, focal and tonic, epileptic spasms and status epilepticus. Both had severe ID and delayed motor development.
Early onset or syndromic epilepsy v1.335 GABRA1 Rebecca Foulger Publications for gene: GABRA1 were set to 24623842; 11992121; 21714819; 16718694
Early onset or syndromic epilepsy v1.334 GABRA2 Rebecca Foulger commented on gene: GABRA2: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girls with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.
Early onset or syndromic epilepsy v1.334 GABRA2 Rebecca Foulger Phenotypes for gene: GABRA2 were changed from Epileptic encephalopathy, early infantile, 78 (MIM 618557) to Epileptic encephalopathy, early infantile, 78, 618557
Early onset or syndromic epilepsy v1.333 KATNB1 Rebecca Foulger Phenotypes for gene: KATNB1 were changed from Lissencephaly 6, with microcephaly, 616212 to Lissencephaly 6, with microcephaly, 616212; seizures
Early onset or syndromic epilepsy v1.332 KATNB1 Rebecca Foulger commented on gene: KATNB1
Early onset or syndromic epilepsy v1.332 KATNB1 Rebecca Foulger Phenotypes for gene: KATNB1 were changed from Lissencephaly 6, with microcephaly (MIM 616212) to Lissencephaly 6, with microcephaly, 616212
Early onset or syndromic epilepsy v1.331 GRIA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIA2.
Early onset or syndromic epilepsy v1.331 KMT5B Rebecca Foulger Source Wessex and West Midlands GLH was added to KMT5B.
Early onset or syndromic epilepsy v1.331 KCNH5 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNH5.
Early onset or syndromic epilepsy v1.331 KCND2 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCND2.
Early onset or syndromic epilepsy v1.331 CSNK2A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to CSNK2A1.
Early onset or syndromic epilepsy v1.331 BCORL1 Rebecca Foulger Source Wessex and West Midlands GLH was added to BCORL1.
Early onset or syndromic epilepsy v1.331 ZNF142 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZNF142.
Early onset or syndromic epilepsy v1.331 ZMIZ1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZMIZ1.
Early onset or syndromic epilepsy v1.331 USP7 Rebecca Foulger Source Wessex and West Midlands GLH was added to USP7.
Early onset or syndromic epilepsy v1.331 TRRAP Rebecca Foulger Source Wessex and West Midlands GLH was added to TRRAP.
Early onset or syndromic epilepsy v1.331 TRPM3 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRPM3.
Early onset or syndromic epilepsy v1.331 SLC35A3 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC35A3.
Early onset or syndromic epilepsy v1.331 RNF13 Rebecca Foulger Source Wessex and West Midlands GLH was added to RNF13.
Early onset or syndromic epilepsy v1.331 PAK1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PAK1.
Early onset or syndromic epilepsy v1.331 NUS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NUS1.
Early onset or syndromic epilepsy v1.331 LSS Rebecca Foulger Source Wessex and West Midlands GLH was added to LSS.
Early onset or syndromic epilepsy v1.331 FUK Rebecca Foulger Source Wessex and West Midlands GLH was added to FUK.
Early onset or syndromic epilepsy v1.331 CLCN6 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLCN6.
Early onset or syndromic epilepsy v1.331 AIMP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to AIMP2.
Early onset or syndromic epilepsy v1.331 AFF3 Rebecca Foulger Source Wessex and West Midlands GLH was added to AFF3.
Early onset or syndromic epilepsy v1.331 ZDHHC9 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZDHHC9.
Early onset or syndromic epilepsy v1.331 WARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to WARS2.
Early onset or syndromic epilepsy v1.331 VPS11 Rebecca Foulger Source Wessex and West Midlands GLH was added to VPS11.
Early onset or syndromic epilepsy v1.331 VAMP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to VAMP2.
Early onset or syndromic epilepsy v1.331 SNAP25 Rebecca Foulger Source Wessex and West Midlands GLH was added to SNAP25.
Early onset or syndromic epilepsy v1.331 SMARCC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SMARCC2.
Early onset or syndromic epilepsy v1.331 PPP2CA Rebecca Foulger Source Wessex and West Midlands GLH was added to PPP2CA.
Early onset or syndromic epilepsy v1.331 PIGB Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGB.
Early onset or syndromic epilepsy v1.331 PARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PARS2.
Early onset or syndromic epilepsy v1.331 P4HTM Rebecca Foulger Source Wessex and West Midlands GLH was added to P4HTM.
Early onset or syndromic epilepsy v1.331 NBEA Rebecca Foulger Source Wessex and West Midlands GLH was added to NBEA.
Early onset or syndromic epilepsy v1.331 KMT2E Rebecca Foulger Source Wessex and West Midlands GLH was added to KMT2E.
Early onset or syndromic epilepsy v1.331 KCNT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNT2.
Early onset or syndromic epilepsy v1.331 DHPS Rebecca Foulger Source Wessex and West Midlands GLH was added to DHPS.
Early onset or syndromic epilepsy v1.331 DEGS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DEGS1.
Early onset or syndromic epilepsy v1.331 CTNNA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CTNNA2.
Early onset or syndromic epilepsy v1.331 CACNA1B Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1B.
Early onset or syndromic epilepsy v1.331 ATN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATN1.
Early onset or syndromic epilepsy v1.331 AP2M1 Rebecca Foulger Source Wessex and West Midlands GLH was added to AP2M1.
Early onset or syndromic epilepsy v1.331 ALKBH8 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALKBH8.
Early onset or syndromic epilepsy v1.331 ACTL6B Rebecca Foulger Source Wessex and West Midlands GLH was added to ACTL6B.
Early onset or syndromic epilepsy v1.330 GRIA2 Rebecca Foulger Source NHS GMS was added to GRIA2.
Early onset or syndromic epilepsy v1.330 KMT5B Rebecca Foulger Source NHS GMS was added to KMT5B.
Early onset or syndromic epilepsy v1.330 KCNH5 Rebecca Foulger Source NHS GMS was added to KCNH5.
Early onset or syndromic epilepsy v1.330 KCND2 Rebecca Foulger Source NHS GMS was added to KCND2.
Early onset or syndromic epilepsy v1.330 CSNK2A1 Rebecca Foulger Source NHS GMS was added to CSNK2A1.
Early onset or syndromic epilepsy v1.330 BCORL1 Rebecca Foulger Source NHS GMS was added to BCORL1.
Early onset or syndromic epilepsy v1.330 ZNF142 Rebecca Foulger Source NHS GMS was added to ZNF142.
Early onset or syndromic epilepsy v1.330 ZMIZ1 Rebecca Foulger Source NHS GMS was added to ZMIZ1.
Early onset or syndromic epilepsy v1.330 USP7 Rebecca Foulger Source NHS GMS was added to USP7.
Early onset or syndromic epilepsy v1.330 TRRAP Rebecca Foulger Source NHS GMS was added to TRRAP.
Early onset or syndromic epilepsy v1.330 TRPM3 Rebecca Foulger Source NHS GMS was added to TRPM3.
Early onset or syndromic epilepsy v1.330 SLC35A3 Rebecca Foulger Source NHS GMS was added to SLC35A3.
Early onset or syndromic epilepsy v1.330 RNF13 Rebecca Foulger Source NHS GMS was added to RNF13.
Early onset or syndromic epilepsy v1.330 PAK1 Rebecca Foulger Source NHS GMS was added to PAK1.
Early onset or syndromic epilepsy v1.330 NUS1 Rebecca Foulger Source NHS GMS was added to NUS1.
Early onset or syndromic epilepsy v1.330 LSS Rebecca Foulger Source NHS GMS was added to LSS.
Early onset or syndromic epilepsy v1.330 FUK Rebecca Foulger Source NHS GMS was added to FUK.
Early onset or syndromic epilepsy v1.330 CLCN6 Rebecca Foulger Source NHS GMS was added to CLCN6.
Early onset or syndromic epilepsy v1.330 AIMP2 Rebecca Foulger Source NHS GMS was added to AIMP2.
Early onset or syndromic epilepsy v1.330 AFF3 Rebecca Foulger Source NHS GMS was added to AFF3.
Early onset or syndromic epilepsy v1.330 ZDHHC9 Rebecca Foulger Source NHS GMS was added to ZDHHC9.
Early onset or syndromic epilepsy v1.330 WARS2 Rebecca Foulger Source NHS GMS was added to WARS2.
Early onset or syndromic epilepsy v1.330 VPS11 Rebecca Foulger Source NHS GMS was added to VPS11.
Early onset or syndromic epilepsy v1.330 VAMP2 Rebecca Foulger Source NHS GMS was added to VAMP2.
Early onset or syndromic epilepsy v1.330 SNAP25 Rebecca Foulger Source NHS GMS was added to SNAP25.
Early onset or syndromic epilepsy v1.330 SMARCC2 Rebecca Foulger Source NHS GMS was added to SMARCC2.
Early onset or syndromic epilepsy v1.330 PPP2CA Rebecca Foulger Source NHS GMS was added to PPP2CA.
Early onset or syndromic epilepsy v1.330 PIGB Rebecca Foulger Source NHS GMS was added to PIGB.
Early onset or syndromic epilepsy v1.330 PARS2 Rebecca Foulger Source NHS GMS was added to PARS2.
Early onset or syndromic epilepsy v1.330 P4HTM Rebecca Foulger Source NHS GMS was added to P4HTM.
Early onset or syndromic epilepsy v1.330 NBEA Rebecca Foulger Source NHS GMS was added to NBEA.
Early onset or syndromic epilepsy v1.330 KMT2E Rebecca Foulger Source NHS GMS was added to KMT2E.
Early onset or syndromic epilepsy v1.330 KCNT2 Rebecca Foulger Source NHS GMS was added to KCNT2.
Early onset or syndromic epilepsy v1.330 DHPS Rebecca Foulger Source NHS GMS was added to DHPS.
Early onset or syndromic epilepsy v1.330 DEGS1 Rebecca Foulger Source NHS GMS was added to DEGS1.
Early onset or syndromic epilepsy v1.330 CTNNA2 Rebecca Foulger Source NHS GMS was added to CTNNA2.
Early onset or syndromic epilepsy v1.330 CACNA1B Rebecca Foulger Source NHS GMS was added to CACNA1B.
Early onset or syndromic epilepsy v1.330 ATN1 Rebecca Foulger Source NHS GMS was added to ATN1.
Early onset or syndromic epilepsy v1.330 AP2M1 Rebecca Foulger Source NHS GMS was added to AP2M1.
Early onset or syndromic epilepsy v1.330 ALKBH8 Rebecca Foulger Source NHS GMS was added to ALKBH8.
Early onset or syndromic epilepsy v1.330 ACTL6B Rebecca Foulger Source NHS GMS was added to ACTL6B.
Early onset or syndromic epilepsy v1.329 CACNA2D2 Konstantinos Varvagiannis reviewed gene: CACNA2D2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23339110, 24358150, 30410802, 29997391, 31402629, 11487633, 11756448, 4177347, 14660671, 15331424; Phenotypes: Cerebellar atrophy with seizures and variable developmental delay (MIM 618501); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v1.329 PIGP Rebecca Foulger changed review comment from: 2 independent cases reported in OMIM: 2 compound heterozygous siblings with early infantile epileptic encephalopathy-55 reported by Johnstone et al., 2017 (PMID:28334793). Plus a 2-year-old girl, with a homozygous 1bp deletion, born of unrelated parents, with EIEE55 reported by Krenn et al.,2019 (PMID:31139695).; to: Summary of cases (see Konstantinos Varvagiannis' review for details). 2 independent cases reported in OMIM: 2 compound heterozygous siblings with early infantile epileptic encephalopathy-55 reported by Johnstone et al., 2017 (PMID:28334793). Plus a 2-year-old girl, with a homozygous 1bp deletion, born of unrelated parents, with EIEE55 reported by Krenn et al.,2019 (PMID:31139695). The third case reported by Konstantinos comes from LOVD.
Early onset or syndromic epilepsy v1.329 PIGP Rebecca Foulger commented on gene: PIGP
Early onset or syndromic epilepsy v1.329 PIGP Rebecca Foulger Phenotypes for gene: PIGP were changed from Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to ?Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Early onset or syndromic epilepsy v1.328 GABRA5 Rebecca Foulger changed review comment from: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date for Epileptic Encephalopathy.; to: Added missense tag because, as Konstantinos Varvagiannis notes, only missense GABRA5 variants reported to date for Epileptic Encephalopathy.
Early onset or syndromic epilepsy v1.328 GABRA5 Rebecca Foulger changed review comment from: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date.; to: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date for Epileptic Encephalopathy.
Early onset or syndromic epilepsy v1.328 GABRA5 Rebecca Foulger commented on gene: GABRA5
Early onset or syndromic epilepsy v1.328 GABRA5 Rebecca Foulger Phenotypes for gene: GABRA5 were changed from Epileptic encephalopathy, early infantile, 79 (MIM 618559) to Epileptic encephalopathy, early infantile, 79, 618559
Early onset or syndromic epilepsy v1.327 GABRA5 Rebecca Foulger Publications for gene: GABRA5 were set to 29961870
Early onset or syndromic epilepsy v1.326 GABRA5 Rebecca Foulger Tag missense tag was added to gene: GABRA5.
Early onset or syndromic epilepsy v1.326 GABRA2 Rebecca Foulger Deleted their comment
Early onset or syndromic epilepsy v1.326 GABRA2 Rebecca Foulger commented on gene: GABRA2: Added 'missense' tag based on Konstantinos Varvagiannis' comment that all variants to-date are missense variants.
Early onset or syndromic epilepsy v1.326 GABRA2 Rebecca Foulger Tag missense tag was added to gene: GABRA2.
Early onset or syndromic epilepsy v1.326 GABRA2 Rebecca Foulger commented on gene: GABRA2
Early onset or syndromic epilepsy v1.326 HNRNPR Catherine Snow Tag watchlist tag was added to gene: HNRNPR.
Early onset or syndromic epilepsy v1.326 HNRNPR Catherine Snow Classified gene: HNRNPR as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.326 HNRNPR Catherine Snow Gene: hnrnpr has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.325 HNRNPR Catherine Snow reviewed gene: HNRNPR: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.325 GABRA2 Konstantinos Varvagiannis changed review comment from: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized in the suppl. table 1 by Sanchis-Juan et al. (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
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As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].; to: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized, Maljevic - Table 1 (7 patients) and/or in the suppl. table 1 by Sanchis-Juan et al. (8 patients) (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
------
GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].
Early onset or syndromic epilepsy v1.325 TRAPPC6B Rebecca Foulger Publications for gene: TRAPPC6B were set to 28626029; 28397838
Early onset or syndromic epilepsy v1.324 TRAPPC6B Rebecca Foulger commented on gene: TRAPPC6B: The Amber review by Konstantinos Varvagiannis (25 Aug 2019) agrees with the current Amber rating of TRAPPC6B: therefore no further curation required.
Early onset or syndromic epilepsy v1.324 GRIA2 Rebecca Foulger Classified gene: GRIA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.324 GRIA2 Rebecca Foulger Added comment: Comment on list classification: Changed rating of GRIA2 from Grey to Amber based on Amber post-Webex review from Helen Lord. Currently insufficient evidence for a diagnostic rating.
Early onset or syndromic epilepsy v1.324 GRIA2 Rebecca Foulger Gene: gria2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.323 NUS1 Rebecca Foulger Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.322 NUS1 Rebecca Foulger Classified gene: NUS1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.322 NUS1 Rebecca Foulger Gene: nus1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.321 NUS1 Rebecca Foulger commented on gene: NUS1: Updated rating from Amber to Green based on Green post-Webex review from Helen Lord. Also updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic' based on Helen's review.
Early onset or syndromic epilepsy v1.321 ZMIZ1 Rebecca Foulger commented on gene: ZMIZ1: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.321 ZDHHC9 Rebecca Foulger commented on gene: ZDHHC9: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.321 WARS2 Rebecca Foulger commented on gene: WARS2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.321 VPS11 Rebecca Foulger commented on gene: VPS11: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.321 VAMP2 Rebecca Foulger commented on gene: VAMP2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.321 SNAP25 Rebecca Foulger commented on gene: SNAP25: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.321 SMARCC2 Rebecca Foulger commented on gene: SMARCC2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.321 SMARCC2 Rebecca Foulger Phenotypes for gene: SMARCC2 were changed from Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features to Coffin-Siris syndrome 8, 618362; Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features
Early onset or syndromic epilepsy v1.320 SLC35A3 Rebecca Foulger commented on gene: SLC35A3: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.320 RNF13 Rebecca Foulger commented on gene: RNF13: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.320 PPP2CA Rebecca Foulger commented on gene: PPP2CA: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.320 POLG Rebecca Foulger commented on gene: POLG: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.320 POLG Rebecca Foulger changed review comment from: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; to: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.320 PIGB Rebecca Foulger commented on gene: PIGB: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.320 PARS2 Rebecca Foulger commented on gene: PARS2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.320 PAK1 Rebecca Foulger Publications for gene: PAK1 were set to 30290153
Early onset or syndromic epilepsy v1.319 P4HTM Rebecca Foulger Phenotypes for gene: P4HTM were changed from Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities, 618493; Abnormality of the eye; Seizures; Dysautonomia; Central hypotonia; Muscular hypotonia; Hypoventilation; Intellectual disability; Sleep apnea; Global developmental delay to Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities, 618493; Seizures; Intellectual disability; Global developmental delay
Early onset or syndromic epilepsy v1.318 P4HTM Rebecca Foulger Phenotypes for gene: P4HTM were changed from Abnormality of the eye; Seizures; Dysautonomia; Central hypotonia; Muscular hypotonia; Hypoventilation; Intellectual disability; Sleep apnea; Global developmental delay to Hypotonia, hyperventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities, 618493; Abnormality of the eye; Seizures; Dysautonomia; Central hypotonia; Muscular hypotonia; Hypoventilation; Intellectual disability; Sleep apnea; Global developmental delay
Early onset or syndromic epilepsy v1.317 NUS1 Rebecca Foulger Phenotypes for gene: NUS1 were changed from #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function to ?Congenital disorder of glycosylation, type 1aa, 617082; Mental retardation, autosomal dominant 55, with seizures, 617831; Abnormality of extrapyramidal motor function
Early onset or syndromic epilepsy v1.316 NBEA Rebecca Foulger commented on gene: NBEA: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.316 LSS Rebecca Foulger commented on gene: LSS: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.316 KMT5B Rebecca Foulger commented on gene: KMT5B: Kept rating as Red based on Red post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.316 KMT5B Rebecca Foulger Publications for gene: KMT5B were set to 29276005
Early onset or syndromic epilepsy v1.315 KMT2E Rebecca Foulger commented on gene: KMT2E: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.315 KCNT2 Rebecca Foulger commented on gene: KCNT2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.315 KCNH5 Rebecca Foulger commented on gene: KCNH5: Kept rating as Red based on Red post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.315 KCNH5 Rebecca Foulger Publications for gene: KCNH5 were set to 23647072
Early onset or syndromic epilepsy v1.314 FUK Rebecca Foulger commented on gene: FUK: Kept rating as Amber based on Amber post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.314 DHPS Rebecca Foulger commented on gene: DHPS: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.314 DEGS1 Rebecca Foulger commented on gene: DEGS1: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.314 CTNNA2 Rebecca Foulger commented on gene: CTNNA2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.314 CACNA1B Rebecca Foulger commented on gene: CACNA1B: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.314 BCORL1 Rebecca Foulger commented on gene: BCORL1: Kept rating as Red based on Red post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.314 BCORL1 Rebecca Foulger Phenotypes for gene: BCORL1 were changed from Intellectual disability and seizures to Intellectual disability and seizures; Shukla-Vernon syndrome, 301029
Early onset or syndromic epilepsy v1.313 BCORL1 Rebecca Foulger Publications for gene: BCORL1 were set to 30941876
Early onset or syndromic epilepsy v1.312 ATN1 Rebecca Foulger commented on gene: ATN1: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.312 ATN1 Rebecca Foulger Phenotypes for gene: ATN1 were changed from Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures; Generalized hypotonia
Early onset or syndromic epilepsy v1.311 ATN1 Rebecca Foulger Phenotypes for gene: ATN1 were changed from Abnormality of the kidney; Seizures; Hypotonia; Cleft palate; Developmental Delay; Abnormality of the cardiovascular system; Epilepsy; Generalized hypotonia; Feeding difficulties; Intellectual disability; Global developmental delay; Digit Abnormalities to Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, 618494; Global developmental delay; Intellectual disability; Seizures
Early onset or syndromic epilepsy v1.310 AP2M1 Rebecca Foulger commented on gene: AP2M1: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.310 AP2M1 Rebecca Foulger Mode of pathogenicity for gene: AP2M1 was changed from Other to Other
Early onset or syndromic epilepsy v1.309 ALKBH8 Rebecca Foulger Phenotypes for gene: ALKBH8 were changed from Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, 618504; Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability
Early onset or syndromic epilepsy v1.308 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.308 ACTL6B Rebecca Foulger Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy to Epileptic encephalopathy, early infantile, 76, 618468; Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy
Early onset or syndromic epilepsy v1.307 USP7 Rebecca Foulger Marked gene: USP7 as ready
Early onset or syndromic epilepsy v1.307 USP7 Rebecca Foulger Gene: usp7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.307 USP7 Rebecca Foulger commented on gene: USP7: Kept rating as Amber based on two post-Webex Amber reviews from Helen Lord and Alison Callaway.
Early onset or syndromic epilepsy v1.307 TRPM3 Rebecca Foulger Marked gene: TRPM3 as ready
Early onset or syndromic epilepsy v1.307 TRPM3 Rebecca Foulger Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.307 TRPM3 Rebecca Foulger Publications for gene: TRPM3 were set to 31278393
Early onset or syndromic epilepsy v1.306 TRPM3 Rebecca Foulger commented on gene: TRPM3: Kept rating as Amber based on two post-Webex Amber reviews from Helen Lord and Alison Callaway.
Early onset or syndromic epilepsy v1.306 KCND2 Rebecca Foulger commented on gene: KCND2: Kept rating as Red based on two post-Webex Red reviews from Helen Lord and Alison Callaway.
Early onset or syndromic epilepsy v1.306 KCND2 Rebecca Foulger Publications for gene: KCND2 were set to 24501278; 16934482
Early onset or syndromic epilepsy v1.305 KCND2 Rebecca Foulger Publications for gene: KCND2 were set to 24501278
Early onset or syndromic epilepsy v1.304 CSNK2A1 Rebecca Foulger commented on gene: CSNK2A1: Kept rating as Red based on post-Webex reviews from Helen Lord and Alison Callaway: Although there is an argument to upgrade to Amber, epilepsy is not a major part of the overall phenotype so on balance kept rating as Red.
Early onset or syndromic epilepsy v1.304 CSNK2A1 Rebecca Foulger Phenotypes for gene: CSNK2A1 were changed from seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome to Neurodevelopmental abnormalities and dysmorphic features; seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome
Early onset or syndromic epilepsy v1.303 CSNK2A1 Rebecca Foulger Publications for gene: CSNK2A1 were set to 30655572
Early onset or syndromic epilepsy v1.302 CLCN6 Rebecca Foulger Classified gene: CLCN6 as Red List (low evidence)
Early onset or syndromic epilepsy v1.302 CLCN6 Rebecca Foulger Added comment: Comment on list classification: Changed rating from Amber to Red based on post-Webex reviews from Helen Lord and Alison Callaway: the current published association between CLCN6 and seizures is weak.
Early onset or syndromic epilepsy v1.302 CLCN6 Rebecca Foulger Gene: clcn6 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.301 AIMP2 Rebecca Foulger commented on gene: AIMP2: Kept rating as Amber based on post-Webex reviews from Helen Lord and Alison Callaway. Added 'watchlist' tag based on PMID:26795593 who report an additional case but there is uncertainty over the clinical significance of the reported variant.
Early onset or syndromic epilepsy v1.301 AIMP2 Rebecca Foulger Tag watchlist tag was added to gene: AIMP2.
Early onset or syndromic epilepsy v1.301 AIMP2 Rebecca Foulger Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Epileptic Encephalopathy; Infantile Spasms; Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Early onset or syndromic epilepsy v1.300 AIMP2 Rebecca Foulger Publications for gene: AIMP2 were set to 29215095
Early onset or syndromic epilepsy v1.299 GABRA2 Konstantinos Varvagiannis reviewed gene: GABRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29422393, 29961870, 31032849, 31032848, doi.org/10.1101/678219; Phenotypes: Epileptic encephalopathy, early infantile, 78 (MIM 618557); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.299 GABRA2 Konstantinos Varvagiannis Deleted their review
Early onset or syndromic epilepsy v1.299 GABRA2 Konstantinos Varvagiannis gene: GABRA2 was added
gene: GABRA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GABRA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GABRA2 were set to 29422393; 29961870; 31032849; 31032848; doi.org/10.1101/678219
Phenotypes for gene: GABRA2 were set to Epileptic encephalopathy, early infantile, 78 (MIM 618557)
Penetrance for gene: GABRA2 were set to unknown
Review for gene: GABRA2 was set to GREEN
Added comment: Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In almost all affected individuals, the variants were missense and had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized in the suppl. table 1 by Sanchis-Juan et al. (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx?download=true). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementionned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various reported mutations to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
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GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
------
As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].
Sources: Literature
Early onset or syndromic epilepsy v1.299 GABRA5 Konstantinos Varvagiannis reviewed gene: GABRA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961870, 31056671; Phenotypes: Epileptic encephalopathy, early infantile, 79 (MIM 618559); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.299 GABRA5 Konstantinos Varvagiannis Deleted their review
Early onset or syndromic epilepsy v1.299 GABRA5 Konstantinos Varvagiannis gene: GABRA5 was added
gene: GABRA5 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GABRA5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GABRA5 were set to 29961870
Phenotypes for gene: GABRA5 were set to Epileptic encephalopathy, early infantile, 79 (MIM 618559)
Penetrance for gene: GABRA5 were set to unknown
Review for gene: GABRA5 was set to GREEN
Added comment: Heterozygous pathogenic GABRA5 variants cause Epileptic encephalopathy, early infantile, 79 (MIM 618559) [entry recently updated in OMIM].

At least 3 relevant individuals with this diagnosis have been reported to date:

- Butler et al. (2018 - PMID: 29961870) described a 2 y.o. boy with early infantile epileptic encephalopathy (seizure onset at the age of 4m). The boy was found to harbor a de novo missense variant (NM_000810.3:c.880G>C - p.Val294Leu) identified following trio-WGS and confirmed by Sanger sequencing. Studies in HEK293 cells demonstrated expression at the surface and incorporation of the mutant subunit in the channel. The α5(V294L)β2γ2s receptors were 10 times more sensitive to GABA compared to wt, but were more likely to desensitize leading to reduced maximum GABA-evoked currents.

- Hernandez et al. (2019 - PMID: 31056671) reported on 2 unrelated individuals with early-onset epileptic encephalopathy due to de novo GABRA5 variants identified by targeted NGS sequencing (480 epilepsy-related genes):

A 3y 10m male with seizure onset at the age of 4m, severe motor delay and ID, frontotemporal atrophy and thin CC upon MRI imaging was found to harbor a de novo missense variant (NM_000810.3:c.880G>T / p.Val294Phe).

A further unrelated subject (a 7 y.o. male) with seizure onset at the age of 3 months, severe DD and ID and cortical atrophy / thin CC upon MRI imaging was heterozygous for another missense variant which had occurred as a de novo event (NM_000810.3:c.1238C>T - p.Ser413Phe).

Functional studies: Expression of HA-tagged α5(V294F) subunits at dendritic GABAergic synapses of rat hippocampal neurons was decreased compared to wt, in contrast with the expression of α5(S413F) subunits which was similar to wt. As the α5(V294F) appeared accumulated in the soma of the neurons, the authors performed additional studies – using HEK293T cells – to show that while the α5(S413F) spread outside the ER, α5(V294F) subunits localized to the ER. This was suggestive of a trafficking defect/ER retention. Co-expression of wt or mutant HA-tagged subunits, with β3 and γ2 subunits in HEK293T cells was carried out to assess assembly and trafficking to cell membranes. Reduced surface levels as well as total (whole cell lysate) levels were shown for α5(V294F). Surface levels and total levels of the α5(S413F) were not changed compared to wt. Surface levels of the β3 subunit were however lower in the case of α5(S413F), a finding which could be suggestive of a dominant negative effect. Both GABRA5 mutations resulted in decreased GABA-evoked current amplitudes in both neuronal and non-neuronal (HEK293T) cells.
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The corresponding phenotype in OMIM is Epileptic encephalopathy, early infantile, 79 (618559).
GABRA5 is not associated with any phenotype in G2P.

This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
-------
As a result, GABRA5 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, 3 unrelated individuals, 3 variants, supporting functional studies for all variants) or amber.
Sources: Literature
Early onset or syndromic epilepsy v1.299 SLC35A2 Rebecca Foulger Marked gene: SLC35A2 as ready
Early onset or syndromic epilepsy v1.299 SLC35A2 Rebecca Foulger Gene: slc35a2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.299 SLC35A2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as XLD based on post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.299 SLC35A2 Rebecca Foulger Mode of inheritance for gene: SLC35A2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.298 SLC35A2 Rebecca Foulger Publications for gene: SLC35A2 were set to 24115232; 27743886; 30746764; 30584598; 29679388
Early onset or syndromic epilepsy v1.297 SLC1A2 Rebecca Foulger Marked gene: SLC1A2 as ready
Early onset or syndromic epilepsy v1.297 SLC1A2 Rebecca Foulger Gene: slc1a2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.297 SLC1A2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.297 SLC1A2 Rebecca Foulger Mode of inheritance for gene: SLC1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.296 SLC16A2 Rebecca Foulger Marked gene: SLC16A2 as ready
Early onset or syndromic epilepsy v1.296 SLC16A2 Rebecca Foulger Gene: slc16a2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.296 SLC16A2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.296 SLC16A2 Rebecca Foulger Mode of inheritance for gene: SLC16A2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.295 SLC16A2 Rebecca Foulger Phenotypes for gene: SLC16A2 were changed from Allan-Herndon-Dudley syndrome, 300523 to Allan-Herndon-Dudley syndrome, 300523; AHDS
Early onset or syndromic epilepsy v1.294 SLC16A2 Rebecca Foulger Publications for gene: SLC16A2 were set to 27212794; 15980113
Early onset or syndromic epilepsy v1.293 SLC16A2 Rebecca Foulger Phenotypes for gene: SLC16A2 were changed from Allan-Herndon-Dudley syndrome to Allan-Herndon-Dudley syndrome, 300523
Early onset or syndromic epilepsy v1.292 SLC16A2 Rebecca Foulger Publications for gene: SLC16A2 were set to Maranduba et al (2006) J Med Genet 43: 457_460
Early onset or syndromic epilepsy v1.291 SLC12A5 Rebecca Foulger Marked gene: SLC12A5 as ready
Early onset or syndromic epilepsy v1.291 SLC12A5 Rebecca Foulger Gene: slc12a5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.291 SLC12A5 Rebecca Foulger Phenotypes for gene: SLC12A5 were changed from epilepsy of infancy with migrating focal seizures (EIMFS) to epilepsy of infancy with migrating focal seizures (EIMFS); Epileptic encephalopathy, early infantile, 34, 616645; {Epilepsy, idiopathic generalized, susceptibility to, 14}, 616685
Early onset or syndromic epilepsy v1.290 SLC12A5 Rebecca Foulger Publications for gene: SLC12A5 were set to PMID: 26333769; 24668262
Early onset or syndromic epilepsy v1.289 SLC12A5 Rebecca Foulger Mode of inheritance for gene: SLC12A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.288 SLC12A5 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed Mode of Inheritance from 'BOTH monoallelic and bialleic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' based on post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.288 SLC12A5 Rebecca Foulger Mode of inheritance for gene: SLC12A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.287 PIGA Rebecca Foulger Marked gene: PIGA as ready
Early onset or syndromic epilepsy v1.287 PIGA Rebecca Foulger Gene: piga has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.287 PIGA Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as XLR based on post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.287 PIGA Rebecca Foulger Mode of inheritance for gene: PIGA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.286 PIGA Rebecca Foulger Phenotypes for gene: PIGA were changed from Multiple congenital anomalies-hypotonia-seizures syndrome 2 to Multiple congenital anomalies-hypotonia-seizures syndrome 2, 300868
Early onset or syndromic epilepsy v1.285 PIGA Rebecca Foulger Publications for gene: PIGA were set to Johnston et al (2012) Am J Hum Genet 90, 295 300
Early onset or syndromic epilepsy v1.284 NRXN1 Rebecca Foulger Marked gene: NRXN1 as ready
Early onset or syndromic epilepsy v1.284 NRXN1 Rebecca Foulger Gene: nrxn1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.284 NRXN1 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on Post-Webex review by Helen Lord.; to: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.284 NRXN1 Rebecca Foulger Publications for gene: NRXN1 were set to 21964664; 19896112; 30031152; 23533028
Early onset or syndromic epilepsy v1.283 NRXN1 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on Post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.283 NRXN1 Rebecca Foulger Mode of inheritance for gene: NRXN1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.282 MED12 Rebecca Foulger Marked gene: MED12 as ready
Early onset or syndromic epilepsy v1.282 MED12 Rebecca Foulger Gene: med12 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.282 MED12 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on Post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.282 MED12 Rebecca Foulger Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.281 MAGI2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic' to 'BIALLELIC' based on Post-Webex review by Helen Lord (AD inheritance was based on deletions including the MAGI2 gene).
Early onset or syndromic epilepsy v1.281 MAGI2 Rebecca Foulger Mode of inheritance for gene: MAGI2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.280 MAGI2 Rebecca Foulger changed review comment from: Comment on mode of inheritance: OMIM lists AR inheritance for 'Nephrotic syndrome, type 15' (MIM:617609). Gene2Phenotype lists 'monoallelic' inheritance for EARLY ONSET EPILEPTIC ENCEPHALOPATHY.; to: Comment on mode of inheritance: OMIM lists AR inheritance for 'Nephrotic syndrome, type 15' (MIM:617609). Gene2Phenotype lists 'monoallelic' inheritance for EARLY ONSET EPILEPTIC ENCEPHALOPATHY based on PMID:18565486 which examines deletions spanning MAGI2.
Early onset or syndromic epilepsy v1.280 IKBKG Rebecca Foulger Marked gene: IKBKG as ready
Early onset or syndromic epilepsy v1.280 IKBKG Rebecca Foulger Gene: ikbkg has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.280 IKBKG Rebecca Foulger Publications for gene: IKBKG were set to 30151858; 28794079; 24339369
Early onset or syndromic epilepsy v1.279 IKBKG Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as XLD based on Post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.279 IKBKG Rebecca Foulger Mode of inheritance for gene: IKBKG was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.278 IDH2 Rebecca Foulger Marked gene: IDH2 as ready
Early onset or syndromic epilepsy v1.278 IDH2 Rebecca Foulger Gene: idh2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.278 IDH2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as MONOALLELIC based on post-Webex review from Helen Lord. Note that the rating of IDH2 was not discussed on the group Webex (2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy) because IDH2 has a Green rating on the 'Inborn errors of metabolism' panel, and therefore will be Green on the Epilepsy super panel for R59.
Early onset or syndromic epilepsy v1.278 IDH2 Rebecca Foulger Mode of inheritance for gene: IDH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.277 HEPACAM Rebecca Foulger Marked gene: HEPACAM as ready
Early onset or syndromic epilepsy v1.277 HEPACAM Rebecca Foulger Gene: hepacam has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.277 HEPACAM Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as BIALLELIC based on post-Webex review from Helen Lord, and original comment from Zornitza Stark that AD form is not associated with seizures.
Early onset or syndromic epilepsy v1.277 HEPACAM Rebecca Foulger Mode of inheritance for gene: HEPACAM was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.276 DEAF1 Rebecca Foulger Marked gene: DEAF1 as ready
Early onset or syndromic epilepsy v1.276 DEAF1 Rebecca Foulger Gene: deaf1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.276 DEAF1 Rebecca Foulger Phenotypes for gene: DEAF1 were changed from ?Dyskinesia, seizures, and intellectual developmental disorder 617171 to ?Dyskinesia, seizures, and intellectual developmental disorder, 617171
Early onset or syndromic epilepsy v1.275 DEAF1 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed Mode of Inheritance from 'BOTH monoallelic and biallelic' to 'BIALLELIC' based on post-Webex reviews from Helen Lord. The original comment from West Midlands, Oxford and Wessex GLH (uploaded for Tracy Lester) also supports biallelic inheritance.
Early onset or syndromic epilepsy v1.275 DEAF1 Rebecca Foulger Mode of inheritance for gene: DEAF1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.274 PIGP Konstantinos Varvagiannis changed review comment from: Johnstone et al. (2017 - PMID: 28334793) report on 2 sibs born to non-consanguineous parents of French-Irish ancestry. Both presented with seizures (onset at the age of 2 and 7 weeks respectively), hypotonia and profound DD. Other features included CVI and feeding difficulties. Extensive metabolic testing as well as prior genetic testing (ARX, STXBP1, MECP2, aCGH) in the family were non-diagnostic. WES suggested the presence of 2 PIGP variants with Sanger sequencing used for confirmation and segregation studies.

PIGP encodes a subunit of the enzyme that catalyzes the first step of glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in other genes whose proteins are in complex with PIGP (PIGA, PIGC, PIGQ, PIGY, DPM2) lead to similar phenotypes. The phenotype overall was also overlapping with the inherited GPI deficiencies (belonging to the broader group of CDGs).

PIGP has 2 isoforms, which differ by 24 amino acids due to utilization of alternative start codons [corresponding to NM_153681.2 (158 aa) and NM_153682.2 (134 aa)].

The variants identified affected both transcripts with the first SNV leading either to loss of the start codon (NM_153682.2:c.2T>C - p.Met1Thr) or to substitution of a methionine at position 25(NM_153681.2:c.74T>C;p.Met25Thr). The second variant led to frameshift in the last exon of both transcripts predicting a longer protein product (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34).

Overall extensive studies demonstrated decreased levels of PIGP mRNA in patient fibroblast, decreased amounts of mutant protein in tranfected HEK293 cells. The decreased levels of GPI-APs further supported the effect of variants :

- mRNA levels in patient fibroblasts were reduced compared to controls. Conclusions could not be drawn from Western blot, since no antibodies could specifically detect PIGP. HEK293 cells transfected of mt or wt HA-tagged PIGP cDNA led to undetectable amounts for the first variant (both M1T/M25T) and a protein product of increased molecular weight for the frameshift one.
- Flow cytometry of patient granulocytes indicated reduced signal of CD16 (a GPI-anchored protein) and FLAER (binding directly to the GPI anchor).
- Reduced levels of GPI-APs were also observed in PIGP deficient HAP1 cells transfected with either wt, or mutant PIGP cDNA (of both isoforms for the M1T/M25T or isoform 2 for the frameshift mutation).

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Krenn et al. (2019 - PMID: 31139695) described a patient born to non-consanguineous Polish parents. Features were highly similar to those reported by Johnstone et al. and incl. intractable infantile seizures (onset at 7m), hypotonia, severe DD and feeding difficulties. Metabolic work-up failed to identify an alternative diagnosis. WES revealed homozygosity for the frameshift variant reported by Johnstone et al. Sanger sequencing confirmed the variant and carrier state in both parents. Identified ROH of less than 7 Mb in the WES data, suggested a founder mutation rather than unreported consanguinity. The variant is present 9 times in gnomAD (AF of 3.2e-5 / no homozygotes). Flow cytometry of patient granulocytes, revealed markedly reduced expression of GPI-APs (CD157, CD59, FLAER) compared to parents/controls.

ALP was normal in all aforementioned individuals (probably in line with PIGP being involved in the 1st step of the GPI anchor biosynthesis).

--------

A further individual with phenotype of EIEE-55;GPIBD-14 is reported in LOVD [Individual #00246132]. This individual, born to conanguineous parents, was tested by WES and found to be homozygous for a frameshift variant, also affecting the last exon in both transcripts (NM_153681.2:c.384delA (p.Glu129ArgfsTer7) / NM_153682.2:c.312delA (p.Glu105ArgfsTer7). This was probably in agreement with segregation studies according to the respective entry. The specific variant is reported as pathogenic [variant ID #0000500090].

--------

?Epileptic encephalopathy, early infantile, 55 (MIM 617599) is the corresponding phenotype in OMIM. There is no relevant G2P entry.
PIGP is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

--------

As a result, PIGP can be considered for inclusion in the ID/epilepsy panels probably as green (3 individuals, role of the gene and similarity to other inherited GPI deficiencies, extensive supporting studies) or amber.

(Please consider inclusion in other possibly relevant panels eg. CDGs, etc).
Sources: Literature; to: Johnstone et al. (2017 - PMID: 28334793) report on 2 sibs born to non-consanguineous parents of French-Irish ancestry. Both presented with seizures (onset at the age of 2 and 7 weeks respectively), hypotonia and profound DD. Other features included CVI and feeding difficulties. Extensive metabolic testing as well as prior genetic testing (ARX, STXBP1, MECP2, aCGH) in the family were non-diagnostic. WES suggested the presence of 2 PIGP variants with Sanger sequencing used for confirmation and segregation studies.

PIGP encodes a subunit of the enzyme that catalyzes the first step of glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in other genes whose proteins are in complex with PIGP (PIGA, PIGC, PIGQ, PIGY, DPM2) lead to similar phenotypes. The phenotype overall was also overlapping with the inherited GPI deficiencies (belonging to the broader group of CDGs).

PIGP has 2 isoforms, which differ by 24 amino acids due to utilization of alternative start codons [corresponding to NM_153681.2 (158 aa) and NM_153682.2 (134 aa)].

The variants identified affected both transcripts with the first SNV leading either to loss of the start codon (NM_153682.2:c.2T>C - p.Met1Thr) or to substitution of a methionine at position 25(NM_153681.2:c.74T>C;p.Met25Thr). The second variant led to frameshift in the last exon of both transcripts predicting a longer protein product (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34).

Overall extensive studies demonstrated decreased levels of PIGP mRNA in patient fibroblast, decreased amounts of mutant protein in tranfected HEK293 cells. The decreased levels of GPI-APs further supported the effect of variants :

- mRNA levels in patient fibroblasts were reduced compared to controls. Conclusions could not be drawn from Western blot, since no antibodies could specifically detect PIGP. HEK293 cells transfected of mt or wt HA-tagged PIGP cDNA led to undetectable amounts for the first variant (both M1T/M25T) and a protein product of increased molecular weight for the frameshift one.
- Flow cytometry of patient granulocytes indicated reduced signal of CD16 (a GPI-anchored protein) and FLAER (binding directly to the GPI anchor).
- Reduced levels of GPI-APs were also observed in PIGP deficient HAP1 cells transfected with either wt, or mutant PIGP cDNA (of both isoforms for the M1T/M25T or isoform 2 for the frameshift mutation).

--------

Krenn et al. (2019 - PMID: 31139695) described a patient born to non-consanguineous Polish parents. Features were highly similar to those reported by Johnstone et al. and incl. intractable infantile seizures (onset at 7m), hypotonia, severe DD and feeding difficulties. Metabolic work-up failed to identify an alternative diagnosis. WES revealed homozygosity for the frameshift variant reported by Johnstone et al. Sanger sequencing confirmed the variant and carrier state in both parents. Identified ROH of less than 7 Mb in the WES data, suggested a founder mutation rather than unreported consanguinity. The variant is present 9 times in gnomAD (AF of 3.2e-5 / no homozygotes). Flow cytometry of patient granulocytes, revealed markedly reduced expression of GPI-APs (CD157, CD59, FLAER) compared to parents/controls.

ALP was normal in all aforementioned individuals (probably in line with PIGP being involved in the 1st step of the GPI anchor biosynthesis).

--------

A further individual with phenotype of EIEE-55;GPIBD-14 is reported in LOVD [Individual #00246132]. This individual, born to consanguineous parents, was tested by WES and found to be homozygous for a frameshift variant, also affecting the last exon in both transcripts [NM_153681.2:c.384delA (p.Glu129ArgfsTer7) / NM_153682.2:c.312delA (p.Glu105ArgfsTer7)]. This was probably in agreement with segregation studies according to the respective entry. The specific variant is reported as pathogenic [variant ID #0000500090].

--------

?Epileptic encephalopathy, early infantile, 55 (MIM 617599) is the corresponding phenotype in OMIM. There is no relevant G2P entry.
PIGP is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

--------

As a result, PIGP can be considered for inclusion in the ID/epilepsy panels probably as green (3 individuals, role of the gene and similarity to other inherited GPI deficiencies, extensive supporting studies) or amber.

(Please consider inclusion in other possibly relevant panels eg. CDGs, etc).
Sources: Literature
Early onset or syndromic epilepsy v1.274 CACNA1D Rebecca Foulger Marked gene: CACNA1D as ready
Early onset or syndromic epilepsy v1.274 CACNA1D Rebecca Foulger Gene: cacna1d has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.274 CACNA1D Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.274 CACNA1D Rebecca Foulger Mode of inheritance for gene: CACNA1D was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.273 ATRX Rebecca Foulger Marked gene: ATRX as ready
Early onset or syndromic epilepsy v1.273 ATRX Rebecca Foulger Gene: atrx has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.273 ATRX Rebecca Foulger Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome; Mental retardation-hypotonic facies syndrome, X-linked to Alpha-thalassemia/mental retardation syndrome, 301040; Mental retardation-hypotonic facies syndrome, X-linked, 309580
Early onset or syndromic epilepsy v1.272 PIGP Konstantinos Varvagiannis gene: PIGP was added
gene: PIGP was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PIGP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGP were set to 28334793; 31139695
Phenotypes for gene: PIGP were set to Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Penetrance for gene: PIGP were set to Complete
Review for gene: PIGP was set to GREEN
Added comment: Johnstone et al. (2017 - PMID: 28334793) report on 2 sibs born to non-consanguineous parents of French-Irish ancestry. Both presented with seizures (onset at the age of 2 and 7 weeks respectively), hypotonia and profound DD. Other features included CVI and feeding difficulties. Extensive metabolic testing as well as prior genetic testing (ARX, STXBP1, MECP2, aCGH) in the family were non-diagnostic. WES suggested the presence of 2 PIGP variants with Sanger sequencing used for confirmation and segregation studies.

PIGP encodes a subunit of the enzyme that catalyzes the first step of glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in other genes whose proteins are in complex with PIGP (PIGA, PIGC, PIGQ, PIGY, DPM2) lead to similar phenotypes. The phenotype overall was also overlapping with the inherited GPI deficiencies (belonging to the broader group of CDGs).

PIGP has 2 isoforms, which differ by 24 amino acids due to utilization of alternative start codons [corresponding to NM_153681.2 (158 aa) and NM_153682.2 (134 aa)].

The variants identified affected both transcripts with the first SNV leading either to loss of the start codon (NM_153682.2:c.2T>C - p.Met1Thr) or to substitution of a methionine at position 25(NM_153681.2:c.74T>C;p.Met25Thr). The second variant led to frameshift in the last exon of both transcripts predicting a longer protein product (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34).

Overall extensive studies demonstrated decreased levels of PIGP mRNA in patient fibroblast, decreased amounts of mutant protein in tranfected HEK293 cells. The decreased levels of GPI-APs further supported the effect of variants :

- mRNA levels in patient fibroblasts were reduced compared to controls. Conclusions could not be drawn from Western blot, since no antibodies could specifically detect PIGP. HEK293 cells transfected of mt or wt HA-tagged PIGP cDNA led to undetectable amounts for the first variant (both M1T/M25T) and a protein product of increased molecular weight for the frameshift one.
- Flow cytometry of patient granulocytes indicated reduced signal of CD16 (a GPI-anchored protein) and FLAER (binding directly to the GPI anchor).
- Reduced levels of GPI-APs were also observed in PIGP deficient HAP1 cells transfected with either wt, or mutant PIGP cDNA (of both isoforms for the M1T/M25T or isoform 2 for the frameshift mutation).

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Krenn et al. (2019 - PMID: 31139695) described a patient born to non-consanguineous Polish parents. Features were highly similar to those reported by Johnstone et al. and incl. intractable infantile seizures (onset at 7m), hypotonia, severe DD and feeding difficulties. Metabolic work-up failed to identify an alternative diagnosis. WES revealed homozygosity for the frameshift variant reported by Johnstone et al. Sanger sequencing confirmed the variant and carrier state in both parents. Identified ROH of less than 7 Mb in the WES data, suggested a founder mutation rather than unreported consanguinity. The variant is present 9 times in gnomAD (AF of 3.2e-5 / no homozygotes). Flow cytometry of patient granulocytes, revealed markedly reduced expression of GPI-APs (CD157, CD59, FLAER) compared to parents/controls.

ALP was normal in all aforementioned individuals (probably in line with PIGP being involved in the 1st step of the GPI anchor biosynthesis).

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A further individual with phenotype of EIEE-55;GPIBD-14 is reported in LOVD [Individual #00246132]. This individual, born to conanguineous parents, was tested by WES and found to be homozygous for a frameshift variant, also affecting the last exon in both transcripts (NM_153681.2:c.384delA (p.Glu129ArgfsTer7) / NM_153682.2:c.312delA (p.Glu105ArgfsTer7). This was probably in agreement with segregation studies according to the respective entry. The specific variant is reported as pathogenic [variant ID #0000500090].

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?Epileptic encephalopathy, early infantile, 55 (MIM 617599) is the corresponding phenotype in OMIM. There is no relevant G2P entry.
PIGP is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

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As a result, PIGP can be considered for inclusion in the ID/epilepsy panels probably as green (3 individuals, role of the gene and similarity to other inherited GPI deficiencies, extensive supporting studies) or amber.

(Please consider inclusion in other possibly relevant panels eg. CDGs, etc).
Sources: Literature
Early onset or syndromic epilepsy v1.272 ATRX Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on Post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.272 ATRX Rebecca Foulger Mode of inheritance for gene: ATRX was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.271 ATRX Rebecca Foulger Publications for gene: ATRX were set to 25606380; 11449489; 7697714; 11050622
Early onset or syndromic epilepsy v1.270 ARHGEF9 Rebecca Foulger Marked gene: ARHGEF9 as ready
Early onset or syndromic epilepsy v1.270 ARHGEF9 Rebecca Foulger Gene: arhgef9 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.270 ARHGEF9 Rebecca Foulger Publications for gene: ARHGEF9 were set to 21633362; 15215304
Early onset or syndromic epilepsy v1.269 ARHGEF9 Rebecca Foulger Publications for gene: ARHGEF9 were set to
Early onset or syndromic epilepsy v1.268 ARHGEF9 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from XLR to XLD based on Post-Webex review by Helen Lord.
Early onset or syndromic epilepsy v1.268 ARHGEF9 Rebecca Foulger Mode of inheritance for gene: ARHGEF9 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.267 TUBB2A Rebecca Foulger Marked gene: TUBB2A as ready
Early onset or syndromic epilepsy v1.267 TUBB2A Rebecca Foulger Gene: tubb2a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.267 TUBB2A Rebecca Foulger commented on gene: TUBB2A: Kept rating as Green based on post-Webex reviews from Helen Lord and Alison Callaway (West Midlands, Oxford and Wessex GLH).
Early onset or syndromic epilepsy v1.267 SLC25A12 Rebecca Foulger Marked gene: SLC25A12 as ready
Early onset or syndromic epilepsy v1.267 SLC25A12 Rebecca Foulger Gene: slc25a12 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.267 SLC25A12 Rebecca Foulger commented on gene: SLC25A12: Kept rating as Green based on post-Webex reviews from Helen Lord and Alison Callaway.
Early onset or syndromic epilepsy v1.267 SLC25A12 Rebecca Foulger Publications for gene: SLC25A12 were set to 24515575; 19641205; 27290639
Early onset or syndromic epilepsy v1.266 KCNMA1 Rebecca Foulger Marked gene: KCNMA1 as ready
Early onset or syndromic epilepsy v1.266 KCNMA1 Rebecca Foulger Gene: kcnma1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.266 KCNMA1 Rebecca Foulger Classified gene: KCNMA1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.266 KCNMA1 Rebecca Foulger Added comment: Comment on list classification: Updated rating of KCNMA1 from Amber to Green based on post-Webex reviews from Helen Lord, Allison Callaway and Konstantinos Varvagiannis.
Early onset or syndromic epilepsy v1.266 KCNMA1 Rebecca Foulger Gene: kcnma1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.265 KCNMA1 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex reviews from Helen Lord and Konstantinos Varvagiannis.
Early onset or syndromic epilepsy v1.265 KCNMA1 Rebecca Foulger Mode of inheritance for gene: KCNMA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.264 ALPL Rebecca Foulger commented on gene: ALPL: Kept rating as Green based on post-Webex reviews from Helen Lord and Alison Callaway.
Early onset or syndromic epilepsy v1.264 ALPL Rebecca Foulger changed review comment from: Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic to 'BIALLELIC' based on Post-Webex review by Helen Lord: AR but not AD Hypophosphatasia associated with seizures.; to: Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic' to 'BIALLELIC' based on Post-Webex review by Helen Lord: AR but not AD Hypophosphatasia is associated with seizures.
Early onset or syndromic epilepsy v1.264 ALPL Rebecca Foulger Added comment: Comment on mode of inheritance: Updated Mode of Inheritance from 'BOTH monoallelic and biallelic to 'BIALLELIC' based on Post-Webex review by Helen Lord: AR but not AD Hypophosphatasia associated with seizures.
Early onset or syndromic epilepsy v1.264 ALPL Rebecca Foulger Mode of inheritance for gene: ALPL was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.263 H3F3B Louise Daugherty Tag new-gene-name tag was added to gene: H3F3B.
Early onset or syndromic epilepsy v1.263 H3F3B Louise Daugherty commented on gene: H3F3B
Early onset or syndromic epilepsy v1.263 H3F3A Louise Daugherty Tag new-gene-name tag was added to gene: H3F3A.
Early onset or syndromic epilepsy v1.263 H3F3A Louise Daugherty commented on gene: H3F3A
Early onset or syndromic epilepsy v1.263 KIF1BP Louise Daugherty Tag new-gene-name tag was added to gene: KIF1BP.
Early onset or syndromic epilepsy v1.263 KIF1BP Louise Daugherty commented on gene: KIF1BP: Added new-gene-name tag, new approved HGNC gene symbol for KIF1BP is KIFBP
Early onset or syndromic epilepsy v1.263 VARS Louise Daugherty Tag new-gene-name tag was added to gene: VARS.
Early onset or syndromic epilepsy v1.263 VARS Louise Daugherty commented on gene: VARS
Early onset or syndromic epilepsy v1.263 QARS Louise Daugherty Tag new-gene-name tag was added to gene: QARS.
Early onset or syndromic epilepsy v1.263 QARS Louise Daugherty commented on gene: QARS
Early onset or syndromic epilepsy v1.263 KARS Louise Daugherty Tag new-gene-name tag was added to gene: KARS.
Early onset or syndromic epilepsy v1.263 KARS Louise Daugherty commented on gene: KARS
Early onset or syndromic epilepsy v1.263 AARS Louise Daugherty Tag new-gene-name tag was added to gene: AARS.
Early onset or syndromic epilepsy v1.263 AARS Louise Daugherty commented on gene: AARS
Early onset or syndromic epilepsy v1.263 KCNA1 Rebecca Foulger Source North West GLH was added to KCNA1.
Early onset or syndromic epilepsy v1.263 SCN9A Rebecca Foulger Source North West GLH was added to SCN9A.
Early onset or syndromic epilepsy v1.263 FLNA Rebecca Foulger Source North West GLH was added to FLNA.
Early onset or syndromic epilepsy v1.262 KCNA1 Rebecca Foulger commented on gene: KCNA1: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Early onset or syndromic epilepsy v1.262 SCN9A Rebecca Foulger commented on gene: SCN9A: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Early onset or syndromic epilepsy v1.262 FLNA Rebecca Foulger commented on gene: FLNA: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Early onset or syndromic epilepsy v1.262 ARHGEF9 Rebecca Foulger commented on gene: ARHGEF9: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 SLC16A2 Rebecca Foulger commented on gene: SLC16A2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 PIGA Rebecca Foulger commented on gene: PIGA: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 MED12 Rebecca Foulger commented on gene: MED12: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 MAGI2 Rebecca Foulger commented on gene: MAGI2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 IDH2 Rebecca Foulger commented on gene: IDH2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded an Amber rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 CACNA1D Rebecca Foulger commented on gene: CACNA1D: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 NRXN1 Rebecca Foulger commented on gene: NRXN1: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 SLC35A2 Rebecca Foulger commented on gene: SLC35A2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 SLC1A2 Rebecca Foulger commented on gene: SLC1A2: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 SLC12A5 Rebecca Foulger commented on gene: SLC12A5: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 IKBKG Rebecca Foulger commented on gene: IKBKG: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 HEPACAM Rebecca Foulger commented on gene: HEPACAM: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 DEAF1 Rebecca Foulger commented on gene: DEAF1: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 ATRX Rebecca Foulger commented on gene: ATRX: Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Early onset or syndromic epilepsy v1.262 GRIA2 Rebecca Foulger edited their review of gene: GRIA2: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 KMT5B Rebecca Foulger reviewed gene: KMT5B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 KCNH5 Rebecca Foulger reviewed gene: KCNH5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 KCND2 Rebecca Foulger reviewed gene: KCND2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 CSNK2A1 Rebecca Foulger commented on gene: CSNK2A1: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.262 BCORL1 Rebecca Foulger edited their review of gene: BCORL1: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 ZNF142 Rebecca Foulger reviewed gene: ZNF142: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 ZMIZ1 Rebecca Foulger reviewed gene: ZMIZ1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 USP7 Rebecca Foulger edited their review of gene: USP7: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 TRRAP Rebecca Foulger edited their review of gene: TRRAP: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 TRPM3 Rebecca Foulger edited their review of gene: TRPM3: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 SLC35A3 Rebecca Foulger edited their review of gene: SLC35A3: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 RNF13 Rebecca Foulger reviewed gene: RNF13: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 PAK1 Rebecca Foulger reviewed gene: PAK1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 NUS1 Rebecca Foulger reviewed gene: NUS1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 LSS Rebecca Foulger reviewed gene: LSS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 FUK Rebecca Foulger reviewed gene: FUK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 CLCN6 Rebecca Foulger reviewed gene: CLCN6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 AIMP2 Rebecca Foulger reviewed gene: AIMP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 AFF3 Rebecca Foulger edited their review of gene: AFF3: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 POLG Rebecca Foulger commented on gene: POLG: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.262 ZDHHC9 Rebecca Foulger reviewed gene: ZDHHC9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 WARS2 Rebecca Foulger reviewed gene: WARS2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 VPS11 Rebecca Foulger reviewed gene: VPS11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 VAMP2 Rebecca Foulger reviewed gene: VAMP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 SNAP25 Rebecca Foulger reviewed gene: SNAP25: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 SMARCC2 Rebecca Foulger edited their review of gene: SMARCC2: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 PPP2CA Rebecca Foulger reviewed gene: PPP2CA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 PIGB Rebecca Foulger reviewed gene: PIGB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 PARS2 Rebecca Foulger reviewed gene: PARS2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 P4HTM Rebecca Foulger reviewed gene: P4HTM: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 NBEA Rebecca Foulger reviewed gene: NBEA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 KMT2E Rebecca Foulger reviewed gene: KMT2E: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 KCNT2 Rebecca Foulger reviewed gene: KCNT2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 DHPS Rebecca Foulger reviewed gene: DHPS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 DEGS1 Rebecca Foulger edited their review of gene: DEGS1: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 CTNNA2 Rebecca Foulger reviewed gene: CTNNA2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 CACNA1B Rebecca Foulger reviewed gene: CACNA1B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 ATN1 Rebecca Foulger reviewed gene: ATN1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 AP2M1 Rebecca Foulger reviewed gene: AP2M1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 ALKBH8 Rebecca Foulger reviewed gene: ALKBH8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.262 ACTL6B Rebecca Foulger edited their review of gene: ACTL6B: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.262 ALPL Rebecca Foulger commented on gene: ALPL: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.262 EMX2 Rebecca Foulger commented on gene: EMX2: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.262 NPRL2 Rebecca Foulger commented on gene: NPRL2: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.262 KCNMA1 Rebecca Foulger commented on gene: KCNMA1: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.262 TUBB2A Rebecca Foulger commented on gene: TUBB2A: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.262 SLC25A12 Rebecca Foulger commented on gene: SLC25A12: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.262 HCN2 Rebecca Foulger commented on gene: HCN2: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v1.261 ARHGEF9 Helen Lord reviewed gene: ARHGEF9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.261 SLC16A2 Helen Lord reviewed gene: SLC16A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.261 PIGA Helen Lord reviewed gene: PIGA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.261 MED12 Helen Lord reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.261 MAGI2 Helen Lord reviewed gene: MAGI2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 IDH2 Helen Lord reviewed gene: IDH2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 CACNA1D Helen Lord reviewed gene: CACNA1D: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 NRXN1 Helen Lord reviewed gene: NRXN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 SLC35A2 Helen Lord reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.261 SLC1A2 Helen Lord reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 SLC12A5 Helen Lord reviewed gene: SLC12A5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 IKBKG Helen Lord reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.261 HEPACAM Helen Lord reviewed gene: HEPACAM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 DEAF1 Helen Lord reviewed gene: DEAF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 ATRX Helen Lord reviewed gene: ATRX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.261 GRIA2 Helen Lord reviewed gene: GRIA2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 KMT5B Helen Lord reviewed gene: KMT5B: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 KCNH5 Helen Lord reviewed gene: KCNH5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 KCND2 Helen Lord reviewed gene: KCND2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 CSNK2A1 Helen Lord reviewed gene: CSNK2A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 BCORL1 Helen Lord reviewed gene: BCORL1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.261 ZNF142 Helen Lord reviewed gene: ZNF142: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 ZMIZ1 Helen Lord reviewed gene: ZMIZ1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 USP7 Helen Lord reviewed gene: USP7: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 TRRAP Helen Lord reviewed gene: TRRAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 TRPM3 Helen Lord reviewed gene: TRPM3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 SLC35A3 Helen Lord reviewed gene: SLC35A3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 RNF13 Helen Lord reviewed gene: RNF13: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 PAK1 Helen Lord reviewed gene: PAK1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 NUS1 Helen Lord reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 LSS Helen Lord reviewed gene: LSS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 FUK Helen Lord reviewed gene: FUK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 CLCN6 Helen Lord reviewed gene: CLCN6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 AIMP2 Helen Lord reviewed gene: AIMP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 AFF3 Helen Lord reviewed gene: AFF3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 POLG Helen Lord reviewed gene: POLG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 ZDHHC9 Helen Lord reviewed gene: ZDHHC9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.261 WARS2 Helen Lord reviewed gene: WARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 VPS11 Helen Lord reviewed gene: VPS11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 VAMP2 Helen Lord reviewed gene: VAMP2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 SNAP25 Helen Lord reviewed gene: SNAP25: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 SMARCC2 Helen Lord reviewed gene: SMARCC2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 PPP2CA Helen Lord reviewed gene: PPP2CA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 PIGB Helen Lord reviewed gene: PIGB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 PARS2 Helen Lord reviewed gene: PARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 P4HTM Helen Lord reviewed gene: P4HTM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 NBEA Helen Lord reviewed gene: NBEA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 KMT2E Helen Lord reviewed gene: KMT2E: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 KCNT2 Helen Lord reviewed gene: KCNT2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 DHPS Helen Lord reviewed gene: DHPS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 DEGS1 Helen Lord reviewed gene: DEGS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 CTNNA2 Helen Lord reviewed gene: CTNNA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 CACNA1B Helen Lord reviewed gene: CACNA1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 ATN1 Helen Lord reviewed gene: ATN1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 AP2M1 Helen Lord reviewed gene: AP2M1: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 ALKBH8 Helen Lord reviewed gene: ALKBH8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 ACTL6B Helen Lord reviewed gene: ACTL6B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 ALPL Helen Lord reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 EMX2 Helen Lord reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 NPRL2 Helen Lord reviewed gene: NPRL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.261 KCNMA1 Helen Lord reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 TUBB2A Helen Lord reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.261 SLC25A12 Helen Lord reviewed gene: SLC25A12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.261 HCN2 Helen Lord reviewed gene: HCN2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.260 KATNB1 Konstantinos Varvagiannis gene: KATNB1 was added
gene: KATNB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KATNB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KATNB1 were set to 25521378; 25521379; 26640080
Phenotypes for gene: KATNB1 were set to Lissencephaly 6, with microcephaly (MIM 616212)
Review for gene: KATNB1 was set to GREEN
Added comment: Biallelic pathogenic KATNB1 variants cause Lissencephaly 6, with microcephaly (MIM 616212). At least 13 affected individuals from 9 (mostly consanguineous) families have probably been reported in the following articles:

- Mishra-Gorur et al. (2014 - PMID: 25521378) [7 individuals from 5 unrelated families]
- Hu et al. (2014 - PMID: 25521379) [5 individuals from 3 families]
- Yigit el al. (2016 - PMID: 26640080) [1 subject born to consanguineous parents]

Seizures can be part of the phenotype (although not universal / reported in all 3 studies in several families). Several different variants have been reported to date. Extensive studies as for the impact of mutations at the cellular level as well as animal models (zebrafish, mouse, drosophila) support involvement of KATNB1. These arguments, provided mainly by the first two studies, are summarized in the respective OMIM entry for the disorder : https://omim.org/entry/616212 (variants and their effect are discussed in the entry for KATNB1 - https://omim.org/entry/602703).

The individual reported by Yigit el al. was a 5 year-old girl with - among others - severely delayed psychomotor development and seizures. The child was found to harbor a homozygous splice site variant (removing the acceptor AG signature). Confirmation of the variant and segregation studies were performed with Sanger sequencing. cDNA studies were carried out and demonstrated aberrant splicing.

KATNB1 is not associated with any disorder in G2P.
The gene is included in panels for ID offered by several diagnostic laboratories (incl. Radboudumc).

As a result, this gene can be considered for inclusion in the current panel probably as green (or amber).
Sources: Literature
Early onset or syndromic epilepsy v1.260 PAK1 Konstantinos Varvagiannis edited their review of gene: PAK1: Added comment: Based on a further recent study, PAK1 can probably be upgraded to green in both ID and epilepsy gene panels:

Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al).

PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function.

CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures).

Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel).

4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events:
c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576].

The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67.

The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable).

PAK1 is included in the gene panel for ID offered by Radboudumc.

(Previous review below); Changed rating: GREEN; Changed publications: 30290153, doi.org/10.1093/brain/awz264
Early onset or syndromic epilepsy v1.260 GABBR2 Rebecca Foulger Phenotypes for gene: GABBR2 were changed from EPILEPTIC ENCEPHALOPATHY; Rett syndrome to EPILEPTIC ENCEPHALOPATHY; Rett syndrome; Epileptic encephalopathy, early infantile, 59, 617904
Early onset or syndromic epilepsy v1.259 GOT2 Catherine Snow Tag treatable tag was added to gene: GOT2.
Tag watchlist tag was added to gene: GOT2.
Early onset or syndromic epilepsy v1.259 GOT2 Catherine Snow Classified gene: GOT2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.259 GOT2 Catherine Snow Gene: got2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.258 GOT2 Catherine Snow reviewed gene: GOT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31422819; Phenotypes: Global developmental delay, Intellectual disability, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.258 ALPL Rebecca Foulger changed review comment from: PMID:30979546: Whyte et al., 2019 report Vitamin B6-dependent seizures in 10/38 (26%) of patients: 7 patients had documented seizures and 3 patients had a family hisotry of seizures based upon medical records.; to: PMID:30979546: Whyte et al., 2019 report Vitamin B6-dependent seizures in 10/38 (26%) of patients: 7 patients had documented seizures and 3 patients had a family history of seizures based upon medical records.
Early onset or syndromic epilepsy v1.258 TRRAP Rebecca Foulger Publications for gene: TRRAP were set to 30827496
Early onset or syndromic epilepsy v1.257 TRRAP Rebecca Foulger Added comment: Comment on phenotypes: MIM:603015 is the gene identifier. Therefore updated OMIM phenotype to the disorder identifier (618454) as per Alison Callaway's review.
Early onset or syndromic epilepsy v1.257 TRRAP Rebecca Foulger Phenotypes for gene: TRRAP were changed from Microcephaly; Seizures; Abnormal heart morphology; Autism; Developmental delay with or without dysmorphic facies and autism, 603015; Intellectual disability; Abnormality of the urinary system; Global developmental delay to Microcephaly; Seizures; Abnormal heart morphology; Autism; Developmental delay with or without dysmorphic facies and autism, 618454; Intellectual disability; Abnormality of the urinary system; Global developmental delay
Early onset or syndromic epilepsy v1.256 KCNMA1 Konstantinos Varvagiannis changed review comment from: In a recent extensive review of the literature, Bailey et al. (2019 - PMID: 31427379) summarize the phenotype of KCNMA1-related channelopathy. Overall the features of 37 subjects with 16 KCNMA1 pathogenic variants are discussed in detail. [An also relevant report by Liang et al. published in 6/2019 - PMID: 31152168 - was also considered for this review].

KCNMA1 encodes the pore-forming α subunit of large-conductance voltage- and Ca(2+)-activated K+ channel (also called BK channel). BK channels have highest expression levels in brain (acting as regulators of neuronal exciatbility) and muscle.

Variants in the review are distinguished in GoF, LoF and VUS (the latter used for variants of unknown/uncharacterized effect on BK channel activity) [NM_002247.3 mentioned as RefSeq]:
- GoF variants included D434G (a variant reported in 13 individuals) and N995S (also reported as N999S or N1053S).
- LoF variants included S351Y, G356R, G375R, N449fs*, I663V, C413Y, P805L, D984N, G354S.
- Uncharacterized variants included R458Ter, Y676Lfs*7 (both presumed to result to LoF), K518N, E656A, N1195S, E884K.

The disorder exhibited in most cases aut. dominant inheritance (either as de novo occurrence of a variant or identification in successive generations), with autosomal recessive inheritance reported in one pedigree (sibs with Y676Lfs*fs) (Tabarki et al. 2016 - PMID: 27567911).

As the authors comment, the hallmark of KCNMA1-related channelopathy is neurological dysfunction incl. seizures, movement disorders, DD and ID.

Epilepsy was a feature in approx. half individuals (18/37) irrespective of mutation type (eg. 9/20 in the case of GoF, 6/13 in LoF variants). Seizure characteristics were highly variable as for the onset, type, EEG pattern, frequency/duration and response to medication. Overlapping types were noted for GoF and LoF mutations incl. myoclonic, GTCS, absence seizures with few being more frequent or specific in certain mutation types.

Individuals with the same variant may present or not certain features eg. 6/13 members of a large family with D434G or 3/7 (all unrelated) individuals with N1053S developed epilepsy.

Animal studies support a role for both LoF and GoF alterations in BK channel activity as for the seizures, with more solid evidence/correlation with GoF mutations. (Other phenotypes eg. movement disorders are also supported by animal models).

Similarly developmental delay has been reported in 21/37 individuals and intellectual disability in 12/37 (both GoF and LoF) with severe presentation in certain cases (eg. in 3 individuals with G375R) while on several occasions severity (or presence of this feature(?)) has probably not been commented on.

The KCNMA1-related disorders in OMIM are the following:
?Cerebellar atrophy, developmental delay, and seizures, 617643 (AR)
Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 (AD)

KCNMA1 is part of the DD panel of G2P associated with Generalized epilepsy and paroxysmal dyskinesia (monoallelic, activating mutations / disease confidence : possible).

KCNMA1 is included in several gene panels for epilepsy incl. those of Radboudumc and Victorian Clinical Genetics and several other panels summarized in the supplement of the review. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

As a result upgrade to green rating can be considered for the epilepsy panel. The gene could possibly be upgraded to amber (or green) in the ID panel, too.; to: In a recent extensive review of the literature, Bailey et al. (2019 - PMID: 31427379) summarize the phenotype of KCNMA1-related channelopathy. Overall the features of 37 subjects with 16 KCNMA1 pathogenic variants are discussed in detail. [An also relevant report by Liang et al. published in 6/2019 - PMID: 31152168 - was also considered for this review].

KCNMA1 encodes the pore-forming α subunit of large-conductance voltage- and Ca(2+)-activated K+ channel (also called BK channel). BK channels have highest expression levels in brain (acting as regulators of neuronal exciatbility) and muscle.

Variants in the review are distinguished in GoF, LoF and VUS (the latter used for variants of unknown/uncharacterized effect on BK channel activity) [NM_002247.3 mentioned as RefSeq]:
- GoF variants included D434G (a variant reported in 13 individuals) and N995S (also reported as N999S or N1053S).
- LoF variants included S351Y, G356R, G375R, N449fs*, I663V, C413Y, P805L, D984N, G354S.
- Uncharacterized variants included R458Ter, Y676Lfs*7 (both presumed to result to LoF), K518N, E656A, N1195S, E884K.

The disorder exhibited in most cases aut. dominant inheritance (either as de novo occurrence of a variant or identification in successive generations), with autosomal recessive inheritance reported in one pedigree (sibs with Y676Lfs*fs) (Tabarki et al. 2016 - PMID: 27567911).

As the authors comment, the hallmark of KCNMA1-related channelopathy is neurological dysfunction incl. seizures, movement disorders, DD and ID.

Epilepsy was a feature in approx. half individuals (18/37) irrespective of mutation type (eg. 9/20 in the case of GoF, 6/13 in LoF variants). Seizure characteristics were highly variable as for the onset, type, EEG pattern, frequency/duration and response to medication. Overlapping types were noted for GoF and LoF mutations incl. myoclonic, GTCS, absence seizures with few being more frequent or specific in certain mutation types.

Individuals with the same variant may present or not certain features eg. 6/13 members of a large family with D434G or 3/7 (all unrelated) individuals with N1053S developed epilepsy.

Animal studies support a role for both LoF and GoF alterations in BK channel activity as for the seizures, with more solid evidence/correlation with GoF mutations. (Other phenotypes eg. movement disorders are also supported by animal models).

Similarly developmental delay has been reported in 21/37 individuals and intellectual disability in 12/37 (both GoF and LoF) with severe presentation in certain cases (eg. in 3 individuals with G375R) while on several occasions severity (or presence of this feature(?)) has probably not been commented on.

The KCNMA1-related disorders in OMIM are the following :
?Cerebellar atrophy, developmental delay, and seizures, 617643 (AR)
Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, 609446 (AD)

KCNMA1 is part of the DD panel of G2P associated with Generalized epilepsy and paroxysmal dyskinesia (monoallelic, activating mutations / disease confidence : possible).

KCNMA1 is included in several gene panels for epilepsy incl. those of Radboudumc and Victorian Clinical Genetics and several other panels summarized in the supplement of the review. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

As a result upgrade to green rating can be considered for the epilepsy panel. The gene could possibly be upgraded to amber (or green) in the ID panel, too.
Early onset or syndromic epilepsy v1.256 HNRNPR Konstantinos Varvagiannis gene: HNRNPR was added
gene: HNRNPR was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPR were set to 31079900; 26795593
Phenotypes for gene: HNRNPR were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit
Penetrance for gene: HNRNPR were set to unknown
Review for gene: HNRNPR was set to AMBER
Added comment: Duijkers et al. (2019 - PMID: 31079900) report on the phenotype of 4 individuals with de novo HNRNPR variants and provide additional information on a previously published case (Helbig et al, 2016 - PMID: 26795593). All 5 were unrelated.

The phenotype consisted of DD (5/5 - moderate to severe in 4 for which this has been commented on), postnatal microcephaly, seizures (4/5), brachydactyly, with additional (cardiac, urogenital, etc) anomalies observed in few. Some partially overlapping facial features were also noted.

3 truncating variants as well as a missense one, all localizing within the last exon of the gene (NM_001102398.2 used as ref. although this exon is shared by all transcripts).

HNRNPR encodes heterogeneous nuclear ribonucleoprotein R, which is part of the spliceosome C. The latter functions in the nucleus to process and transport mRNA. Apart from splicing hnRNPs are also involved in other levels of gene regulation (PMID: 27215579). Some hnRNPs have been found in the cytoplasm in stress granules, aggregations of protein, RNAs and stalled initiation complexes that are formed as stress response upon oxidative insult and dissipate upon cessation of this insult.

Western blot in LCLs from affected individuals demonstrated the presence of the truncated protein as well as the full-length and short isoform (as expected by the variant localization).
As the C-terminal part has features of a "prion-like domain" (PrLD), critical for the formation of stress granules in the case of hnRNP-related disorders, comparison of fibroblasts from affected and healthy individuals revealed abnormal persistence of these granules in affected individuals following a recovery period, despite similar formation either at basal levels or under conditions of stress.

In line with a role of hnRNPs in splicing and gene regulation, RNA-Sequencing in fibroblasts from 2 affected individuals revealed abnormal splicing of some genes (eg. HOXA5, HOXB3, LHX9) and significant dysregulation of genes important for the development (upregulation of FOXG1, TBX1, several members of the HOX family and downregulation of LHX9, IRX3, etc) possibly contributing to the patient features.

Helbig et al. provide details on animal studies incl.expression in neural tissues (cerebrum and cerebellum), higher levels of expression early in the development (of both R1/R2 isoforms), etc (extensive discussion in the supplement with several articles cited).

HNRNPR is not associated with any phenotype in OMIM/G2P.

As a result this gene can be considered for inclusion as amber (seizures in 4/5) or green.
Sources: Literature
Early onset or syndromic epilepsy v1.256 GOT2 Konstantinos Varvagiannis gene: GOT2 was added
gene: GOT2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GOT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOT2 were set to 31422819
Phenotypes for gene: GOT2 were set to Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology
Penetrance for gene: GOT2 were set to Complete
Review for gene: GOT2 was set to GREEN
Added comment: van Karnebeek et al. (2019 - PMID: 31422819) report on 4 individuals from 3 families, with biallelic GOT2 pathogenic variants (3 missense SNVs and 1 in-frame deletion).

The phenotype corresponded to a metabolic encephalopathy with onset of epilepsy in the first year of life (4/4) with DD and ID (4/4). Additional features included postnatal microcephaly, failure to thrive/feeding difficulties and cerebral anomalies (atrophy and white matter). All subjects had high blood lactate and hyperammonemia. Plasma serine was low in one case (alternative causes were ruled out).

Administration of serine and pyridoxine led to clinical improvement (cessation / better control of seizures) in 2 subjects suggesting that GOT2 deficiency may be amenable to therapeutic intervention. [Treatment could not be started in the 2 further affected individuals].

GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase, a component of the malate-aspartate shuttle (MAS). The latter is important for intracellular NAD(H) redox homeostasis.

The authors provide several lines of evidence that GOT2 deficiency explains the patients' phenotype and metabolic defects incl. :
- Reduced GOT2 protein levels (due to lower expression/impaired stability) and diminished activity in patient fibroblasts (lower activity was also shown for carriers). Rescue of the GOT enzymatic activity was observed upon transduction of patient fibroblasts using lentiviral particles with wt GOT2.
- Impairment of de novo serine biosynthesis in patient (and to a lesser extent in carrier) fibroblasts compared to controls. This was similar in GOT2-knockout HEK293 cells. Serine biosynthesis in these cells was restored by pyruvate supplementation.
- CRISPR/Cas9 Got2-knockout mice resulted in early lethality (during pregnancy). Heterozygous mice were viable and healthy.
- Morpholino knockdown of got2a in zebrafish was shown to perturb embryonic development (smaller head, slow circulation, bend body, brain developmental defects, etc). Pyridoxine and serine in embryo water resulted in milder phenotypes/improved morphant survival. Zebrafish got2a morphants had seizure-like spikes upon EEG that were rescued by treatment with pyridoxine.

GOT2 is not associated with any phenotype in OMIM/G2P.

As a result, this gene can be considered for inclusion in both epilepsy and ID gene panels probably as green (3 families, relevant phenotypes and severity, evidence from cell and animal studies) or amber.

[Please consider inclusion in other relevant panels eg. mitochondrial disorders, metabolic disorders and/or addition of the 'treatable' tag].
Sources: Literature
Early onset or syndromic epilepsy v1.256 TRAPPC6B Konstantinos Varvagiannis reviewed gene: TRAPPC6B: Rating: AMBER; Mode of pathogenicity: None; Publications: 28626029, 28397838, DOI 10.1055/s-0039-1693664; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.256 KCNMA1 Konstantinos Varvagiannis reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31427379, 31152168, 27567911; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v1.256 KCND2 Alison Callaway reviewed gene: KCND2: Rating: RED; Mode of pathogenicity: None; Publications: 16934482; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 CSNK2A1 Alison Callaway reviewed gene: CSNK2A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27048600; Phenotypes: Neurodevelopmental abnormalities and dysmorphic features; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 ZNF142 Alison Callaway reviewed gene: ZNF142: Rating: AMBER; Mode of pathogenicity: None; Publications: 31036918; Phenotypes: NEURODEVELOPMENTAL DISORDER WITH IMPAIRED SPEECH AND HYPERKINETIC MOVEMENTS; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 USP7 Alison Callaway reviewed gene: USP7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 TRRAP Alison Callaway reviewed gene: TRRAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 28628100, 30827496; Phenotypes: DEVELOPMENTAL DELAY WITH OR WITHOUT DYSMORPHIC FACIES AND AUTISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.256 TRPM3 Alison Callaway reviewed gene: TRPM3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29156220; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 CLCN6 Alison Callaway reviewed gene: CLCN6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 AIMP2 Alison Callaway reviewed gene: AIMP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26795593; Phenotypes: Epileptic Encephalopathy, Infantile Spasms; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.256 AFF3 Alison Callaway reviewed gene: AFF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 ALPL Alison Callaway changed review comment from: Epilepsy can be associated with hypophosphasia; no further literature identified. From reviews below, appears to have sufficient evidence for a green gene.; to: Epilepsy can be associated with hypophosphatasia; no further literature identified. From reviews below, appears to have sufficient evidence for a green gene.
Early onset or syndromic epilepsy v1.256 ALPL Alison Callaway reviewed gene: ALPL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 EMX2 Alison Callaway reviewed gene: EMX2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 NPRL2 Alison Callaway reviewed gene: NPRL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 KCNMA1 Alison Callaway reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29933521; Phenotypes: Generalised epilepsy and paroxysmal dyskinesia; Mode of inheritance: None
Early onset or syndromic epilepsy v1.256 TUBB2A Alison Callaway reviewed gene: TUBB2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24702957; Phenotypes: CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.256 SLC25A12 Alison Callaway reviewed gene: SLC25A12: Rating: GREEN; Mode of pathogenicity: None; Publications: 19641205, 24515575, 27290639, 26633542; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.256 HCN2 Alison Callaway reviewed gene: HCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29064616, 22131395; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.256 HCN2 Alison Callaway Deleted their review
Early onset or syndromic epilepsy v1.256 HCN2 Alison Callaway reviewed gene: HCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29064616, 22131395; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.256 SPATA5 Sarah Leigh Publications for gene: SPATA5 were set to PMID: 27246907; 29343804; 26299366
Early onset or syndromic epilepsy v1.255 SPATA5 Sarah Leigh Classified gene: SPATA5 as Green List (high evidence)
Early onset or syndromic epilepsy v1.255 SPATA5 Sarah Leigh Added comment: Comment on list classification: Based on review from Rachel Jones (GSTT): Tanaka et al PMID: 26299366 identified "14 individuals [from 10 families] with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants" in SPATA5 Puussep et al PMID: 29343804 describes 5 further patients "with psychomotor developmental delay, microcephaly, epilepsy and hearing impairment, who were thought clinically to have a mitochondrial disease with subsequent whole-exome sequencing analysis detecting compound heterozygous variants in the SPATA5 gene" Szczaluba et al PMID: 28293831 describes a family where a sibling has isolated sensorineural hearing loss and the same two pathogenic SPATA5 variants as her more typically affected sister. In addition, typically affected individuals may present as congenital SNHL on newborn hearing screen prior to onset of seizures, microcephaly and intellectual disability.
Early onset or syndromic epilepsy v1.255 SPATA5 Sarah Leigh Gene: spata5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.254 SPATA5 Rachel Jones gene: SPATA5 was added
gene: SPATA5 was added to Genetic epilepsy syndromes. Sources: Other
Mode of inheritance for gene: SPATA5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5 were set to PMID: 27246907; 29343804; 26299366
Phenotypes for gene: SPATA5 were set to Epilepsy, hearing loss, and mental retardation syndrome 616577
Penetrance for gene: SPATA5 were set to Incomplete
Review for gene: SPATA5 was set to GREEN
Added comment: Greater than 15 families have been identified in multiple publications showing that patients with SPATA5 biallelic variants present with intellectual disability, epilepsy, microcephaly and hearing loss. May present as epileptic encephalopathy/epilepsy in the first year of life prior to onset of obvious developmental delay.
Sources: Other
Early onset or syndromic epilepsy v1.254 SLC2A1 Ellen McDonagh edited their review of gene: SLC2A1: Added comment: Added the tag 'treatable' as a ketogenic diet can help ameloriate symptoms (PMID: 29303961).; Changed publications: 29303961
Early onset or syndromic epilepsy v1.254 SLC2A1 Ellen McDonagh Tag treatable tag was added to gene: SLC2A1.
Early onset or syndromic epilepsy v1.254 KMT2E Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIM id
Early onset or syndromic epilepsy v1.254 KMT2E Louise Daugherty Phenotypes for gene: KMT2E were changed from Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size to O'Donnell-Luria-Rodan syndrome, 618512; Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size
Early onset or syndromic epilepsy v1.253 CACNA1B Louise Daugherty Added comment: Comment on phenotypes: added OMIM MIM id
Early onset or syndromic epilepsy v1.253 CACNA1B Louise Daugherty Phenotypes for gene: CACNA1B were changed from Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia to Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, 618497; Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement; Progressive Epilepsy-Dyskinesia
Early onset or syndromic epilepsy v1.252 ISCA-46290-Gain Rebecca Foulger Haploinsufficiency Score for ISCA-46290-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-46290-Gain.
Early onset or syndromic epilepsy v1.251 ISCA-37493-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37493-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37493-Loss.
Early onset or syndromic epilepsy v1.250 ISCA-37478-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37478-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37478-Loss.
Early onset or syndromic epilepsy v1.249 ISCA-37478-Gain Rebecca Foulger Haploinsufficiency Score for ISCA-37478-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-37478-Gain.
Early onset or syndromic epilepsy v1.248 ISCA-37434-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37434-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37434-Loss.
Early onset or syndromic epilepsy v1.247 ISCA-37432-Gain Rebecca Foulger Haploinsufficiency Score for ISCA-37432-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-37432-Gain.
Early onset or syndromic epilepsy v1.246 ISCA-37430-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37430-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37430-Loss.
Early onset or syndromic epilepsy v1.245 ISCA-37429-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37429-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37429-Loss.
Early onset or syndromic epilepsy v1.244 ISCA-37423-Gain Rebecca Foulger Haploinsufficiency Score for ISCA-37423-Gain was changed from to None.
Source NHS GMS was added to Region: ISCA-37423-Gain.
Early onset or syndromic epilepsy v1.243 ISCA-37415-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37415-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37415-Loss.
Early onset or syndromic epilepsy v1.242 ISCA-37411-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37411-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37411-Loss.
Early onset or syndromic epilepsy v1.241 ISCA-37404-Loss Rebecca Foulger Triplosensitivity Score for ISCA-37404-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-37404-Loss.
Early onset or syndromic epilepsy v1.240 ISCA-46295-Loss Rebecca Foulger Triplosensitivity Score for ISCA-46295-Loss was changed from to None.
Source NHS GMS was added to Region: ISCA-46295-Loss.
Early onset or syndromic epilepsy v1.239 ISCA-46295-Loss Rebecca Foulger commented on Region: ISCA-46295-Loss
Early onset or syndromic epilepsy v1.239 ISCA-46290-Gain Rebecca Foulger commented on Region: ISCA-46290-Gain
Early onset or syndromic epilepsy v1.239 ISCA-37493-Loss Rebecca Foulger reviewed Region: ISCA-37493-Loss: Rating: ; Mode of pathogenicity: None; Publications: 28283832; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.239 ISCA-37478-Loss Rebecca Foulger commented on Region: ISCA-37478-Loss
Early onset or syndromic epilepsy v1.239 ISCA-37478-Gain Rebecca Foulger commented on Region: ISCA-37478-Gain
Early onset or syndromic epilepsy v1.239 ISCA-37434-Loss Rebecca Foulger commented on Region: ISCA-37434-Loss
Early onset or syndromic epilepsy v1.239 ISCA-37432-Gain Rebecca Foulger commented on Region: ISCA-37432-Gain
Early onset or syndromic epilepsy v1.239 ISCA-37430-Loss Rebecca Foulger commented on Region: ISCA-37430-Loss
Early onset or syndromic epilepsy v1.239 ISCA-37429-Loss Rebecca Foulger commented on Region: ISCA-37429-Loss
Early onset or syndromic epilepsy v1.239 ISCA-37415-Loss Rebecca Foulger reviewed Region: ISCA-37415-Loss: Rating: ; Mode of pathogenicity: None; Publications: 10573006; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.239 ISCA-37423-Gain Rebecca Foulger reviewed Region: ISCA-37423-Gain: Rating: ; Mode of pathogenicity: None; Publications: 28533195; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.239 ISCA-37411-Loss Rebecca Foulger reviewed Region: ISCA-37411-Loss: Rating: ; Mode of pathogenicity: None; Publications: 19289393; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.239 ISCA-37404-Loss Rebecca Foulger commented on Region: ISCA-37404-Loss
Early onset or syndromic epilepsy v1.239 GATM Rebecca Foulger Phenotypes for gene: GATM were changed from to Cerebral creatine deficiency syndrome 3, 612718
Early onset or syndromic epilepsy v1.238 GATM Rebecca Foulger Mode of inheritance for gene: GATM was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.237 GATM Rebecca Foulger Publications for gene: GATM were set to
Early onset or syndromic epilepsy v1.236 SETD5 Rebecca Foulger changed review comment from: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although four reviewers agreed it should be on EE panel, there is limited evidence of a seizure phenotype. PMID:26482601: (Kobayashi et al., 2016) examined 11 patients with early-onset epileptic encephalopathy, and SETD5 variants were amongst the findings. Therefore awaited clinical input on whether SETD5 should be demoted on this panel.; to: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: although four reviewers agreed it should be on EE panel, there is limited evidence of a seizure phenotype. PMID:26482601: (Kobayashi et al., 2016) examined 11 patients with early-onset epileptic encephalopathy, and SETD5 variants were amongst the findings. Therefore consider demoting SETD5.
Early onset or syndromic epilepsy v1.236 LYST Rebecca Foulger changed review comment from: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although the mouse model displays seizures (PMID:16518687), there is limited evidence of patients with seizures (no mention of seizures in PMID:9215679, and one 1990 report of Chédiak-Higashi syndrome with seizures from PMID:10450360). Therefore awaiting clinical opinion on whether LYST should be demoted on this panel.; to: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: although the mouse model displays seizures (PMID:16518687), there is limited evidence of patients with seizures (no mention of seizures in PMID:9215679, and one 1990 report of Chédiak-Higashi syndrome with seizures from PMID:10450360). Therefore consider demoting LYST.
Early onset or syndromic epilepsy v1.236 KIF1BP Rebecca Foulger changed review comment from: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although the association with GOLDBERG-SHPRINTZEN MEGACOLON SYNDROME is strong, there is little direct evidence for seizures (PMID:28277559 identifies one case). Therefore awaiting clinical opinion on whether KIF1BP should be demoted.; to: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: although the association with GOLDBERG-SHPRINTZEN MEGACOLON SYNDROME is strong, there is little direct evidence for seizures (PMID:28277559 identifies one case). Therefore consider demoting KIF1BP.
Early onset or syndromic epilepsy v1.236 AKT1 Rebecca Foulger Marked gene: AKT1 as ready
Early onset or syndromic epilepsy v1.236 AKT1 Rebecca Foulger Gene: akt1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.236 PTEN Rebecca Foulger Marked gene: PTEN as ready
Early onset or syndromic epilepsy v1.236 PTEN Rebecca Foulger Gene: pten has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.236 PIK3CA Rebecca Foulger Marked gene: PIK3CA as ready
Early onset or syndromic epilepsy v1.236 PIK3CA Rebecca Foulger Gene: pik3ca has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.236 PIK3CA Rebecca Foulger Classified gene: PIK3CA as Red List (low evidence)
Early onset or syndromic epilepsy v1.236 PIK3CA Rebecca Foulger Gene: pik3ca has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.235 PIK3CA Rebecca Foulger commented on gene: PIK3CA: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote PIK3CA from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.
Early onset or syndromic epilepsy v1.235 PTEN Rebecca Foulger commented on gene: PTEN: Added tags: 'mosaicism' and 'somatic'.
Early onset or syndromic epilepsy v1.235 PTEN Rebecca Foulger Classified gene: PTEN as Red List (low evidence)
Early onset or syndromic epilepsy v1.235 PTEN Rebecca Foulger Gene: pten has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.234 PTEN Rebecca Foulger commented on gene: PTEN: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote AKT1 from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.
Early onset or syndromic epilepsy v1.234 PTEN Rebecca Foulger Tag mosaicism tag was added to gene: PTEN.
Tag somatic tag was added to gene: PTEN.
Early onset or syndromic epilepsy v1.234 AKT1 Rebecca Foulger Classified gene: AKT1 as Red List (low evidence)
Early onset or syndromic epilepsy v1.234 AKT1 Rebecca Foulger Gene: akt1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.233 AKT1 Rebecca Foulger commented on gene: AKT1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed to demote AKT1 from Green to Red. This panel is not the appropriate test for somatic variant detection due to the coverage. R110 Segmental overgrowth disorders (panel #98) should be used where megalencephaly is present to allow detection of somatic mosaic mutations.
Early onset or syndromic epilepsy v1.233 WDR37 Rebecca Foulger Marked gene: WDR37 as ready
Early onset or syndromic epilepsy v1.233 WDR37 Rebecca Foulger Gene: wdr37 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.233 PEX5 Rebecca Foulger Marked gene: PEX5 as ready
Early onset or syndromic epilepsy v1.233 PEX5 Rebecca Foulger Gene: pex5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.233 KIAA1109 Rebecca Foulger Marked gene: KIAA1109 as ready
Early onset or syndromic epilepsy v1.233 KIAA1109 Rebecca Foulger Gene: kiaa1109 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.233 GTPBP3 Rebecca Foulger Marked gene: GTPBP3 as ready
Early onset or syndromic epilepsy v1.233 GTPBP3 Rebecca Foulger Gene: gtpbp3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.233 EIF2B3 Rebecca Foulger Marked gene: EIF2B3 as ready
Early onset or syndromic epilepsy v1.233 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.233 EIF2B1 Rebecca Foulger Marked gene: EIF2B1 as ready
Early onset or syndromic epilepsy v1.233 EIF2B1 Rebecca Foulger Gene: eif2b1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.233 EFHC1 Rebecca Foulger Marked gene: EFHC1 as ready
Early onset or syndromic epilepsy v1.233 EFHC1 Rebecca Foulger Gene: efhc1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.233 DPM2 Rebecca Foulger Marked gene: DPM2 as ready
Early onset or syndromic epilepsy v1.233 DPM2 Rebecca Foulger Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.233 CUL4B Rebecca Foulger Marked gene: CUL4B as ready
Early onset or syndromic epilepsy v1.233 CUL4B Rebecca Foulger Gene: cul4b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.233 CNPY3 Rebecca Foulger Marked gene: CNPY3 as ready
Early onset or syndromic epilepsy v1.233 CNPY3 Rebecca Foulger Gene: cnpy3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.233 PTS Rebecca Foulger Marked gene: PTS as ready
Early onset or syndromic epilepsy v1.233 PTS Rebecca Foulger Gene: pts has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.233 PTS Rebecca Foulger Classified gene: PTS as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.233 PTS Rebecca Foulger Gene: pts has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.232 PTS Rebecca Foulger commented on gene: PTS: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber to match the rating on the 'Inborn errors of metabolism' panel. The prevailing phenotype is a movement disorder. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.232 PTS Rebecca Foulger commented on gene: PTS: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: Severe Hyperphenylalaninemia, BH4-deficient, is accepted to include seizures (PMID:8801112). Because this condition is diagnosed and treated from an early age, seizures may not be reported frequently. PMID:31000854 (Ahmed et al., 2019)assessed hyperphenylalaninemia patients and found 14/18 (78%) had seizures and ID however genetic analysis to see which of these had PTPS/PTS variants was not performed. PMID:9222757 report 1 case of seizures.
Early onset or syndromic epilepsy v1.232 KCNA1 Rebecca Foulger Marked gene: KCNA1 as ready
Early onset or syndromic epilepsy v1.232 KCNA1 Rebecca Foulger Gene: kcna1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.232 KCNA1 Rebecca Foulger commented on gene: KCNA1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.232 WDR62 Rebecca Foulger Marked gene: WDR62 as ready
Early onset or syndromic epilepsy v1.232 WDR62 Rebecca Foulger Gene: wdr62 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.232 WDR62 Rebecca Foulger Classified gene: WDR62 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.232 WDR62 Rebecca Foulger Gene: wdr62 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.231 WDR62 Rebecca Foulger commented on gene: WDR62: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber- the microcephaly panels are more appropriate for testing. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.231 TSEN2 Rebecca Foulger Marked gene: TSEN2 as ready
Early onset or syndromic epilepsy v1.231 TSEN2 Rebecca Foulger Gene: tsen2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.231 TSEN2 Rebecca Foulger Classified gene: TSEN2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.231 TSEN2 Rebecca Foulger Gene: tsen2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.230 TSEN2 Rebecca Foulger commented on gene: TSEN2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber because epilepsy is unlikely to be the primary presenting feature. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.230 SCN9A Rebecca Foulger Marked gene: SCN9A as ready
Early onset or syndromic epilepsy v1.230 SCN9A Rebecca Foulger Gene: scn9a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.230 SCN9A Rebecca Foulger commented on gene: SCN9A: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.230 FLNA Rebecca Foulger Marked gene: FLNA as ready
Early onset or syndromic epilepsy v1.230 FLNA Rebecca Foulger Gene: flna has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.230 FLNA Rebecca Foulger commented on gene: FLNA: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.230 FGFR3 Rebecca Foulger Classified gene: FGFR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.230 FGFR3 Rebecca Foulger Gene: fgfr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.229 FGFR3 Rebecca Foulger Marked gene: FGFR3 as ready
Early onset or syndromic epilepsy v1.229 FGFR3 Rebecca Foulger Gene: fgfr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.229 FGFR3 Rebecca Foulger Classified gene: FGFR3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.229 FGFR3 Rebecca Foulger Gene: fgfr3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.228 FGFR3 Rebecca Foulger commented on gene: FGFR3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber because the Craniosynostosis panel is more appropriate for testing. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.228 ATP1A2 Rebecca Foulger Marked gene: ATP1A2 as ready
Early onset or syndromic epilepsy v1.228 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.228 ATP1A2 Rebecca Foulger commented on gene: ATP1A2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.228 LYST Rebecca Foulger Marked gene: LYST as ready
Early onset or syndromic epilepsy v1.228 LYST Rebecca Foulger Gene: lyst has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.228 SETD5 Rebecca Foulger Marked gene: SETD5 as ready
Early onset or syndromic epilepsy v1.228 SETD5 Rebecca Foulger Gene: setd5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.228 WDR45B Rebecca Foulger Marked gene: WDR45B as ready
Early onset or syndromic epilepsy v1.228 WDR45B Rebecca Foulger Gene: wdr45b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.228 WDR45B Rebecca Foulger Classified gene: WDR45B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.228 WDR45B Rebecca Foulger Gene: wdr45b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.227 WDR45B Rebecca Foulger commented on gene: WDR45B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green, and an Amber rating is appropriate. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.227 WDR45B Rebecca Foulger commented on gene: WDR45B: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary, the evidence is borderline: PMID:28503735 (Suleiman et al) report 6 individuals from 3 families with homozygous pathogenic variants in WDR45B, and 2 of the families (5 indivs) had seizures- seizures were not reported in the sole individual from family 3.
Early onset or syndromic epilepsy v1.227 SETD5 Rebecca Foulger Classified gene: SETD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.227 SETD5 Rebecca Foulger Gene: setd5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.226 SETD5 Rebecca Foulger commented on gene: SETD5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green, and an Amber rating is appropriate. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.226 SETD5 Rebecca Foulger commented on gene: SETD5: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although four reviewers agreed it should be on EE panel, there is limited evidence of a seizure phenotype. PMID:26482601: (Kobayashi et al., 2016) examined 11 patients with early-onset epileptic encephalopathy, and SETD5 variants were amongst the findings. Therefore awaited clinical input on whether SETD5 should be demoted on this panel.
Early onset or syndromic epilepsy v1.226 LYST Rebecca Foulger Classified gene: LYST as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.226 LYST Rebecca Foulger Gene: lyst has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.225 LYST Rebecca Foulger commented on gene: LYST: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green, and an Amber rating is appropriate. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.225 LYST Rebecca Foulger commented on gene: LYST: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although the mouse model displays seizures (PMID:16518687), there is limited evidence of patients with seizures (no mention of seizures in PMID:9215679, and one 1990 report of Chédiak-Higashi syndrome with seizures from PMID:10450360). Therefore awaiting clinical opinion on whether LYST should be demoted on this panel.
Early onset or syndromic epilepsy v1.225 KIF1BP Rebecca Foulger Marked gene: KIF1BP as ready
Early onset or syndromic epilepsy v1.225 KIF1BP Rebecca Foulger Gene: kif1bp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.225 KIF1BP Rebecca Foulger Classified gene: KIF1BP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.225 KIF1BP Rebecca Foulger Gene: kif1bp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.224 KIF1BP Rebecca Foulger commented on gene: KIF1BP: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green, and an Amber rating is appropriate. Demoted from Green to Amber.
Early onset or syndromic epilepsy v1.224 KIF1BP Rebecca Foulger commented on gene: KIF1BP: Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. Although the association with GOLDBERG-SHPRINTZEN MEGACOLON SYNDROME is strong, there is little direct evidence for seizures (PMID:28277559 identifies one case). Therefore awaiting clinical opinion on whether KIF1BP should be demoted.
Early onset or syndromic epilepsy v1.224 GRIA2 Rebecca Foulger changed review comment from: PMID:8938126 (animal model): GluR2 heterozygous (+/−) mice showed reduced motor coordination but no sign of seizure activity as measured by observation, EEG, or post-mortem analysis.; to: PMID:8938126- animal model doesn't report seizures: GluR2 heterozygous (+/−) mice showed reduced motor coordination but no sign of seizure activity as measured by observation, EEG, or post-mortem analysis.
Early onset or syndromic epilepsy v1.224 WDR37 Rebecca Foulger Classified gene: WDR37 as Green List (high evidence)
Early onset or syndromic epilepsy v1.224 WDR37 Rebecca Foulger Gene: wdr37 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.223 WDR37 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Grey to Green.
Early onset or syndromic epilepsy v1.223 WDR37 Rebecca Foulger commented on gene: WDR37: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green.
Early onset or syndromic epilepsy v1.223 WDR37 Rebecca Foulger commented on gene: WDR37: WDR37 was added to the panel and rated Green by Konstantinos Varvagiannis. Although WDR37 is not yet associated with a disorder in OMIM or Gene2Phenotype, (as Konstantinos notes) there are sufficient unrelated cases from PMID:31327510 and PMID:31327508 with seizures (all 9 patients) for inclusion on the panel.
Early onset or syndromic epilepsy v1.223 WDR37 Rebecca Foulger changed review comment from: Added missense tag: only missense variants reported so far (PMID:31327510).; to: Added missense tag: only missense variants reported so far (PMIDs 31327510, 31327508).
Early onset or syndromic epilepsy v1.223 WDR37 Rebecca Foulger commented on gene: WDR37
Early onset or syndromic epilepsy v1.223 WDR37 Rebecca Foulger Tag missense tag was added to gene: WDR37.
Early onset or syndromic epilepsy v1.223 PIGU Rebecca Foulger Marked gene: PIGU as ready
Early onset or syndromic epilepsy v1.223 PIGU Rebecca Foulger Gene: pigu has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.223 PIGH Rebecca Foulger Marked gene: PIGH as ready
Early onset or syndromic epilepsy v1.223 PIGH Rebecca Foulger Gene: pigh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.223 PIGC Rebecca Foulger Marked gene: PIGC as ready
Early onset or syndromic epilepsy v1.223 PIGC Rebecca Foulger Gene: pigc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.223 RRM2B Rebecca Foulger Marked gene: RRM2B as ready
Early onset or syndromic epilepsy v1.223 RRM2B Rebecca Foulger Gene: rrm2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.223 TRAF7 Rebecca Foulger Marked gene: TRAF7 as ready
Early onset or syndromic epilepsy v1.223 TRAF7 Rebecca Foulger Gene: traf7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.223 TRAPPC12 Rebecca Foulger Marked gene: TRAPPC12 as ready
Early onset or syndromic epilepsy v1.223 TRAPPC12 Rebecca Foulger Gene: trappc12 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.223 TRAPPC6B Rebecca Foulger Marked gene: TRAPPC6B as ready
Early onset or syndromic epilepsy v1.223 TRAPPC6B Rebecca Foulger Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.223 GNB5 Rebecca Foulger Marked gene: GNB5 as ready
Early onset or syndromic epilepsy v1.223 GNB5 Rebecca Foulger Gene: gnb5 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.223 GNB5 Rebecca Foulger commented on gene: GNB5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green.
Early onset or syndromic epilepsy v1.223 TRAPPC6B Rebecca Foulger commented on gene: TRAPPC6B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber.
Early onset or syndromic epilepsy v1.223 TRAPPC12 Rebecca Foulger commented on gene: TRAPPC12: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber:
Early onset or syndromic epilepsy v1.223 TRAF7 Rebecca Foulger commented on gene: TRAF7: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: TRAF7 is Green on the Intellectual disability and Paediatric disorders panels, which would be appropriate for the presenting phenotype.
Early onset or syndromic epilepsy v1.223 RRM2B Rebecca Foulger commented on gene: RRM2B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: RRM2B is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Early onset or syndromic epilepsy v1.223 PIGU Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Grey to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Grey to Green.
Early onset or syndromic epilepsy v1.223 PIGH Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.223 PIGC Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.223 PEX5 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: PEX5 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: PEX5 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Early onset or syndromic epilepsy v1.223 KIAA1109 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green- although epilepsy may be secondary to the cerebral malformations presentation, include KIAA1109 so that cases recruited through different routes are not missed. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green- although epilepsy may be secondary to the cerebral malformations presentation, include KIAA1109 so that cases recruited through different routes are not missed. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.223 EIF2B3 Rebecca Foulger Classified gene: EIF2B3 as Green List (high evidence)
Early onset or syndromic epilepsy v1.223 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.222 EIF2B3 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.222 EIF2B1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.222 EFHC1 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene should remain as Amber: EFHC1 may be a susceptibility locus. Currently insufficient evidence to support a monogenic association with epilepsy.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should remain as Amber: EFHC1 may be a susceptibility locus. Currently insufficient evidence to support a monogenic association with epilepsy.
Early onset or syndromic epilepsy v1.222 DPM2 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: DPM2 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: DPM2 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Early onset or syndromic epilepsy v1.222 CUL4B Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.222 CNPY3 Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Helen Lord (Oxford Medical Genetics Laboratories) notes that there are two further 2019 paper supporting inclusion. Promoted from Amber to Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Helen Lord (Oxford Medical Genetics Laboratories) notes that there are two further 2019 paper supporting inclusion. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.222 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Early onset or syndromic epilepsy v1.221 PIGU Rebecca Foulger Classified gene: PIGU as Green List (high evidence)
Early onset or syndromic epilepsy v1.221 PIGU Rebecca Foulger Gene: pigu has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.220 PIGU Rebecca Foulger commented on gene: PIGU: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Grey to Green.
Early onset or syndromic epilepsy v1.220 PIGU Rebecca Foulger changed review comment from: PMID:31353022 (Knaus et al. 2019) report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in 5 individuals from 3 unrelated families. All individuals presented with global DD severe-to-profound ID, muscular hypotonia, seizures (myoclonic and focal myoclonic in all 5 probands), brain anomalies, scoliosis, and mild facial dysmorphism. Sequencing confirmed that all parents were healthy carriers. c.209T>A has not been observed in gnomAD while c.1149C>A has been observed only in the heterozygous state (7/277194).; to: PMID:31353022 (Knaus et al. 2019) report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in 5 individuals from 3 unrelated families. All individuals presented with global DD severe-to-profound ID, muscular hypotonia, seizures (myoclonic/focal myoclonic in all 5 probands), brain anomalies, scoliosis, and mild facial dysmorphism. Sequencing confirmed that all parents were healthy carriers. c.209T>A has not been observed in gnomAD while c.1149C>A has been observed only in the heterozygous state (7/277194).
Early onset or syndromic epilepsy v1.220 PIGU Rebecca Foulger commented on gene: PIGU: PIGU is not yet associated with a disorder in OMIM or Gene2Phenotype.
Early onset or syndromic epilepsy v1.220 PIGU Rebecca Foulger commented on gene: PIGU: PMID:31353022 (Knaus et al. 2019) report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in 5 individuals from 3 unrelated families. All individuals presented with global DD severe-to-profound ID, muscular hypotonia, seizures (myoclonic and focal myoclonic in all 5 probands), brain anomalies, scoliosis, and mild facial dysmorphism. Sequencing confirmed that all parents were healthy carriers. c.209T>A has not been observed in gnomAD while c.1149C>A has been observed only in the heterozygous state (7/277194).
Early onset or syndromic epilepsy v1.220 PIGH Rebecca Foulger Classified gene: PIGH as Green List (high evidence)
Early onset or syndromic epilepsy v1.220 PIGH Rebecca Foulger Gene: pigh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.219 PIGH Rebecca Foulger commented on gene: PIGH: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.219 PIGC Rebecca Foulger Classified gene: PIGC as Green List (high evidence)
Early onset or syndromic epilepsy v1.219 PIGC Rebecca Foulger Gene: pigc has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.218 PIGC Rebecca Foulger commented on gene: PIGC: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green: PIGx genes act in the same biochemical pathway. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.218 PEX5 Rebecca Foulger commented on gene: PEX5: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: PEX5 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Early onset or syndromic epilepsy v1.218 KIAA1109 Rebecca Foulger Classified gene: KIAA1109 as Green List (high evidence)
Early onset or syndromic epilepsy v1.218 KIAA1109 Rebecca Foulger Gene: kiaa1109 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.217 KIAA1109 Rebecca Foulger commented on gene: KIAA1109: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green- although epilepsy may be secondary to the cerebral malformations presentation, include KIAA1109 so that cases recruited through different routes are not missed. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.217 GTPBP3 Rebecca Foulger commented on gene: GTPBP3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: GTPBP3 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Early onset or syndromic epilepsy v1.217 EIF2B3 Rebecca Foulger Classified gene: EIF2B3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.217 EIF2B3 Rebecca Foulger Gene: eif2b3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.216 EIF2B3 Rebecca Foulger commented on gene: EIF2B3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.216 EIF2B1 Rebecca Foulger Classified gene: EIF2B1 as Green List (high evidence)
Early onset or syndromic epilepsy v1.216 EIF2B1 Rebecca Foulger Gene: eif2b1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.215 EIF2B1 Rebecca Foulger commented on gene: EIF2B1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Epilepsy is a feature of Vanishing White Matter Disorder, and therefore should include on the panel for early diagnosis in children. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.215 EFHC1 Rebecca Foulger commented on gene: EFHC1: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene should remain as Amber: EFHC1 may be a susceptibility locus. Currently insufficient evidence to support a monogenic association with epilepsy.
Early onset or syndromic epilepsy v1.215 DPM2 Rebecca Foulger commented on gene: DPM2: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that this gene can remain as Amber: DPM2 is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Early onset or syndromic epilepsy v1.215 CUL4B Rebecca Foulger Classified gene: CUL4B as Green List (high evidence)
Early onset or syndromic epilepsy v1.215 CUL4B Rebecca Foulger Gene: cul4b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.214 CUL4B Rebecca Foulger commented on gene: CUL4B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.214 CNPY3 Rebecca Foulger Classified gene: CNPY3 as Green List (high evidence)
Early onset or syndromic epilepsy v1.214 CNPY3 Rebecca Foulger Gene: cnpy3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.213 CNPY3 Rebecca Foulger commented on gene: CNPY3: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Helen Lord (Oxford Medical Genetics Laboratories) notes that there are two further 2019 paper supporting inclusion. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.213 NPRL2 Rebecca Foulger commented on gene: NPRL2: NPRL2 re-reviewed for curation of GMS epilepsy panel: Sufficient cases for inclusion but variants in unaffected family members (explained by the authors as incomplete penetrance). Other members of the complex, NPRL3 and DEPDC5, are Green on the panel. Since the last curation there has been a Green review by Deb Pal (Kings College London): PMID:30093711 (2019) note 3 further probands with epilepsy (including 1 with infantile spasm and unclear effect on the protein). They also note incomplete penetrance for variants in their cohort of 73 patients (covering DEPDC5 + NPRL2 + NPRL3 genes which all form the GATOR1 complex together). Awaiting clinical review for final gene rating.
Early onset or syndromic epilepsy v1.213 IKBKG Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM lists XLD inheritance for Incontinentia pigmenti (MIM:308300).
Early onset or syndromic epilepsy v1.213 IKBKG Rebecca Foulger Mode of inheritance for gene: IKBKG was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.212 ARHGEF9 Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM lists XLR mode of inheritance for 'Epileptic encephalopathy, early infantile, 8' (MIM:300607). Gene2Phenotype lists hemizygous mode of inheritance (XLR) for EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 8.
Early onset or syndromic epilepsy v1.212 ARHGEF9 Rebecca Foulger Mode of inheritance for gene: ARHGEF9 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.211 NDUFA1 Rebecca Foulger Added comment: Comment on mode of inheritance: There is a case of female with variant and symptoms in PMID:21596602. (Mayr et al., 2011), but she does not have epilepsy but rather a metabolic defect. Therefore XLD is appropriate for metabolism panel but MOI is kept as XLR on this epilepsy panel for now.
Early onset or syndromic epilepsy v1.211 NDUFA1 Rebecca Foulger Mode of inheritance for gene: NDUFA1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.210 SLC16A2 Rebecca Foulger Added comment: Comment on mode of inheritance: MOI is recorded as hemizygous in Gene2Phenotype and XL in OMIM. XLR inheritance was confirmed with reviewer, as stated by Ellen McDonagh.
Early onset or syndromic epilepsy v1.210 SLC16A2 Rebecca Foulger Mode of inheritance for gene: SLC16A2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.209 PIGA Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM records XLR inheritance for 'Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MIM:300868). Gene2Phenotype reports 'hemizygous' allelic requirement for MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 2. Johnston et al., 2012 (PMID:22305531) report 3 deceased males and 2 carrier females. Both carrier females had 100% skewed X-inactivation and neither presented with a phenotype.
Early onset or syndromic epilepsy v1.209 PIGA Rebecca Foulger Mode of inheritance for gene: PIGA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.208 MED12 Rebecca Foulger Added comment: Comment on mode of inheritance: Allelic requirement listed in Gene2Phenotype is 'hemizygous' for both 'OPITZ-KAVEGGIA SYNDROME' and 'LUJAN-FRYNS SYNDROME'.
Early onset or syndromic epilepsy v1.208 MED12 Rebecca Foulger Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.207 MAGI2 Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM lists AR inheritance for 'Nephrotic syndrome, type 15' (MIM:617609). Gene2Phenotype lists 'monoallelic' inheritance for EARLY ONSET EPILEPTIC ENCEPHALOPATHY.
Early onset or syndromic epilepsy v1.207 MAGI2 Rebecca Foulger Mode of inheritance for gene: MAGI2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.206 IDH2 Rebecca Foulger Added comment: Comment on mode of inheritance: The mode of inheritance for IDH2 is currently MONOALLELIC on the 'Intellectual disability' panel, and the 'Inborn errors of metabolism' panel.
Early onset or syndromic epilepsy v1.206 IDH2 Rebecca Foulger Mode of inheritance for gene: IDH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.205 IDH2 Rebecca Foulger Phenotypes for gene: IDH2 were changed from D-2-hydroxyglutaric aciduria 2 to D-2-hydroxyglutaric aciduria 2, 613657
Early onset or syndromic epilepsy v1.204 IDH2 Rebecca Foulger Publications for gene: IDH2 were set to
Early onset or syndromic epilepsy v1.203 NRXN1 Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:30031152 (Al Shehhi et al.) report heterozygous deletions of NRXN1 with phenotypes including seizures. At least PMID:21964664 (Harrison et al.) and PMID:19896112 report a biallelic mode of inheritance.
Early onset or syndromic epilepsy v1.203 NRXN1 Rebecca Foulger Mode of inheritance for gene: NRXN1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.202 SLC35A2 Rebecca Foulger Added comment: Comment on mode of inheritance: MOI in OMIM for SLC35A2 is listed as X-linked dominant.
Early onset or syndromic epilepsy v1.202 SLC35A2 Rebecca Foulger Mode of inheritance for gene: SLC35A2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.201 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded.; to: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plu review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.
Early onset or syndromic epilepsy v1.201 KCNJ11 Rebecca Foulger Mode of inheritance for gene: KCNJ11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.200 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded.; to: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded.
Early onset or syndromic epilepsy v1.200 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given.; to: Comment on mode of inheritance: Most seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded.
Early onset or syndromic epilepsy v1.200 KCNJ11 Rebecca Foulger Publications for gene: KCNJ11 were set to 25678012; 16670688; 16609879; 27681997; 17065345; 28943513
Early onset or syndromic epilepsy v1.199 KCNJ11 Rebecca Foulger Added comment: Comment on mode of inheritance: Most seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given.
Early onset or syndromic epilepsy v1.199 KCNJ11 Rebecca Foulger Mode of inheritance for gene: KCNJ11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.198 TUBB2A Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Green following advice from Helen Brittain: 3 unrelated cases from literature. Although not all with the genotype may develop seizures, there are sufficient cases of the epilepsy phenotype for inclusion on the panel.; to: Comment on list classification: Updated rating from Red to Green following advice from Helen Brittain: 3 unrelated cases from literature (two cases from PMID:24702957 and one from large-scale study PMID:25326637. Although not all with the genotype may develop seizures, there are sufficient cases of the epilepsy phenotype for inclusion on the panel.
Early onset or syndromic epilepsy v1.198 HCN2 Rebecca Foulger changed review comment from: Comment on mode of inheritance: PMID:22131395: DiFrancesco et al. 2011 report a homozygous HCN2 variant (p.E515K) in a patient with idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the variant. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.; to: Comment on mode of inheritance: PMID:22131395: DiFrancesco et al. 2011 report a homozygous HCN2 variant (p.E515K) in a patient with idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the variant. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance. Hence MOI listed as BOTH monoallelic and biallelic.
Early onset or syndromic epilepsy v1.198 POLG2 Sarah Leigh Classified gene: POLG2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.198 POLG2 Sarah Leigh Added comment: Comment on list classification: Single case of recessive epilepsy.
Early onset or syndromic epilepsy v1.198 POLG2 Sarah Leigh Gene: polg2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.197 POLG2 Sarah Leigh gene: POLG2 was added
gene: POLG2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: POLG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLG2 were set to 31286721; 27592148; 30157269
Phenotypes for gene: POLG2 were set to Autosomal Recessive Epilepsy Family Without Ophthalmoplegia
Review for gene: POLG2 was set to AMBER
Added comment: Single case of Autosomal Recessive Epilepsy Family Without Ophthalmoplegia in a 27-year-old Pakistani male, who was homozygous for POLG2 c.694G>A, p.G232S. Both his parents were heterozygous for this variant, and none of them had liver disease, ophthalmoplegia, ptosis, nystagmus, or myopathy, and the parents showed no symptoms of epilepsy or ophthalmoplegia.
Sources: Literature
Early onset or syndromic epilepsy v1.196 AFF3 Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
----
As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
----
As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature

---------------

Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
Early onset or syndromic epilepsy v1.196 AFF3 Rebecca Foulger Tag missense tag was added to gene: AFF3.
Tag watchlist tag was added to gene: AFF3.
Early onset or syndromic epilepsy v1.196 AFF3 Rebecca Foulger Classified gene: AFF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.196 AFF3 Rebecca Foulger Gene: aff3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.195 AFF3 Rebecca Foulger commented on gene: AFF3
Early onset or syndromic epilepsy v1.195 WWOX Rebecca Foulger commented on gene: WWOX: Usha Kini (Oxford Medical Genetics Laboratories) confirmed that WWOX should be on the epilepsy panel (personal communication via email on August 8th, 2019).
Early onset or syndromic epilepsy v1.195 AFF3 Rebecca Foulger Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures; Abnormality of skeletal morphology; Abnormality of the urinary system; Hypertrichosis; Abnormality of the respiratory system to Intellectual disability; Seizures; KINSSHIP syndrome
Early onset or syndromic epilepsy v1.194 PIGU Rebecca Foulger commented on gene: PIGU
Early onset or syndromic epilepsy v1.194 PIGU Rebecca Foulger Tag missense tag was added to gene: PIGU.
Early onset or syndromic epilepsy v1.194 GRIA2 Rebecca Foulger commented on gene: GRIA2: GRIA2 is not yet associated with a disorder in OMIM or Gene2Phenotype.
Early onset or syndromic epilepsy v1.194 GRIA2 Rebecca Foulger commented on gene: GRIA2: PMID:8938126 (animal model): GluR2 heterozygous (+/−) mice showed reduced motor coordination but no sign of seizure activity as measured by observation, EEG, or post-mortem analysis.
Early onset or syndromic epilepsy v1.194 GRIA2 Rebecca Foulger Phenotypes for gene: GRIA2 were changed from Intellectual disability; Seizures; Autism to Intellectual disability; Seizures; myoclonic seizures; status epilepticus; tonic-clonic seizures; focal seizures
Early onset or syndromic epilepsy v1.193 GRIA2 Rebecca Foulger commented on gene: GRIA2
Early onset or syndromic epilepsy v1.193 GRIA2 Konstantinos Varvagiannis gene: GRIA2 was added
gene: GRIA2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GRIA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GRIA2 were set to 31300657
Phenotypes for gene: GRIA2 were set to Intellectual disability; Seizures; Autism
Penetrance for gene: GRIA2 were set to unknown
Review for gene: GRIA2 was set to AMBER
Added comment: There is a recent publication by Salpietro et al. (2019 - PMID: 31300657) reporting on 28 unrelated individuals. Seizures were observed in 12/28 (~40%), so the gene may also be relevant for the current panel.

The phenotype overall corresponds to a NDD disorder with DD, ID (universal feature in those with appropriate age for evaluation, relevant severity), ASD, Rett-like features and seizures. All types of variants were reported (15 missense, 2 splice-site, 1 in-frame del, 1 stopgain, 2 frameshift ones, 3 CNVs spanning GRIA2 and other genes, the latter more tolerant to LoF). The role of this gene (encoding AMPA receptor GluA2 subunit), functional studies (loss of function demonstrated for the majority of mutations, though by multiple molecular mechanisms), overlapping phenotype with disorders due to other ionotropic glutamate receptor subunit genes (eg. GRIA3/4 - ID with or without seizures), animal models (PMID cited: 8938126) are among the arguments provided.
Sources: Literature
Early onset or syndromic epilepsy v1.193 AFF3 Konstantinos Varvagiannis gene: AFF3 was added
gene: AFF3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: AFF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733
Phenotypes for gene: AFF3 were set to Intellectual disability; Seizures; Abnormality of skeletal morphology; Abnormality of the urinary system; Hypertrichosis; Abnormality of the respiratory system
Penetrance for gene: AFF3 were set to unknown
Mode of pathogenicity for gene: AFF3 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: AFF3 was set to GREEN
Added comment: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
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In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
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As a result this gene can be considered for inclusion in the epilepsy panel as green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).
Sources: Literature
Early onset or syndromic epilepsy v1.193 PIGU Konstantinos Varvagiannis gene: PIGU was added
gene: PIGU was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PIGU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGU were set to 31353022
Phenotypes for gene: PIGU were set to Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Penetrance for gene: PIGU were set to Complete
Review for gene: PIGU was set to GREEN
Added comment: Knaus et al. (2019 - PMID: 31353022) report on 5 affected individuals (from 3 unrelated families) with biallelic pathogenic PIGU variants.

Common features included tone abnormalities, global DD, ID, seizures, CNS anomalies (cerebral atrophy and/or cerebellar hypoplasia), scoliosis. Affected individuals presented also with facial similarities. DD/ID were universal features and their severity appears to be relevant to the panel. Seizures were also reported in all individuals (myoclonic in 3, for whom this was specified). ALP was normal in all.

Three individuals from 2 non-consanguineous families (one from Norway, the other not specified) were homozygous for a missense variant NM_080476.4:c.1149C>A (or p.Asn383Lys) present with an AF of 7/277197 in Europeans. Two individuals born to consanguineous parents from Turkey were homozygous for another missense variant (c.209T>A or p.Ile70Lys - same RefSeq).

Segregation analyses in parents and unaffected sibs were carried out.

PIGU encodes a subunit of the GPI transaminidase, a heteropentameric complex (other subunits encoded by PIGK, PIGS, PIGT and GPAA1) that mediates attachment in the endoplasmic reticulum of glycosylphosphatidylinositol (GPI) to the C-termini of proteins which are subsequently anchored to the cell surface.

Pathogenic variants in 18 of 29 genes implicated in biosynthesis of the GPI anchor have been identified as a cause of GPI biosynthesis disorders, with ID and seizures as principal features. Mutations in other genes encoding components of the GPI transaminidase complex (GPAA1, PIGT and PIGS) lead to neurodevelopmental disorders.

Functional impairment of PIGU was supported by flow-cytometric analysis showing significant reduction of cell surface expression of GPI anchored proteins (mainly FLAER, CD16 and CD24) on granulocytes from affected individuals. In addition accumulation of free GPI anchors on the cell surface of B cells from affected individuals further suggested deficiency of the GPI transaminidase.

Transient expression of mutant (Asn383Lys) protein failed to rescue expression of GPI-APs to the same extent as wt in a CHO cell line deficient for PIGU.

Feature analysis demonstrated similarities among individuals with mutations in other genes of the GPI transamidase complex (GPAA1 and PIGT) as well as with GPI biosynthesis disorders. Facial analysis was also suggestive of facial similarities between individuals with GPAA1 and PIGU mutations.

PIGU is not associated with any phenotype in OMIM or G2P.

As a result this gene can be considered for inclusion in the ID and epilepsy panels probably as green (3 families, ID of relevant severity and seizures in all affected individuals, known group of disorders and supportive evidence) or amber.
Sources: Literature
Early onset or syndromic epilepsy v1.193 WDR37 Konstantinos Varvagiannis gene: WDR37 was added
gene: WDR37 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WDR37 were set to 31327510; 31327508
Phenotypes for gene: WDR37 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system
Penetrance for gene: WDR37 were set to unknown
Mode of pathogenicity for gene: WDR37 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: WDR37 was set to GREEN
Added comment: Two concurrent publications by Reis et al. and Kanca et al. (2019 - PMIDs: 31327510, 31327508) report on the phenotype of individuals with de novo WDR37 mutations.

The study by Reis et al. provides clinical details on 4 affected individuals, while 5 further are described by Kanca et al.

4 different de novo variants were reported in these individuals who appear to be unrelated in (and between) the 2 studies [NM_014023.3]:
- c.356C>T (p.Ser119Phe) [Reis indiv. 1 - 3y, Kanca proband 3 - 5m2w]
- c.389C>T (p.Thr130Ile) [Reis indiv. 2 - 22m , Kanca proband 5 - 6 w]
- c.374C>T (p.Thr125Ile) [Reis indiv. 3 - 8y , Kanca proband 1 - 7y]
- c.386C>G (p.Ser129Cys) [Reis indiv. 4 - unkn age, Kanca probands 2 and 4, 6.5y and 19y]

Common features included DD/ID (severity relevant for the current panel), seizures (9/9), ocular anomalies (corneal opacity/Peters anomaly, coloboma, microphthalmia etc.) and variable brain, hearing, cardiovascular, skeletal and genitourinary anomalies. Some facial and/or other dysmorphic features (incl. excess nuchal skin / webbed neck) were also frequent among affected individuals. Feeding difficulties and growth deficiency were also among the features observed.

The function of WDR37 is not known. Variants demonstrated comparable protein levels and cellular localization compared to wt.

Reis et al. provide evidence using CRISPR-Cas9 mediated genome editing in zebrafish, to introduce the Ser129Cys variant observed in affected individuals as well as novel missense and frameshift variants. Poor growth (similar to the human phenotype) and larval lethality were noted for missense variants. Head size was proportionately small. Ocular (coloboma/corneal) or craniofacial anomalies were not observed. Zebrafish heterozygous for LoF variants survived to adulthood.

Based on these a dominant-negative mechanism was postulated for missense alleles.

RNA-seq analysis in zebrafish showed upregulation of cholesterol biosynthesis pathways (among the most dysregulated ones).

Previous data in mice, suggest a broad expression pattern for Wdr37 with enrichment in ocular and brain tissues, significant associations in homozygous mutant mice for decreased body weight, grip strength, skeletal anomalies and possible increase (p =< 0.05) in ocular (lens/corneal) and other anomalies [BioGPS and International Mouse Phenotyping Consortium cited].

CG12333 loss (the Drosophila WDR37 ortholog) causes increased bang sensitivity in flies (analogous to the human epilepsy phenotype), defects in copulation and grip strength, phenotypes that were rescued by human reference but not variant cDNAs.

As discussed by Kanca et al. based on data from Drosophila and mice, limited phenotypic similarity of CNVs spanning WDR37 and adjacent genes with the reported individuals and the presence of LoF variants in control populations haploinsufficiency appears unlikely. Gain-of-function is also unlikely, as expression of human variants in flies did not exacerbate the observed phenotypes. A dominant-negative effect is again proposed.

WDR37 is not associated with any phenotype in OMIM/G2P.

As a result WDR37 can be considered for inclusion in the ID and epilepsy panels with green (relevant phenotype, sufficient cases, animal models) or amber rating.
Sources: Literature
Early onset or syndromic epilepsy v1.193 ATN1_CAG Rebecca Foulger Source NHS GMS was added to STR: ATN1_CAG.
Early onset or syndromic epilepsy v1.192 CSTB_CCCCGCCCCGCG Rebecca Foulger Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Early onset or syndromic epilepsy v1.191 CSTB_CCCCGCCCCGCG Rebecca Foulger commented on STR: CSTB_CCCCGCCCCGCG
Early onset or syndromic epilepsy v1.191 ATN1_CAG Rebecca Foulger commented on STR: ATN1_CAG
Early onset or syndromic epilepsy v1.191 CUL4B Rebecca Foulger Source Wessex and West Midlands GLH was added to CUL4B.
Early onset or syndromic epilepsy v1.191 TUBA3E Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBA3E.
Early onset or syndromic epilepsy v1.191 SLC6A5 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC6A5.
Early onset or syndromic epilepsy v1.191 SHH Rebecca Foulger Source Wessex and West Midlands GLH was added to SHH.
Early onset or syndromic epilepsy v1.191 SEC24D Rebecca Foulger Source Wessex and West Midlands GLH was added to SEC24D.
Early onset or syndromic epilepsy v1.191 SCN2B Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN2B.
Early onset or syndromic epilepsy v1.191 RYR3 Rebecca Foulger Source Wessex and West Midlands GLH was added to RYR3.
Early onset or syndromic epilepsy v1.191 RUBCN Rebecca Foulger Source Wessex and West Midlands GLH was added to RUBCN.
Early onset or syndromic epilepsy v1.191 PSMB8 Rebecca Foulger Source Wessex and West Midlands GLH was added to PSMB8.
Early onset or syndromic epilepsy v1.191 PRICKLE2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PRICKLE2.
Early onset or syndromic epilepsy v1.191 PCDHB4 Rebecca Foulger Source Wessex and West Midlands GLH was added to PCDHB4.
Early onset or syndromic epilepsy v1.191 NRAS Rebecca Foulger Source Wessex and West Midlands GLH was added to NRAS.
Early onset or syndromic epilepsy v1.191 NID1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NID1.
Early onset or syndromic epilepsy v1.191 NDUFA11 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFA11.
Early onset or syndromic epilepsy v1.191 MT-TL1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MT-TL1.
Early onset or syndromic epilepsy v1.191 MATN4 Rebecca Foulger Source Wessex and West Midlands GLH was added to MATN4.
Early onset or syndromic epilepsy v1.191 MAPK10 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAPK10.
Early onset or syndromic epilepsy v1.191 KAT5 Rebecca Foulger Source Wessex and West Midlands GLH was added to KAT5.
Early onset or syndromic epilepsy v1.191 INO80 Rebecca Foulger Source Wessex and West Midlands GLH was added to INO80.
Early onset or syndromic epilepsy v1.191 H3F3B Rebecca Foulger Source Wessex and West Midlands GLH was added to H3F3B.
Early onset or syndromic epilepsy v1.191 H3F3A Rebecca Foulger Source Wessex and West Midlands GLH was added to H3F3A.
Early onset or syndromic epilepsy v1.191 GLRB Rebecca Foulger Source Wessex and West Midlands GLH was added to GLRB.
Early onset or syndromic epilepsy v1.191 GCSH Rebecca Foulger Source Wessex and West Midlands GLH was added to GCSH.
Early onset or syndromic epilepsy v1.191 GATM Rebecca Foulger Source Wessex and West Midlands GLH was added to GATM.
Early onset or syndromic epilepsy v1.191 GATAD2B Rebecca Foulger Source Wessex and West Midlands GLH was added to GATAD2B.
Early onset or syndromic epilepsy v1.191 GAL Rebecca Foulger Source Wessex and West Midlands GLH was added to GAL.
Early onset or syndromic epilepsy v1.191 GABRD Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRD.
Early onset or syndromic epilepsy v1.191 FTL Rebecca Foulger Source Wessex and West Midlands GLH was added to FTL.
Early onset or syndromic epilepsy v1.191 FIG4 Rebecca Foulger Source Wessex and West Midlands GLH was added to FIG4.
Early onset or syndromic epilepsy v1.191 DMBX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DMBX1.
Early onset or syndromic epilepsy v1.191 CYP27A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to CYP27A1.
Early onset or syndromic epilepsy v1.191 CSNK1G1 Rebecca Foulger Source Wessex and West Midlands GLH was added to CSNK1G1.
Early onset or syndromic epilepsy v1.191 CRH Rebecca Foulger Source Wessex and West Midlands GLH was added to CRH.
Early onset or syndromic epilepsy v1.191 CNTN2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNTN2.
Early onset or syndromic epilepsy v1.191 CLN6 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLN6.
Early onset or syndromic epilepsy v1.191 CLN5 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLN5.
Early onset or syndromic epilepsy v1.191 CLCN2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLCN2.
Early onset or syndromic epilepsy v1.191 CBL Rebecca Foulger Source Wessex and West Midlands GLH was added to CBL.
Early onset or syndromic epilepsy v1.191 CASR Rebecca Foulger Source Wessex and West Midlands GLH was added to CASR.
Early onset or syndromic epilepsy v1.191 CAMK2G Rebecca Foulger Source Wessex and West Midlands GLH was added to CAMK2G.
Early onset or syndromic epilepsy v1.191 CACNB4 Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNB4.
Early onset or syndromic epilepsy v1.191 ASAH1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ASAH1.
Early onset or syndromic epilepsy v1.191 ALG2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG2.
Early onset or syndromic epilepsy v1.191 ALG12 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG12.
Early onset or syndromic epilepsy v1.191 ADGRV1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ADGRV1.
Early onset or syndromic epilepsy v1.191 AARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to AARS2.
Early onset or syndromic epilepsy v1.191 VLDLR Rebecca Foulger Source Wessex and West Midlands GLH was added to VLDLR.
Early onset or syndromic epilepsy v1.191 UFC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to UFC1.
Early onset or syndromic epilepsy v1.191 TXNRD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TXNRD1.
Early onset or syndromic epilepsy v1.191 TUBB Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB.
Early onset or syndromic epilepsy v1.191 TUBA8 Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBA8.
Early onset or syndromic epilepsy v1.191 TSFM Rebecca Foulger Source Wessex and West Midlands GLH was added to TSFM.
Early onset or syndromic epilepsy v1.191 TSEN34 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSEN34.
Early onset or syndromic epilepsy v1.191 TSEN15 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSEN15.
Early onset or syndromic epilepsy v1.191 TRIP13 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRIP13.
Early onset or syndromic epilepsy v1.191 TRAPPC6B Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAPPC6B.
Early onset or syndromic epilepsy v1.191 TRAPPC12 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAPPC12.
Early onset or syndromic epilepsy v1.191 TRAF7 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAF7.
Early onset or syndromic epilepsy v1.191 TNK2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TNK2.
Early onset or syndromic epilepsy v1.191 TIMM50 Rebecca Foulger Source Wessex and West Midlands GLH was added to TIMM50.
Early onset or syndromic epilepsy v1.191 TFE3 Rebecca Foulger Source Wessex and West Midlands GLH was added to TFE3.
Early onset or syndromic epilepsy v1.191 TELO2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TELO2.
Early onset or syndromic epilepsy v1.191 TBC1D20 Rebecca Foulger Source Wessex and West Midlands GLH was added to TBC1D20.
Early onset or syndromic epilepsy v1.191 SUCLG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SUCLG1.
Early onset or syndromic epilepsy v1.191 ST3GAL3 Rebecca Foulger Source Wessex and West Midlands GLH was added to ST3GAL3.
Early onset or syndromic epilepsy v1.191 SRPX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SRPX2.
Early onset or syndromic epilepsy v1.191 SPR Rebecca Foulger Source Wessex and West Midlands GLH was added to SPR.
Early onset or syndromic epilepsy v1.191 SNIP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SNIP1.
Early onset or syndromic epilepsy v1.191 SMC1A Rebecca Foulger Source Wessex and West Midlands GLH was added to SMC1A.
Early onset or syndromic epilepsy v1.191 SLC45A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC45A1.
Early onset or syndromic epilepsy v1.191 SLC35A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC35A1.
Early onset or syndromic epilepsy v1.191 SIX3 Rebecca Foulger Source Wessex and West Midlands GLH was added to SIX3.
Early onset or syndromic epilepsy v1.191 SETD1B Rebecca Foulger Source Wessex and West Midlands GLH was added to SETD1B.
Early onset or syndromic epilepsy v1.191 SDHA Rebecca Foulger Source Wessex and West Midlands GLH was added to SDHA.
Early onset or syndromic epilepsy v1.191 RYR2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RYR2.
Early onset or syndromic epilepsy v1.191 RUSC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RUSC2.
Early onset or syndromic epilepsy v1.191 RRM2B Rebecca Foulger Source Wessex and West Midlands GLH was added to RRM2B.
Early onset or syndromic epilepsy v1.191 RPIA Rebecca Foulger Source Wessex and West Midlands GLH was added to RPIA.
Early onset or syndromic epilepsy v1.191 RNU4ATAC Rebecca Foulger Source Wessex and West Midlands GLH was added to RNU4ATAC.
Early onset or syndromic epilepsy v1.191 RAB3GAP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RAB3GAP2.
Early onset or syndromic epilepsy v1.191 RAB3GAP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to RAB3GAP1.
Early onset or syndromic epilepsy v1.191 PTF1A Rebecca Foulger Source Wessex and West Midlands GLH was added to PTF1A.
Early onset or syndromic epilepsy v1.191 PSPH Rebecca Foulger Source Wessex and West Midlands GLH was added to PSPH.
Early onset or syndromic epilepsy v1.191 PSAT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PSAT1.
Early onset or syndromic epilepsy v1.191 POMT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to POMT2.
Early onset or syndromic epilepsy v1.191 PIGQ Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGQ.
Early onset or syndromic epilepsy v1.191 PIGH Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGH.
Early onset or syndromic epilepsy v1.191 PIGC Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGC.
Early onset or syndromic epilepsy v1.191 PEX5 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX5.
Early onset or syndromic epilepsy v1.191 PDSS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PDSS2.
Early onset or syndromic epilepsy v1.191 PCLO Rebecca Foulger Source Wessex and West Midlands GLH was added to PCLO.
Early onset or syndromic epilepsy v1.191 OTX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to OTX2.
Early onset or syndromic epilepsy v1.191 NUBPL Rebecca Foulger Source Wessex and West Midlands GLH was added to NUBPL.
Early onset or syndromic epilepsy v1.191 NPRL2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NPRL2.
Early onset or syndromic epilepsy v1.191 NEDD4L Rebecca Foulger Source Wessex and West Midlands GLH was added to NEDD4L.
Early onset or syndromic epilepsy v1.191 NECAP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NECAP1.
Early onset or syndromic epilepsy v1.191 NDUFS7 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS7.
Early onset or syndromic epilepsy v1.191 NDUFS6 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS6.
Early onset or syndromic epilepsy v1.191 NDUFS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS2.
Early onset or syndromic epilepsy v1.191 NDUFS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS1.
Early onset or syndromic epilepsy v1.191 NDUFAF4 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFAF4.
Early onset or syndromic epilepsy v1.191 NDUFAF3 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFAF3.
Early onset or syndromic epilepsy v1.191 NDUFA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFA2.
Early onset or syndromic epilepsy v1.191 NDP Rebecca Foulger Source Wessex and West Midlands GLH was added to NDP.
Early onset or syndromic epilepsy v1.191 MED17 Rebecca Foulger Source Wessex and West Midlands GLH was added to MED17.
Early onset or syndromic epilepsy v1.191 MAST1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAST1.
Early onset or syndromic epilepsy v1.191 MANBA Rebecca Foulger Source Wessex and West Midlands GLH was added to MANBA.
Early onset or syndromic epilepsy v1.191 LNPK Rebecca Foulger Source Wessex and West Midlands GLH was added to LNPK.
Early onset or syndromic epilepsy v1.191 LIPT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to LIPT2.
Early onset or syndromic epilepsy v1.191 LARGE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to LARGE1.
Early onset or syndromic epilepsy v1.191 KPTN Rebecca Foulger Source Wessex and West Midlands GLH was added to KPTN.
Early onset or syndromic epilepsy v1.191 KIAA1109 Rebecca Foulger Source Wessex and West Midlands GLH was added to KIAA1109.
Early onset or syndromic epilepsy v1.191 KCNMA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNMA1.
Early onset or syndromic epilepsy v1.191 ISPD Rebecca Foulger Source Wessex and West Midlands GLH was added to ISPD.
Early onset or syndromic epilepsy v1.191 HSPD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HSPD1.
Early onset or syndromic epilepsy v1.191 HPRT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HPRT1.
Early onset or syndromic epilepsy v1.191 HOXA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HOXA1.
Early onset or syndromic epilepsy v1.191 HEXB Rebecca Foulger Source Wessex and West Midlands GLH was added to HEXB.
Early onset or syndromic epilepsy v1.191 HCCS Rebecca Foulger Source Wessex and West Midlands GLH was added to HCCS.
Early onset or syndromic epilepsy v1.191 GTPBP3 Rebecca Foulger Source Wessex and West Midlands GLH was added to GTPBP3.
Early onset or syndromic epilepsy v1.191 GLRA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GLRA1.
Early onset or syndromic epilepsy v1.191 GLI3 Rebecca Foulger Source Wessex and West Midlands GLH was added to GLI3.
Early onset or syndromic epilepsy v1.191 FOXRED1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FOXRED1.
Early onset or syndromic epilepsy v1.191 FKRP Rebecca Foulger Source Wessex and West Midlands GLH was added to FKRP.
Early onset or syndromic epilepsy v1.191 FASTKD2 Rebecca Foulger Source Wessex and West Midlands GLH was added to FASTKD2.
Early onset or syndromic epilepsy v1.191 EIF2B3 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B3.
Early onset or syndromic epilepsy v1.191 EIF2B1 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B1.
Early onset or syndromic epilepsy v1.191 EFHC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to EFHC1.
Early onset or syndromic epilepsy v1.191 DPM2 Rebecca Foulger Source Wessex and West Midlands GLH was added to DPM2.
Early onset or syndromic epilepsy v1.191 DOLK Rebecca Foulger Source Wessex and West Midlands GLH was added to DOLK.
Early onset or syndromic epilepsy v1.191 DNAJC6 Rebecca Foulger Source Wessex and West Midlands GLH was added to DNAJC6.
Early onset or syndromic epilepsy v1.191 DHCR24 Rebecca Foulger Source Wessex and West Midlands GLH was added to DHCR24.
Early onset or syndromic epilepsy v1.191 DBT Rebecca Foulger Source Wessex and West Midlands GLH was added to DBT.
Early onset or syndromic epilepsy v1.191 CUX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CUX2.
Early onset or syndromic epilepsy v1.191 CSNK2B Rebecca Foulger Source Wessex and West Midlands GLH was added to CSNK2B.
Early onset or syndromic epilepsy v1.191 COX15 Rebecca Foulger Source Wessex and West Midlands GLH was added to COX15.
Early onset or syndromic epilepsy v1.191 COX10 Rebecca Foulger Source Wessex and West Midlands GLH was added to COX10.
Early onset or syndromic epilepsy v1.191 COQ6 Rebecca Foulger Source Wessex and West Midlands GLH was added to COQ6.
Early onset or syndromic epilepsy v1.191 COG8 Rebecca Foulger Source Wessex and West Midlands GLH was added to COG8.
Early onset or syndromic epilepsy v1.191 COG6 Rebecca Foulger Source Wessex and West Midlands GLH was added to COG6.
Early onset or syndromic epilepsy v1.191 COG4 Rebecca Foulger Source Wessex and West Midlands GLH was added to COG4.
Early onset or syndromic epilepsy v1.191 CNPY3 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNPY3.
Early onset or syndromic epilepsy v1.191 CCND2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CCND2.
Early onset or syndromic epilepsy v1.191 CCDC88C Rebecca Foulger Source Wessex and West Midlands GLH was added to CCDC88C.
Early onset or syndromic epilepsy v1.191 CCDC88A Rebecca Foulger Source Wessex and West Midlands GLH was added to CCDC88A.
Early onset or syndromic epilepsy v1.191 CACNA2D2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA2D2.
Early onset or syndromic epilepsy v1.191 CACNA1H Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1H.
Early onset or syndromic epilepsy v1.191 ATP6AP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP6AP2.
Early onset or syndromic epilepsy v1.191 ATP5A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP5A1.
Early onset or syndromic epilepsy v1.191 ATP1A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP1A2.
Early onset or syndromic epilepsy v1.191 ADAT3 Rebecca Foulger Source Wessex and West Midlands GLH was added to ADAT3.
Early onset or syndromic epilepsy v1.191 ZBTB18 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZBTB18.
Early onset or syndromic epilepsy v1.191 YWHAG Rebecca Foulger Source Wessex and West Midlands GLH was added to YWHAG.
Early onset or syndromic epilepsy v1.191 WDR73 Rebecca Foulger Source Wessex and West Midlands GLH was added to WDR73.
Early onset or syndromic epilepsy v1.191 WDR62 Rebecca Foulger Source Wessex and West Midlands GLH was added to WDR62.
Early onset or syndromic epilepsy v1.191 WASF1 Rebecca Foulger Source Wessex and West Midlands GLH was added to WASF1.
Early onset or syndromic epilepsy v1.191 VARS Rebecca Foulger Source Wessex and West Midlands GLH was added to VARS.
Early onset or syndromic epilepsy v1.191 UNC80 Rebecca Foulger Source Wessex and West Midlands GLH was added to UNC80.
Early onset or syndromic epilepsy v1.191 UFM1 Rebecca Foulger Source Wessex and West Midlands GLH was added to UFM1.
Early onset or syndromic epilepsy v1.191 UBA5 Rebecca Foulger Source Wessex and West Midlands GLH was added to UBA5.
Early onset or syndromic epilepsy v1.191 TUBG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBG1.
Early onset or syndromic epilepsy v1.191 TUBB4A Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB4A.
Early onset or syndromic epilepsy v1.191 TUBB3 Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB3.
Early onset or syndromic epilepsy v1.191 TUBB2B Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB2B.
Early onset or syndromic epilepsy v1.191 TUBB2A Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBB2A.
Early onset or syndromic epilepsy v1.191 TUBA1A Rebecca Foulger Source Wessex and West Midlands GLH was added to TUBA1A.
Early onset or syndromic epilepsy v1.191 TSEN54 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSEN54.
Early onset or syndromic epilepsy v1.191 TSEN2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSEN2.
Early onset or syndromic epilepsy v1.191 TSC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSC2.
Early onset or syndromic epilepsy v1.191 TSC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TSC1.
Early onset or syndromic epilepsy v1.191 TRIM8 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRIM8.
Early onset or syndromic epilepsy v1.191 TREX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TREX1.
Early onset or syndromic epilepsy v1.191 TMEM70 Rebecca Foulger Source Wessex and West Midlands GLH was added to TMEM70.
Early onset or syndromic epilepsy v1.191 TBL1XR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TBL1XR1.
Early onset or syndromic epilepsy v1.191 TBCK Rebecca Foulger Source Wessex and West Midlands GLH was added to TBCK.
Early onset or syndromic epilepsy v1.191 TBCD Rebecca Foulger Source Wessex and West Midlands GLH was added to TBCD.
Early onset or syndromic epilepsy v1.191 TANGO2 Rebecca Foulger Source Wessex and West Midlands GLH was added to TANGO2.
Early onset or syndromic epilepsy v1.191 SYN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SYN1.
Early onset or syndromic epilepsy v1.191 SURF1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SURF1.
Early onset or syndromic epilepsy v1.191 SUCLA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SUCLA2.
Early onset or syndromic epilepsy v1.191 STAMBP Rebecca Foulger Source Wessex and West Midlands GLH was added to STAMBP.
Early onset or syndromic epilepsy v1.191 STAG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to STAG1.
Early onset or syndromic epilepsy v1.191 ST3GAL5 Rebecca Foulger Source Wessex and West Midlands GLH was added to ST3GAL5.
Early onset or syndromic epilepsy v1.191 SNORD118 Rebecca Foulger Source Wessex and West Midlands GLH was added to SNORD118.
Early onset or syndromic epilepsy v1.191 SMS Rebecca Foulger Source Wessex and West Midlands GLH was added to SMS.
Early onset or syndromic epilepsy v1.191 SMARCA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SMARCA2.
Early onset or syndromic epilepsy v1.191 SLC6A8 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC6A8.
Early onset or syndromic epilepsy v1.191 SLC25A12 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC25A12.
Early onset or syndromic epilepsy v1.191 SLC1A4 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC1A4.
Early onset or syndromic epilepsy v1.191 SETBP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SETBP1.
Early onset or syndromic epilepsy v1.191 SEPSECS Rebecca Foulger Source Wessex and West Midlands GLH was added to SEPSECS.
Early onset or syndromic epilepsy v1.191 SCO2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SCO2.
Early onset or syndromic epilepsy v1.191 SCO1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SCO1.
Early onset or syndromic epilepsy v1.191 SCN3A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN3A.
Early onset or syndromic epilepsy v1.191 SAMHD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SAMHD1.
Early onset or syndromic epilepsy v1.191 RTTN Rebecca Foulger Source Wessex and West Midlands GLH was added to RTTN.
Early onset or syndromic epilepsy v1.191 RTN4IP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to RTN4IP1.
Early onset or syndromic epilepsy v1.191 RORB Rebecca Foulger Source Wessex and West Midlands GLH was added to RORB.
Early onset or syndromic epilepsy v1.191 RORA Rebecca Foulger Source Wessex and West Midlands GLH was added to RORA.
Early onset or syndromic epilepsy v1.191 ROGDI Rebecca Foulger Source Wessex and West Midlands GLH was added to ROGDI.
Early onset or syndromic epilepsy v1.191 RNASET2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RNASET2.
Early onset or syndromic epilepsy v1.191 RNASEH2C Rebecca Foulger Source Wessex and West Midlands GLH was added to RNASEH2C.
Early onset or syndromic epilepsy v1.191 RNASEH2B Rebecca Foulger Source Wessex and West Midlands GLH was added to RNASEH2B.
Early onset or syndromic epilepsy v1.191 RNASEH2A Rebecca Foulger Source Wessex and West Midlands GLH was added to RNASEH2A.
Early onset or syndromic epilepsy v1.191 RMND1 Rebecca Foulger Source Wessex and West Midlands GLH was added to RMND1.
Early onset or syndromic epilepsy v1.191 RHOBTB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RHOBTB2.
Early onset or syndromic epilepsy v1.191 RFT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to RFT1.
Early onset or syndromic epilepsy v1.191 RELN Rebecca Foulger Source Wessex and West Midlands GLH was added to RELN.
Early onset or syndromic epilepsy v1.191 RARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RARS2.
Early onset or syndromic epilepsy v1.191 RALA Rebecca Foulger Source Wessex and West Midlands GLH was added to RALA.
Early onset or syndromic epilepsy v1.191 RAB18 Rebecca Foulger Source Wessex and West Midlands GLH was added to RAB18.
Early onset or syndromic epilepsy v1.191 RAB11B Rebecca Foulger Source Wessex and West Midlands GLH was added to RAB11B.
Early onset or syndromic epilepsy v1.191 QDPR Rebecca Foulger Source Wessex and West Midlands GLH was added to QDPR.
Early onset or syndromic epilepsy v1.191 PTS Rebecca Foulger Source Wessex and West Midlands GLH was added to PTS.
Early onset or syndromic epilepsy v1.191 PTPN23 Rebecca Foulger Source Wessex and West Midlands GLH was added to PTPN23.
Early onset or syndromic epilepsy v1.191 PTEN Rebecca Foulger Source Wessex and West Midlands GLH was added to PTEN.
Early onset or syndromic epilepsy v1.191 PSAP Rebecca Foulger Source Wessex and West Midlands GLH was added to PSAP.
Early onset or syndromic epilepsy v1.191 PRMT7 Rebecca Foulger Source Wessex and West Midlands GLH was added to PRMT7.
Early onset or syndromic epilepsy v1.191 PRICKLE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PRICKLE1.
Early onset or syndromic epilepsy v1.191 PPT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PPT1.
Early onset or syndromic epilepsy v1.191 PPP3CA Rebecca Foulger Source Wessex and West Midlands GLH was added to PPP3CA.
Early onset or syndromic epilepsy v1.191 POMT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to POMT1.
Early onset or syndromic epilepsy v1.191 POMGNT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to POMGNT1.
Early onset or syndromic epilepsy v1.191 PMM2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PMM2.
Early onset or syndromic epilepsy v1.191 PLAA Rebecca Foulger Source Wessex and West Midlands GLH was added to PLAA.
Early onset or syndromic epilepsy v1.191 PIK3R2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PIK3R2.
Early onset or syndromic epilepsy v1.191 PIK3CA Rebecca Foulger Source Wessex and West Midlands GLH was added to PIK3CA.
Early onset or syndromic epilepsy v1.191 PIGW Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGW.
Early onset or syndromic epilepsy v1.191 PIGO Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGO.
Early onset or syndromic epilepsy v1.191 PIGG Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGG.
Early onset or syndromic epilepsy v1.191 PHGDH Rebecca Foulger Source Wessex and West Midlands GLH was added to PHGDH.
Early onset or syndromic epilepsy v1.191 PHACTR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PHACTR1.
Early onset or syndromic epilepsy v1.191 PEX7 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX7.
Early onset or syndromic epilepsy v1.191 PEX6 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX6.
Early onset or syndromic epilepsy v1.191 PEX3 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX3.
Early onset or syndromic epilepsy v1.191 PEX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX2.
Early onset or syndromic epilepsy v1.191 PEX19 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX19.
Early onset or syndromic epilepsy v1.191 PEX13 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX13.
Early onset or syndromic epilepsy v1.191 PEX12 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX12.
Early onset or syndromic epilepsy v1.191 PEX10 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX10.
Early onset or syndromic epilepsy v1.191 PEX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PEX1.
Early onset or syndromic epilepsy v1.191 PET100 Rebecca Foulger Source Wessex and West Midlands GLH was added to PET100.
Early onset or syndromic epilepsy v1.191 PDHX Rebecca Foulger Source Wessex and West Midlands GLH was added to PDHX.
Early onset or syndromic epilepsy v1.191 PDHA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PDHA1.
Early onset or syndromic epilepsy v1.191 PCDH12 Rebecca Foulger Source Wessex and West Midlands GLH was added to PCDH12.
Early onset or syndromic epilepsy v1.191 PCCB Rebecca Foulger Source Wessex and West Midlands GLH was added to PCCB.
Early onset or syndromic epilepsy v1.191 PCCA Rebecca Foulger Source Wessex and West Midlands GLH was added to PCCA.
Early onset or syndromic epilepsy v1.191 PAH Rebecca Foulger Source Wessex and West Midlands GLH was added to PAH.
Early onset or syndromic epilepsy v1.191 PAFAH1B1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PAFAH1B1.
Early onset or syndromic epilepsy v1.191 PACS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PACS2.
Early onset or syndromic epilepsy v1.191 PACS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PACS1.
Early onset or syndromic epilepsy v1.191 OTUD6B Rebecca Foulger Source Wessex and West Midlands GLH was added to OTUD6B.
Early onset or syndromic epilepsy v1.191 OPHN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to OPHN1.
Early onset or syndromic epilepsy v1.191 OCLN Rebecca Foulger Source Wessex and West Midlands GLH was added to OCLN.
Early onset or syndromic epilepsy v1.191 NTRK2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NTRK2.
Early onset or syndromic epilepsy v1.191 NSDHL Rebecca Foulger Source Wessex and West Midlands GLH was added to NSDHL.
Early onset or syndromic epilepsy v1.191 NSD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NSD1.
Early onset or syndromic epilepsy v1.191 NRXN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NRXN1.
Early onset or syndromic epilepsy v1.191 NPRL3 Rebecca Foulger Source Wessex and West Midlands GLH was added to NPRL3.
Early onset or syndromic epilepsy v1.191 NHLRC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NHLRC1.
Early onset or syndromic epilepsy v1.191 NGLY1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NGLY1.
Early onset or syndromic epilepsy v1.191 NDUFV1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFV1.
Early onset or syndromic epilepsy v1.191 NDUFS8 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS8.
Early onset or syndromic epilepsy v1.191 NDUFS4 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFS4.
Early onset or syndromic epilepsy v1.191 NDUFAF5 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFAF5.
Early onset or syndromic epilepsy v1.191 NDUFAF2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFAF2.
Early onset or syndromic epilepsy v1.191 NDUFA10 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFA10.
Early onset or syndromic epilepsy v1.191 NDUFA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDUFA1.
Early onset or syndromic epilepsy v1.191 NDE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NDE1.
Early onset or syndromic epilepsy v1.191 NARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to NARS2.
Early onset or syndromic epilepsy v1.191 NAGA Rebecca Foulger Source Wessex and West Midlands GLH was added to NAGA.
Early onset or syndromic epilepsy v1.191 MTR Rebecca Foulger Source Wessex and West Midlands GLH was added to MTR.
Early onset or syndromic epilepsy v1.191 MTHFR Rebecca Foulger Source Wessex and West Midlands GLH was added to MTHFR.
Early onset or syndromic epilepsy v1.191 MPDU1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MPDU1.
Early onset or syndromic epilepsy v1.191 MOCS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MOCS2.
Early onset or syndromic epilepsy v1.191 MOCS1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MOCS1.
Early onset or syndromic epilepsy v1.191 MMADHC Rebecca Foulger Source Wessex and West Midlands GLH was added to MMADHC.
Early onset or syndromic epilepsy v1.191 MMACHC Rebecca Foulger Source Wessex and West Midlands GLH was added to MMACHC.
Early onset or syndromic epilepsy v1.191 MLC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MLC1.
Early onset or syndromic epilepsy v1.191 MFSD8 Rebecca Foulger Source Wessex and West Midlands GLH was added to MFSD8.
Early onset or syndromic epilepsy v1.191 MED12 Rebecca Foulger Source Wessex and West Midlands GLH was added to MED12.
Early onset or syndromic epilepsy v1.191 MAP2K2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAP2K2.
Early onset or syndromic epilepsy v1.191 MAP2K1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAP2K1.
Early onset or syndromic epilepsy v1.191 MAGI2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MAGI2.
Early onset or syndromic epilepsy v1.191 MAF Rebecca Foulger Source Wessex and West Midlands GLH was added to MAF.
Early onset or syndromic epilepsy v1.191 MACF1 Rebecca Foulger Source Wessex and West Midlands GLH was added to MACF1.
Early onset or syndromic epilepsy v1.191 LYST Rebecca Foulger Source Wessex and West Midlands GLH was added to LYST.
Early onset or syndromic epilepsy v1.191 LIAS Rebecca Foulger Source Wessex and West Midlands GLH was added to LIAS.
Early onset or syndromic epilepsy v1.191 KRAS Rebecca Foulger Source Wessex and West Midlands GLH was added to KRAS.
Early onset or syndromic epilepsy v1.191 KIF5C Rebecca Foulger Source Wessex and West Midlands GLH was added to KIF5C.
Early onset or syndromic epilepsy v1.191 KIF2A Rebecca Foulger Source Wessex and West Midlands GLH was added to KIF2A.
Early onset or syndromic epilepsy v1.191 KIF1A Rebecca Foulger Source Wessex and West Midlands GLH was added to KIF1A.
Early onset or syndromic epilepsy v1.191 KCTD3 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCTD3.
Early onset or syndromic epilepsy v1.191 KCNQ5 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNQ5.
Early onset or syndromic epilepsy v1.191 KCNK4 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNK4.
Early onset or syndromic epilepsy v1.191 KCNJ11 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNJ11.
Early onset or syndromic epilepsy v1.191 KCNA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNA1.
Early onset or syndromic epilepsy v1.191 KARS Rebecca Foulger Source Wessex and West Midlands GLH was added to KARS.
Early onset or syndromic epilepsy v1.191 IRF2BPL Rebecca Foulger Source Wessex and West Midlands GLH was added to IRF2BPL.
Early onset or syndromic epilepsy v1.191 IKBKG Rebecca Foulger Source Wessex and West Midlands GLH was added to IKBKG.
Early onset or syndromic epilepsy v1.191 IFIH1 Rebecca Foulger Source Wessex and West Midlands GLH was added to IFIH1.
Early onset or syndromic epilepsy v1.191 HSD17B4 Rebecca Foulger Source Wessex and West Midlands GLH was added to HSD17B4.
Early onset or syndromic epilepsy v1.191 HRAS Rebecca Foulger Source Wessex and West Midlands GLH was added to HRAS.
Early onset or syndromic epilepsy v1.191 HLCS Rebecca Foulger Source Wessex and West Midlands GLH was added to HLCS.
Early onset or syndromic epilepsy v1.191 HEXA Rebecca Foulger Source Wessex and West Midlands GLH was added to HEXA.
Early onset or syndromic epilepsy v1.191 HEPACAM Rebecca Foulger Source Wessex and West Midlands GLH was added to HEPACAM.
Early onset or syndromic epilepsy v1.191 HCN2 Rebecca Foulger Source Wessex and West Midlands GLH was added to HCN2.
Early onset or syndromic epilepsy v1.191 HCFC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HCFC1.
Early onset or syndromic epilepsy v1.191 HAX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HAX1.
Early onset or syndromic epilepsy v1.191 HACE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HACE1.
Early onset or syndromic epilepsy v1.191 GTPBP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GTPBP2.
Early onset or syndromic epilepsy v1.191 GRIN2D Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIN2D.
Early onset or syndromic epilepsy v1.191 GRIA4 Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIA4.
Early onset or syndromic epilepsy v1.191 GPHN Rebecca Foulger Source Wessex and West Midlands GLH was added to GPHN.
Early onset or syndromic epilepsy v1.191 GOSR2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GOSR2.
Early onset or syndromic epilepsy v1.191 GNB5 Rebecca Foulger Source Wessex and West Midlands GLH was added to GNB5.
Early onset or syndromic epilepsy v1.191 GNB1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GNB1.
Early onset or syndromic epilepsy v1.191 GNAQ Rebecca Foulger Source Wessex and West Midlands GLH was added to GNAQ.
Early onset or syndromic epilepsy v1.191 GM2A Rebecca Foulger Source Wessex and West Midlands GLH was added to GM2A.
Early onset or syndromic epilepsy v1.191 GLUL Rebecca Foulger Source Wessex and West Midlands GLH was added to GLUL.
Early onset or syndromic epilepsy v1.191 GLUD1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GLUD1.
Early onset or syndromic epilepsy v1.191 GLDC Rebecca Foulger Source Wessex and West Midlands GLH was added to GLDC.
Early onset or syndromic epilepsy v1.191 GLB1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GLB1.
Early onset or syndromic epilepsy v1.191 GFM1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GFM1.
Early onset or syndromic epilepsy v1.191 GFAP Rebecca Foulger Source Wessex and West Midlands GLH was added to GFAP.
Early onset or syndromic epilepsy v1.191 GCH1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GCH1.
Early onset or syndromic epilepsy v1.191 GBA Rebecca Foulger Source Wessex and West Midlands GLH was added to GBA.
Early onset or syndromic epilepsy v1.191 GAMT Rebecca Foulger Source Wessex and West Midlands GLH was added to GAMT.
Early onset or syndromic epilepsy v1.191 GALC Rebecca Foulger Source Wessex and West Midlands GLH was added to GALC.
Early onset or syndromic epilepsy v1.191 GABRB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRB2.
Early onset or syndromic epilepsy v1.191 FUT8 Rebecca Foulger Source Wessex and West Midlands GLH was added to FUT8.
Early onset or syndromic epilepsy v1.191 FUCA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FUCA1.
Early onset or syndromic epilepsy v1.191 FRRS1L Rebecca Foulger Source Wessex and West Midlands GLH was added to FRRS1L.
Early onset or syndromic epilepsy v1.191 FOLR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FOLR1.
Early onset or syndromic epilepsy v1.191 FLNA Rebecca Foulger Source Wessex and West Midlands GLH was added to FLNA.
Early onset or syndromic epilepsy v1.191 FKTN Rebecca Foulger Source Wessex and West Midlands GLH was added to FKTN.
Early onset or syndromic epilepsy v1.191 FH Rebecca Foulger Source Wessex and West Midlands GLH was added to FH.
Early onset or syndromic epilepsy v1.191 FGFR3 Rebecca Foulger Source Wessex and West Midlands GLH was added to FGFR3.
Early onset or syndromic epilepsy v1.191 FGF12 Rebecca Foulger Source Wessex and West Midlands GLH was added to FGF12.
Early onset or syndromic epilepsy v1.191 FBXO11 Rebecca Foulger Source Wessex and West Midlands GLH was added to FBXO11.
Early onset or syndromic epilepsy v1.191 FBXL4 Rebecca Foulger Source Wessex and West Midlands GLH was added to FBXL4.
Early onset or syndromic epilepsy v1.191 FARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to FARS2.
Early onset or syndromic epilepsy v1.191 FAR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FAR1.
Early onset or syndromic epilepsy v1.191 EXOSC3 Rebecca Foulger Source Wessex and West Midlands GLH was added to EXOSC3.
Early onset or syndromic epilepsy v1.191 ETHE1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ETHE1.
Early onset or syndromic epilepsy v1.191 EMX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EMX2.
Early onset or syndromic epilepsy v1.191 EIF3F Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF3F.
Early onset or syndromic epilepsy v1.191 EIF2S3 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2S3.
Early onset or syndromic epilepsy v1.191 EIF2B5 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B5.
Early onset or syndromic epilepsy v1.191 EIF2B4 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B4.
Early onset or syndromic epilepsy v1.191 EIF2B2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EIF2B2.
Early onset or syndromic epilepsy v1.191 EFTUD2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EFTUD2.
Early onset or syndromic epilepsy v1.191 EEF1A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EEF1A2.
Early onset or syndromic epilepsy v1.191 EARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to EARS2.
Early onset or syndromic epilepsy v1.191 DYNC1H1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DYNC1H1.
Early onset or syndromic epilepsy v1.191 DPM1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DPM1.
Early onset or syndromic epilepsy v1.191 DPAGT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DPAGT1.
Early onset or syndromic epilepsy v1.191 DNM1L Rebecca Foulger Source Wessex and West Midlands GLH was added to DNM1L.
Early onset or syndromic epilepsy v1.191 DHX30 Rebecca Foulger Source Wessex and West Midlands GLH was added to DHX30.
Early onset or syndromic epilepsy v1.191 DHDDS Rebecca Foulger Source Wessex and West Midlands GLH was added to DHDDS.
Early onset or syndromic epilepsy v1.191 DHCR7 Rebecca Foulger Source Wessex and West Midlands GLH was added to DHCR7.
Early onset or syndromic epilepsy v1.191 DENND5A Rebecca Foulger Source Wessex and West Midlands GLH was added to DENND5A.
Early onset or syndromic epilepsy v1.191 DEAF1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DEAF1.
Early onset or syndromic epilepsy v1.191 DDX3X Rebecca Foulger Source Wessex and West Midlands GLH was added to DDX3X.
Early onset or syndromic epilepsy v1.191 DCX Rebecca Foulger Source Wessex and West Midlands GLH was added to DCX.
Early onset or syndromic epilepsy v1.191 D2HGDH Rebecca Foulger Source Wessex and West Midlands GLH was added to D2HGDH.
Early onset or syndromic epilepsy v1.191 CTSD Rebecca Foulger Source Wessex and West Midlands GLH was added to CTSD.
Early onset or syndromic epilepsy v1.191 CSTB Rebecca Foulger Source Wessex and West Midlands GLH was added to CSTB.
Early onset or syndromic epilepsy v1.191 CREBBP Rebecca Foulger Source Wessex and West Midlands GLH was added to CREBBP.
Early onset or syndromic epilepsy v1.191 COQ9 Rebecca Foulger Source Wessex and West Midlands GLH was added to COQ9.
Early onset or syndromic epilepsy v1.191 COQ4 Rebecca Foulger Source Wessex and West Midlands GLH was added to COQ4.
Early onset or syndromic epilepsy v1.191 COQ2 Rebecca Foulger Source Wessex and West Midlands GLH was added to COQ2.
Early onset or syndromic epilepsy v1.191 COL4A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to COL4A2.
Early onset or syndromic epilepsy v1.191 COL4A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to COL4A1.
Early onset or syndromic epilepsy v1.191 COL18A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to COL18A1.
Early onset or syndromic epilepsy v1.191 COG7 Rebecca Foulger Source Wessex and West Midlands GLH was added to COG7.
Early onset or syndromic epilepsy v1.191 CNNM2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNNM2.
Early onset or syndromic epilepsy v1.191 CLN3 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLN3.
Early onset or syndromic epilepsy v1.191 CLCN4 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLCN4.
Early onset or syndromic epilepsy v1.191 CC2D2A Rebecca Foulger Source Wessex and West Midlands GLH was added to CC2D2A.
Early onset or syndromic epilepsy v1.191 CASK Rebecca Foulger Source Wessex and West Midlands GLH was added to CASK.
Early onset or syndromic epilepsy v1.191 CAD Rebecca Foulger Source Wessex and West Midlands GLH was added to CAD.
Early onset or syndromic epilepsy v1.191 CACNA1G Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1G.
Early onset or syndromic epilepsy v1.191 CACNA1E Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1E.
Early onset or syndromic epilepsy v1.191 CACNA1A Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1A.
Early onset or syndromic epilepsy v1.191 C12orf57 Rebecca Foulger Source Wessex and West Midlands GLH was added to C12orf57.
Early onset or syndromic epilepsy v1.191 BTD Rebecca Foulger Source Wessex and West Midlands GLH was added to BTD.
Early onset or syndromic epilepsy v1.191 BRAF Rebecca Foulger Source Wessex and West Midlands GLH was added to BRAF.
Early onset or syndromic epilepsy v1.191 BOLA3 Rebecca Foulger Source Wessex and West Midlands GLH was added to BOLA3.
Early onset or syndromic epilepsy v1.191 BCS1L Rebecca Foulger Source Wessex and West Midlands GLH was added to BCS1L.
Early onset or syndromic epilepsy v1.191 BCKDHB Rebecca Foulger Source Wessex and West Midlands GLH was added to BCKDHB.
Early onset or syndromic epilepsy v1.191 BCKDHA Rebecca Foulger Source Wessex and West Midlands GLH was added to BCKDHA.
Early onset or syndromic epilepsy v1.191 ATP7A Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP7A.
Early onset or syndromic epilepsy v1.191 ATP6V1A Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP6V1A.
Early onset or syndromic epilepsy v1.191 ATP1A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP1A1.
Early onset or syndromic epilepsy v1.191 ASPA Rebecca Foulger Source Wessex and West Midlands GLH was added to ASPA.
Early onset or syndromic epilepsy v1.191 ARV1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ARV1.
Early onset or syndromic epilepsy v1.191 ARID1B Rebecca Foulger Source Wessex and West Midlands GLH was added to ARID1B.
Early onset or syndromic epilepsy v1.191 ARG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ARG1.
Early onset or syndromic epilepsy v1.191 ARFGEF2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ARFGEF2.
Early onset or syndromic epilepsy v1.191 AP3B2 Rebecca Foulger Source Wessex and West Midlands GLH was added to AP3B2.
Early onset or syndromic epilepsy v1.191 AMT Rebecca Foulger Source Wessex and West Midlands GLH was added to AMT.
Early onset or syndromic epilepsy v1.191 AMPD2 Rebecca Foulger Source Wessex and West Midlands GLH was added to AMPD2.
Early onset or syndromic epilepsy v1.191 ALPL Rebecca Foulger Source Wessex and West Midlands GLH was added to ALPL.
Early onset or syndromic epilepsy v1.191 ALG9 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG9.
Early onset or syndromic epilepsy v1.191 ALG8 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG8.
Early onset or syndromic epilepsy v1.191 ALG6 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG6.
Early onset or syndromic epilepsy v1.191 ALG3 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG3.
Early onset or syndromic epilepsy v1.191 ALG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG1.
Early onset or syndromic epilepsy v1.191 ALDH5A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALDH5A1.
Early onset or syndromic epilepsy v1.191 AKT3 Rebecca Foulger Source Wessex and West Midlands GLH was added to AKT3.
Early onset or syndromic epilepsy v1.191 AKT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to AKT1.
Early onset or syndromic epilepsy v1.191 AIMP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to AIMP1.
Early onset or syndromic epilepsy v1.191 ADPRHL2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ADPRHL2.
Early onset or syndromic epilepsy v1.191 ADGRG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ADGRG1.
Early onset or syndromic epilepsy v1.191 ADAR Rebecca Foulger Source Wessex and West Midlands GLH was added to ADAR.
Early onset or syndromic epilepsy v1.191 ACOX1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ACOX1.
Early onset or syndromic epilepsy v1.191 ABAT Rebecca Foulger Source Wessex and West Midlands GLH was added to ABAT.
Early onset or syndromic epilepsy v1.191 ZEB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ZEB2.
Early onset or syndromic epilepsy v1.191 WWOX Rebecca Foulger Source Wessex and West Midlands GLH was added to WWOX.
Early onset or syndromic epilepsy v1.191 WDR45B Rebecca Foulger Source Wessex and West Midlands GLH was added to WDR45B.
Early onset or syndromic epilepsy v1.191 WDR45 Rebecca Foulger Source Wessex and West Midlands GLH was added to WDR45.
Early onset or syndromic epilepsy v1.191 UBE3A Rebecca Foulger Source Wessex and West Midlands GLH was added to UBE3A.
Early onset or syndromic epilepsy v1.191 UBE2A Rebecca Foulger Source Wessex and West Midlands GLH was added to UBE2A.
Early onset or syndromic epilepsy v1.191 TRPM6 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRPM6.
Early onset or syndromic epilepsy v1.191 TRAK1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TRAK1.
Early onset or syndromic epilepsy v1.191 TPP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TPP1.
Early onset or syndromic epilepsy v1.191 TCF4 Rebecca Foulger Source Wessex and West Midlands GLH was added to TCF4.
Early onset or syndromic epilepsy v1.191 TBC1D24 Rebecca Foulger Source Wessex and West Midlands GLH was added to TBC1D24.
Early onset or syndromic epilepsy v1.191 SZT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SZT2.
Early onset or syndromic epilepsy v1.191 SYNJ1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SYNJ1.
Early onset or syndromic epilepsy v1.191 SYNGAP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SYNGAP1.
Early onset or syndromic epilepsy v1.191 SUOX Rebecca Foulger Source Wessex and West Midlands GLH was added to SUOX.
Early onset or syndromic epilepsy v1.191 STXBP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to STXBP1.
Early onset or syndromic epilepsy v1.191 STX1B Rebecca Foulger Source Wessex and West Midlands GLH was added to STX1B.
Early onset or syndromic epilepsy v1.191 STRADA Rebecca Foulger Source Wessex and West Midlands GLH was added to STRADA.
Early onset or syndromic epilepsy v1.191 SPTAN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SPTAN1.
Early onset or syndromic epilepsy v1.191 SLC9A6 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC9A6.
Early onset or syndromic epilepsy v1.191 SLC6A19 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC6A19.
Early onset or syndromic epilepsy v1.191 SLC6A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC6A1.
Early onset or syndromic epilepsy v1.191 SLC35A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC35A2.
Early onset or syndromic epilepsy v1.191 SLC2A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC2A1.
Early onset or syndromic epilepsy v1.191 SLC25A22 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC25A22.
Early onset or syndromic epilepsy v1.191 SLC25A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC25A1.
Early onset or syndromic epilepsy v1.191 SLC1A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC1A2.
Early onset or syndromic epilepsy v1.191 SLC16A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC16A2.
Early onset or syndromic epilepsy v1.191 SLC13A5 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC13A5.
Early onset or syndromic epilepsy v1.191 SLC12A5 Rebecca Foulger Source Wessex and West Midlands GLH was added to SLC12A5.
Early onset or syndromic epilepsy v1.191 SIK1 Rebecca Foulger Source Wessex and West Midlands GLH was added to SIK1.
Early onset or syndromic epilepsy v1.191 SETD5 Rebecca Foulger Source Wessex and West Midlands GLH was added to SETD5.
Early onset or syndromic epilepsy v1.191 SCN9A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN9A.
Early onset or syndromic epilepsy v1.191 SCN8A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN8A.
Early onset or syndromic epilepsy v1.191 SCN2A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN2A.
Early onset or syndromic epilepsy v1.191 SCN1B Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN1B.
Early onset or syndromic epilepsy v1.191 SCN1A Rebecca Foulger Source Wessex and West Midlands GLH was added to SCN1A.
Early onset or syndromic epilepsy v1.191 SCARB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SCARB2.
Early onset or syndromic epilepsy v1.191 RANBP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RANBP2.
Early onset or syndromic epilepsy v1.191 QARS Rebecca Foulger Source Wessex and West Midlands GLH was added to QARS.
Early onset or syndromic epilepsy v1.191 PURA Rebecca Foulger Source Wessex and West Midlands GLH was added to PURA.
Early onset or syndromic epilepsy v1.191 PRRT2 Rebecca Foulger Source Wessex and West Midlands GLH was added to PRRT2.
Early onset or syndromic epilepsy v1.191 PRODH Rebecca Foulger Source Wessex and West Midlands GLH was added to PRODH.
Early onset or syndromic epilepsy v1.191 POLG Rebecca Foulger Source Wessex and West Midlands GLH was added to POLG.
Early onset or syndromic epilepsy v1.191 PNPO Rebecca Foulger Source Wessex and West Midlands GLH was added to PNPO.
Early onset or syndromic epilepsy v1.191 PNKP Rebecca Foulger Source Wessex and West Midlands GLH was added to PNKP.
Early onset or syndromic epilepsy v1.191 PLPBP Rebecca Foulger Source Wessex and West Midlands GLH was added to PLPBP.
Early onset or syndromic epilepsy v1.191 PLCB1 Rebecca Foulger Source Wessex and West Midlands GLH was added to PLCB1.
Early onset or syndromic epilepsy v1.191 PIGT Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGT.
Early onset or syndromic epilepsy v1.191 PIGN Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGN.
Early onset or syndromic epilepsy v1.191 PIGA Rebecca Foulger Source Wessex and West Midlands GLH was added to PIGA.
Early onset or syndromic epilepsy v1.191 PCDH19 Rebecca Foulger Source Wessex and West Midlands GLH was added to PCDH19.
Early onset or syndromic epilepsy v1.191 NEXMIF Rebecca Foulger Source Wessex and West Midlands GLH was added to NEXMIF.
Early onset or syndromic epilepsy v1.191 NACC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to NACC1.
Early onset or syndromic epilepsy v1.191 MTOR Rebecca Foulger Source Wessex and West Midlands GLH was added to MTOR.
Early onset or syndromic epilepsy v1.191 MOGS Rebecca Foulger Source Wessex and West Midlands GLH was added to MOGS.
Early onset or syndromic epilepsy v1.191 MFF Rebecca Foulger Source Wessex and West Midlands GLH was added to MFF.
Early onset or syndromic epilepsy v1.191 MEF2C Rebecca Foulger Source Wessex and West Midlands GLH was added to MEF2C.
Early onset or syndromic epilepsy v1.191 MECP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MECP2.
Early onset or syndromic epilepsy v1.191 MDH2 Rebecca Foulger Source Wessex and West Midlands GLH was added to MDH2.
Early onset or syndromic epilepsy v1.191 MBOAT7 Rebecca Foulger Source Wessex and West Midlands GLH was added to MBOAT7.
Early onset or syndromic epilepsy v1.191 MBD5 Rebecca Foulger Source Wessex and West Midlands GLH was added to MBD5.
Early onset or syndromic epilepsy v1.191 LGI1 Rebecca Foulger Source Wessex and West Midlands GLH was added to LGI1.
Early onset or syndromic epilepsy v1.191 KIF1BP Rebecca Foulger Source Wessex and West Midlands GLH was added to KIF1BP.
Early onset or syndromic epilepsy v1.191 KCTD7 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCTD7.
Early onset or syndromic epilepsy v1.191 KCNT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNT1.
Early onset or syndromic epilepsy v1.191 KCNQ3 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNQ3.
Early onset or syndromic epilepsy v1.191 KCNQ2 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNQ2.
Early onset or syndromic epilepsy v1.191 KCNJ10 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNJ10.
Early onset or syndromic epilepsy v1.191 KCNC1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNC1.
Early onset or syndromic epilepsy v1.191 KCNB1 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNB1.
Early onset or syndromic epilepsy v1.191 KCNA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to KCNA2.
Early onset or syndromic epilepsy v1.191 ITPA Rebecca Foulger Source Wessex and West Midlands GLH was added to ITPA.
Early onset or syndromic epilepsy v1.191 IQSEC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to IQSEC2.
Early onset or syndromic epilepsy v1.191 IER3IP1 Rebecca Foulger Source Wessex and West Midlands GLH was added to IER3IP1.
Early onset or syndromic epilepsy v1.191 IDH2 Rebecca Foulger Source Wessex and West Midlands GLH was added to IDH2.
Early onset or syndromic epilepsy v1.191 HTRA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to HTRA2.
Early onset or syndromic epilepsy v1.191 HNRNPU Rebecca Foulger Source Wessex and West Midlands GLH was added to HNRNPU.
Early onset or syndromic epilepsy v1.191 HNRNPH2 Rebecca Foulger Source Wessex and West Midlands GLH was added to HNRNPH2.
Early onset or syndromic epilepsy v1.191 HMGCL Rebecca Foulger Source Wessex and West Midlands GLH was added to HMGCL.
Early onset or syndromic epilepsy v1.191 HECW2 Rebecca Foulger Source Wessex and West Midlands GLH was added to HECW2.
Early onset or syndromic epilepsy v1.191 HCN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to HCN1.
Early onset or syndromic epilepsy v1.191 GSS Rebecca Foulger Source Wessex and West Midlands GLH was added to GSS.
Early onset or syndromic epilepsy v1.191 GRIN2B Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIN2B.
Early onset or syndromic epilepsy v1.191 GRIN2A Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIN2A.
Early onset or syndromic epilepsy v1.191 GRIN1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GRIN1.
Early onset or syndromic epilepsy v1.191 GPAA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GPAA1.
Early onset or syndromic epilepsy v1.191 GNAO1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GNAO1.
Early onset or syndromic epilepsy v1.191 GLYCTK Rebecca Foulger Source Wessex and West Midlands GLH was added to GLYCTK.
Early onset or syndromic epilepsy v1.191 GABRG2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRG2.
Early onset or syndromic epilepsy v1.191 GABRB3 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRB3.
Early onset or syndromic epilepsy v1.191 GABRA1 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABRA1.
Early onset or syndromic epilepsy v1.191 GABBR2 Rebecca Foulger Source Wessex and West Midlands GLH was added to GABBR2.
Early onset or syndromic epilepsy v1.191 FOXG1 Rebecca Foulger Source Wessex and West Midlands GLH was added to FOXG1.
Early onset or syndromic epilepsy v1.191 EPM2A Rebecca Foulger Source Wessex and West Midlands GLH was added to EPM2A.
Early onset or syndromic epilepsy v1.191 EPG5 Rebecca Foulger Source Wessex and West Midlands GLH was added to EPG5.
Early onset or syndromic epilepsy v1.191 EML1 Rebecca Foulger Source Wessex and West Midlands GLH was added to EML1.
Early onset or syndromic epilepsy v1.191 EHMT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to EHMT1.
Early onset or syndromic epilepsy v1.191 DYRK1A Rebecca Foulger Source Wessex and West Midlands GLH was added to DYRK1A.
Early onset or syndromic epilepsy v1.191 DPYD Rebecca Foulger Source Wessex and West Midlands GLH was added to DPYD.
Early onset or syndromic epilepsy v1.191 DOCK7 Rebecca Foulger Source Wessex and West Midlands GLH was added to DOCK7.
Early onset or syndromic epilepsy v1.191 DNM1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DNM1.
Early onset or syndromic epilepsy v1.191 DIAPH1 Rebecca Foulger Source Wessex and West Midlands GLH was added to DIAPH1.
Early onset or syndromic epilepsy v1.191 DEPDC5 Rebecca Foulger Source Wessex and West Midlands GLH was added to DEPDC5.
Early onset or syndromic epilepsy v1.191 CYFIP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CYFIP2.
Early onset or syndromic epilepsy v1.191 CPA6 Rebecca Foulger Source Wessex and West Midlands GLH was added to CPA6.
Early onset or syndromic epilepsy v1.191 CNTNAP2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNTNAP2.
Early onset or syndromic epilepsy v1.191 CNKSR2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CNKSR2.
Early onset or syndromic epilepsy v1.191 CLTC Rebecca Foulger Source Wessex and West Midlands GLH was added to CLTC.
Early onset or syndromic epilepsy v1.191 CLN8 Rebecca Foulger Source Wessex and West Midlands GLH was added to CLN8.
Early onset or syndromic epilepsy v1.191 CIC Rebecca Foulger Source Wessex and West Midlands GLH was added to CIC.
Early onset or syndromic epilepsy v1.191 CHRNB2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CHRNB2.
Early onset or syndromic epilepsy v1.191 CHRNA4 Rebecca Foulger Source Wessex and West Midlands GLH was added to CHRNA4.
Early onset or syndromic epilepsy v1.191 CHRNA2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CHRNA2.
Early onset or syndromic epilepsy v1.191 CHD2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CHD2.
Early onset or syndromic epilepsy v1.191 CDKL5 Rebecca Foulger Source Wessex and West Midlands GLH was added to CDKL5.
Early onset or syndromic epilepsy v1.191 CACNA1D Rebecca Foulger Source Wessex and West Midlands GLH was added to CACNA1D.
Early onset or syndromic epilepsy v1.191 BSCL2 Rebecca Foulger Source Wessex and West Midlands GLH was added to BSCL2.
Early onset or syndromic epilepsy v1.191 BRAT1 Rebecca Foulger Source Wessex and West Midlands GLH was added to BRAT1.
Early onset or syndromic epilepsy v1.191 ATRX Rebecca Foulger Source Wessex and West Midlands GLH was added to ATRX.
Early onset or syndromic epilepsy v1.191 ATP6V0A2 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP6V0A2.
Early onset or syndromic epilepsy v1.191 ATP1A3 Rebecca Foulger Source Wessex and West Midlands GLH was added to ATP1A3.
Early onset or syndromic epilepsy v1.191 ARX Rebecca Foulger Source Wessex and West Midlands GLH was added to ARX.
Early onset or syndromic epilepsy v1.191 ARHGEF9 Rebecca Foulger Source Wessex and West Midlands GLH was added to ARHGEF9.
Early onset or syndromic epilepsy v1.191 ALG13 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG13.
Early onset or syndromic epilepsy v1.191 ALG11 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALG11.
Early onset or syndromic epilepsy v1.191 ALDH7A1 Rebecca Foulger Source Wessex and West Midlands GLH was added to ALDH7A1.
Early onset or syndromic epilepsy v1.191 ADSL Rebecca Foulger Source Wessex and West Midlands GLH was added to ADSL.
Early onset or syndromic epilepsy v1.191 AARS Rebecca Foulger Source Wessex and West Midlands GLH was added to AARS.
Early onset or syndromic epilepsy v1.190 TUBA3E Rebecca Foulger Source NHS GMS was added to TUBA3E.
Early onset or syndromic epilepsy v1.190 SLC6A5 Rebecca Foulger Source NHS GMS was added to SLC6A5.
Early onset or syndromic epilepsy v1.190 SHH Rebecca Foulger Source NHS GMS was added to SHH.
Early onset or syndromic epilepsy v1.190 SEC24D Rebecca Foulger Source NHS GMS was added to SEC24D.
Early onset or syndromic epilepsy v1.190 SCN2B Rebecca Foulger Source NHS GMS was added to SCN2B.
Early onset or syndromic epilepsy v1.190 RYR3 Rebecca Foulger Source NHS GMS was added to RYR3.
Early onset or syndromic epilepsy v1.190 RUBCN Rebecca Foulger Source NHS GMS was added to RUBCN.
Early onset or syndromic epilepsy v1.190 PSMB8 Rebecca Foulger Source NHS GMS was added to PSMB8.
Early onset or syndromic epilepsy v1.190 PRICKLE2 Rebecca Foulger Source NHS GMS was added to PRICKLE2.
Early onset or syndromic epilepsy v1.190 PCDHB4 Rebecca Foulger Source NHS GMS was added to PCDHB4.
Early onset or syndromic epilepsy v1.190 NRAS Rebecca Foulger Source NHS GMS was added to NRAS.
Early onset or syndromic epilepsy v1.190 NID1 Rebecca Foulger Source NHS GMS was added to NID1.
Early onset or syndromic epilepsy v1.190 NDUFA11 Rebecca Foulger Source NHS GMS was added to NDUFA11.
Early onset or syndromic epilepsy v1.190 MT-TL1 Rebecca Foulger Source NHS GMS was added to MT-TL1.
Early onset or syndromic epilepsy v1.190 MATN4 Rebecca Foulger Source NHS GMS was added to MATN4.
Early onset or syndromic epilepsy v1.190 MAPK10 Rebecca Foulger Source NHS GMS was added to MAPK10.
Early onset or syndromic epilepsy v1.190 KAT5 Rebecca Foulger Source NHS GMS was added to KAT5.
Early onset or syndromic epilepsy v1.190 INO80 Rebecca Foulger Source NHS GMS was added to INO80.
Early onset or syndromic epilepsy v1.190 H3F3B Rebecca Foulger Source NHS GMS was added to H3F3B.
Early onset or syndromic epilepsy v1.190 H3F3A Rebecca Foulger Source NHS GMS was added to H3F3A.
Early onset or syndromic epilepsy v1.190 GLRB Rebecca Foulger Source NHS GMS was added to GLRB.
Early onset or syndromic epilepsy v1.190 GCSH Rebecca Foulger Source NHS GMS was added to GCSH.
Early onset or syndromic epilepsy v1.190 GATM Rebecca Foulger Source NHS GMS was added to GATM.
Early onset or syndromic epilepsy v1.190 GATAD2B Rebecca Foulger Source NHS GMS was added to GATAD2B.
Early onset or syndromic epilepsy v1.190 GAL Rebecca Foulger Source NHS GMS was added to GAL.
Early onset or syndromic epilepsy v1.190 GABRD Rebecca Foulger Source NHS GMS was added to GABRD.
Early onset or syndromic epilepsy v1.190 FTL Rebecca Foulger Source NHS GMS was added to FTL.
Early onset or syndromic epilepsy v1.190 FIG4 Rebecca Foulger Source NHS GMS was added to FIG4.
Early onset or syndromic epilepsy v1.190 DMBX1 Rebecca Foulger Source NHS GMS was added to DMBX1.
Early onset or syndromic epilepsy v1.190 CYP27A1 Rebecca Foulger Source NHS GMS was added to CYP27A1.
Early onset or syndromic epilepsy v1.190 CSNK1G1 Rebecca Foulger Source NHS GMS was added to CSNK1G1.
Early onset or syndromic epilepsy v1.190 CRH Rebecca Foulger Source NHS GMS was added to CRH.
Early onset or syndromic epilepsy v1.190 CNTN2 Rebecca Foulger Source NHS GMS was added to CNTN2.
Early onset or syndromic epilepsy v1.190 CLN6 Rebecca Foulger Source NHS GMS was added to CLN6.
Early onset or syndromic epilepsy v1.190 CLN5 Rebecca Foulger Source NHS GMS was added to CLN5.
Early onset or syndromic epilepsy v1.190 CLCN2 Rebecca Foulger Source NHS GMS was added to CLCN2.
Early onset or syndromic epilepsy v1.190 CBL Rebecca Foulger Source NHS GMS was added to CBL.
Early onset or syndromic epilepsy v1.190 CASR Rebecca Foulger Source NHS GMS was added to CASR.
Early onset or syndromic epilepsy v1.190 CAMK2G Rebecca Foulger Source NHS GMS was added to CAMK2G.
Early onset or syndromic epilepsy v1.190 CACNB4 Rebecca Foulger Source NHS GMS was added to CACNB4.
Early onset or syndromic epilepsy v1.190 ASAH1 Rebecca Foulger Source NHS GMS was added to ASAH1.
Early onset or syndromic epilepsy v1.190 ALG2 Rebecca Foulger Source NHS GMS was added to ALG2.
Early onset or syndromic epilepsy v1.190 ALG12 Rebecca Foulger Source NHS GMS was added to ALG12.
Early onset or syndromic epilepsy v1.190 ADGRV1 Rebecca Foulger Source NHS GMS was added to ADGRV1.
Early onset or syndromic epilepsy v1.190 AARS2 Rebecca Foulger Source NHS GMS was added to AARS2.
Early onset or syndromic epilepsy v1.190 VLDLR Rebecca Foulger Source NHS GMS was added to VLDLR.
Early onset or syndromic epilepsy v1.190 UFC1 Rebecca Foulger Source NHS GMS was added to UFC1.
Early onset or syndromic epilepsy v1.190 TXNRD1 Rebecca Foulger Source NHS GMS was added to TXNRD1.
Early onset or syndromic epilepsy v1.190 TUBB Rebecca Foulger Source NHS GMS was added to TUBB.
Early onset or syndromic epilepsy v1.190 TUBA8 Rebecca Foulger Source NHS GMS was added to TUBA8.
Early onset or syndromic epilepsy v1.190 TSFM Rebecca Foulger Source NHS GMS was added to TSFM.
Early onset or syndromic epilepsy v1.190 TSEN34 Rebecca Foulger Source NHS GMS was added to TSEN34.
Early onset or syndromic epilepsy v1.190 TSEN15 Rebecca Foulger Source NHS GMS was added to TSEN15.
Early onset or syndromic epilepsy v1.190 TRIP13 Rebecca Foulger Source NHS GMS was added to TRIP13.
Early onset or syndromic epilepsy v1.190 TRAPPC6B Rebecca Foulger Source NHS GMS was added to TRAPPC6B.
Early onset or syndromic epilepsy v1.190 TRAPPC12 Rebecca Foulger Source NHS GMS was added to TRAPPC12.
Early onset or syndromic epilepsy v1.190 TRAF7 Rebecca Foulger Source NHS GMS was added to TRAF7.
Early onset or syndromic epilepsy v1.190 TNK2 Rebecca Foulger Source NHS GMS was added to TNK2.
Early onset or syndromic epilepsy v1.190 TIMM50 Rebecca Foulger Source NHS GMS was added to TIMM50.
Early onset or syndromic epilepsy v1.190 TFE3 Rebecca Foulger Source NHS GMS was added to TFE3.
Early onset or syndromic epilepsy v1.190 TELO2 Rebecca Foulger Source NHS GMS was added to TELO2.
Early onset or syndromic epilepsy v1.190 TBC1D20 Rebecca Foulger Source NHS GMS was added to TBC1D20.
Early onset or syndromic epilepsy v1.190 SUCLG1 Rebecca Foulger Source NHS GMS was added to SUCLG1.
Early onset or syndromic epilepsy v1.190 ST3GAL3 Rebecca Foulger Source NHS GMS was added to ST3GAL3.
Early onset or syndromic epilepsy v1.190 SRPX2 Rebecca Foulger Source NHS GMS was added to SRPX2.
Early onset or syndromic epilepsy v1.190 SPR Rebecca Foulger Source NHS GMS was added to SPR.
Early onset or syndromic epilepsy v1.190 SNIP1 Rebecca Foulger Source NHS GMS was added to SNIP1.
Early onset or syndromic epilepsy v1.190 SMC1A Rebecca Foulger Source NHS GMS was added to SMC1A.
Early onset or syndromic epilepsy v1.190 SLC45A1 Rebecca Foulger Source NHS GMS was added to SLC45A1.
Early onset or syndromic epilepsy v1.190 SLC35A1 Rebecca Foulger Source NHS GMS was added to SLC35A1.
Early onset or syndromic epilepsy v1.190 SIX3 Rebecca Foulger Source NHS GMS was added to SIX3.
Early onset or syndromic epilepsy v1.190 SETD1B Rebecca Foulger Source NHS GMS was added to SETD1B.
Early onset or syndromic epilepsy v1.190 SDHA Rebecca Foulger Source NHS GMS was added to SDHA.
Early onset or syndromic epilepsy v1.190 RYR2 Rebecca Foulger Source NHS GMS was added to RYR2.
Early onset or syndromic epilepsy v1.190 RUSC2 Rebecca Foulger Source NHS GMS was added to RUSC2.
Early onset or syndromic epilepsy v1.190 RRM2B Rebecca Foulger Source NHS GMS was added to RRM2B.
Early onset or syndromic epilepsy v1.190 RPIA Rebecca Foulger Source NHS GMS was added to RPIA.
Early onset or syndromic epilepsy v1.190 RNU4ATAC Rebecca Foulger Source NHS GMS was added to RNU4ATAC.
Early onset or syndromic epilepsy v1.190 RAB3GAP2 Rebecca Foulger Source NHS GMS was added to RAB3GAP2.
Early onset or syndromic epilepsy v1.190 RAB3GAP1 Rebecca Foulger Source NHS GMS was added to RAB3GAP1.
Early onset or syndromic epilepsy v1.190 PTF1A Rebecca Foulger Source NHS GMS was added to PTF1A.
Early onset or syndromic epilepsy v1.190 PSPH Rebecca Foulger Source NHS GMS was added to PSPH.
Early onset or syndromic epilepsy v1.190 PSAT1 Rebecca Foulger Source NHS GMS was added to PSAT1.
Early onset or syndromic epilepsy v1.190 POMT2 Rebecca Foulger Source NHS GMS was added to POMT2.
Early onset or syndromic epilepsy v1.190 PIGQ Rebecca Foulger Source NHS GMS was added to PIGQ.
Early onset or syndromic epilepsy v1.190 PIGH Rebecca Foulger Source NHS GMS was added to PIGH.
Early onset or syndromic epilepsy v1.190 PIGC Rebecca Foulger Source NHS GMS was added to PIGC.
Early onset or syndromic epilepsy v1.190 PEX5 Rebecca Foulger Source NHS GMS was added to PEX5.
Early onset or syndromic epilepsy v1.190 PDSS2 Rebecca Foulger Source NHS GMS was added to PDSS2.
Early onset or syndromic epilepsy v1.190 PCLO Rebecca Foulger Source NHS GMS was added to PCLO.
Early onset or syndromic epilepsy v1.190 OTX2 Rebecca Foulger Source NHS GMS was added to OTX2.
Early onset or syndromic epilepsy v1.190 NUBPL Rebecca Foulger Source NHS GMS was added to NUBPL.
Early onset or syndromic epilepsy v1.190 NPRL2 Rebecca Foulger Source NHS GMS was added to NPRL2.
Early onset or syndromic epilepsy v1.190 NEDD4L Rebecca Foulger Source NHS GMS was added to NEDD4L.
Early onset or syndromic epilepsy v1.190 NECAP1 Rebecca Foulger Source NHS GMS was added to NECAP1.
Early onset or syndromic epilepsy v1.190 NDUFS7 Rebecca Foulger Source NHS GMS was added to NDUFS7.
Early onset or syndromic epilepsy v1.190 NDUFS6 Rebecca Foulger Source NHS GMS was added to NDUFS6.
Early onset or syndromic epilepsy v1.190 NDUFS2 Rebecca Foulger Source NHS GMS was added to NDUFS2.
Early onset or syndromic epilepsy v1.190 NDUFS1 Rebecca Foulger Source NHS GMS was added to NDUFS1.
Early onset or syndromic epilepsy v1.190 NDUFAF4 Rebecca Foulger Source NHS GMS was added to NDUFAF4.
Early onset or syndromic epilepsy v1.190 NDUFAF3 Rebecca Foulger Source NHS GMS was added to NDUFAF3.
Early onset or syndromic epilepsy v1.190 NDUFA2 Rebecca Foulger Source NHS GMS was added to NDUFA2.
Early onset or syndromic epilepsy v1.190 NDP Rebecca Foulger Source NHS GMS was added to NDP.
Early onset or syndromic epilepsy v1.190 MED17 Rebecca Foulger Source NHS GMS was added to MED17.
Early onset or syndromic epilepsy v1.190 MAST1 Rebecca Foulger Source NHS GMS was added to MAST1.
Early onset or syndromic epilepsy v1.190 MANBA Rebecca Foulger Source NHS GMS was added to MANBA.
Early onset or syndromic epilepsy v1.190 LNPK Rebecca Foulger Source NHS GMS was added to LNPK.
Early onset or syndromic epilepsy v1.190 LIPT2 Rebecca Foulger Source NHS GMS was added to LIPT2.
Early onset or syndromic epilepsy v1.190 LARGE1 Rebecca Foulger Source NHS GMS was added to LARGE1.
Early onset or syndromic epilepsy v1.190 KPTN Rebecca Foulger Source NHS GMS was added to KPTN.
Early onset or syndromic epilepsy v1.190 KIAA1109 Rebecca Foulger Source NHS GMS was added to KIAA1109.
Early onset or syndromic epilepsy v1.190 KCNMA1 Rebecca Foulger Source NHS GMS was added to KCNMA1.
Early onset or syndromic epilepsy v1.190 ISPD Rebecca Foulger Source NHS GMS was added to ISPD.
Early onset or syndromic epilepsy v1.190 HSPD1 Rebecca Foulger Source NHS GMS was added to HSPD1.
Early onset or syndromic epilepsy v1.190 HPRT1 Rebecca Foulger Source NHS GMS was added to HPRT1.
Early onset or syndromic epilepsy v1.190 HOXA1 Rebecca Foulger Source NHS GMS was added to HOXA1.
Early onset or syndromic epilepsy v1.190 HEXB Rebecca Foulger Source NHS GMS was added to HEXB.
Early onset or syndromic epilepsy v1.190 HCCS Rebecca Foulger Source NHS GMS was added to HCCS.
Early onset or syndromic epilepsy v1.190 GTPBP3 Rebecca Foulger Source NHS GMS was added to GTPBP3.
Early onset or syndromic epilepsy v1.190 GLRA1 Rebecca Foulger Source NHS GMS was added to GLRA1.
Early onset or syndromic epilepsy v1.190 GLI3 Rebecca Foulger Source NHS GMS was added to GLI3.
Early onset or syndromic epilepsy v1.190 FOXRED1 Rebecca Foulger Source NHS GMS was added to FOXRED1.
Early onset or syndromic epilepsy v1.190 FKRP Rebecca Foulger Source NHS GMS was added to FKRP.
Early onset or syndromic epilepsy v1.190 FASTKD2 Rebecca Foulger Source NHS GMS was added to FASTKD2.
Early onset or syndromic epilepsy v1.190 EIF2B3 Rebecca Foulger Source NHS GMS was added to EIF2B3.
Early onset or syndromic epilepsy v1.190 EIF2B1 Rebecca Foulger Source NHS GMS was added to EIF2B1.
Early onset or syndromic epilepsy v1.190 EFHC1 Rebecca Foulger Source NHS GMS was added to EFHC1.
Early onset or syndromic epilepsy v1.190 DPM2 Rebecca Foulger Source NHS GMS was added to DPM2.
Early onset or syndromic epilepsy v1.190 DOLK Rebecca Foulger Source NHS GMS was added to DOLK.
Early onset or syndromic epilepsy v1.190 DNAJC6 Rebecca Foulger Source NHS GMS was added to DNAJC6.
Early onset or syndromic epilepsy v1.190 DHCR24 Rebecca Foulger Source NHS GMS was added to DHCR24.
Early onset or syndromic epilepsy v1.190 DBT Rebecca Foulger Source NHS GMS was added to DBT.
Early onset or syndromic epilepsy v1.190 CUX2 Rebecca Foulger Source NHS GMS was added to CUX2.
Early onset or syndromic epilepsy v1.190 CSNK2B Rebecca Foulger Source NHS GMS was added to CSNK2B.
Early onset or syndromic epilepsy v1.190 COX15 Rebecca Foulger Source NHS GMS was added to COX15.
Early onset or syndromic epilepsy v1.190 COX10 Rebecca Foulger Source NHS GMS was added to COX10.
Early onset or syndromic epilepsy v1.190 COQ6 Rebecca Foulger Source NHS GMS was added to COQ6.
Early onset or syndromic epilepsy v1.190 COG8 Rebecca Foulger Source NHS GMS was added to COG8.
Early onset or syndromic epilepsy v1.190 COG6 Rebecca Foulger Source NHS GMS was added to COG6.
Early onset or syndromic epilepsy v1.190 COG4 Rebecca Foulger Source NHS GMS was added to COG4.
Early onset or syndromic epilepsy v1.190 CNPY3 Rebecca Foulger Source NHS GMS was added to CNPY3.
Early onset or syndromic epilepsy v1.190 CCND2 Rebecca Foulger Source NHS GMS was added to CCND2.
Early onset or syndromic epilepsy v1.190 CCDC88C Rebecca Foulger Source NHS GMS was added to CCDC88C.
Early onset or syndromic epilepsy v1.190 CCDC88A Rebecca Foulger Source NHS GMS was added to CCDC88A.
Early onset or syndromic epilepsy v1.190 CACNA2D2 Rebecca Foulger Source NHS GMS was added to CACNA2D2.
Early onset or syndromic epilepsy v1.190 CACNA1H Rebecca Foulger Source NHS GMS was added to CACNA1H.
Early onset or syndromic epilepsy v1.190 ATP6AP2 Rebecca Foulger Source NHS GMS was added to ATP6AP2.
Early onset or syndromic epilepsy v1.190 ATP5A1 Rebecca Foulger Source NHS GMS was added to ATP5A1.
Early onset or syndromic epilepsy v1.190 ATP1A2 Rebecca Foulger Source NHS GMS was added to ATP1A2.
Early onset or syndromic epilepsy v1.190 ADAT3 Rebecca Foulger Source NHS GMS was added to ADAT3.
Early onset or syndromic epilepsy v1.190 ZBTB18 Rebecca Foulger Source NHS GMS was added to ZBTB18.
Early onset or syndromic epilepsy v1.190 YWHAG Rebecca Foulger Source NHS GMS was added to YWHAG.
Early onset or syndromic epilepsy v1.190 WDR73 Rebecca Foulger Source NHS GMS was added to WDR73.
Early onset or syndromic epilepsy v1.190 WDR62 Rebecca Foulger Source NHS GMS was added to WDR62.
Early onset or syndromic epilepsy v1.190 WASF1 Rebecca Foulger Source NHS GMS was added to WASF1.
Early onset or syndromic epilepsy v1.190 VARS Rebecca Foulger Source NHS GMS was added to VARS.
Early onset or syndromic epilepsy v1.190 UNC80 Rebecca Foulger Source NHS GMS was added to UNC80.
Early onset or syndromic epilepsy v1.190 UFM1 Rebecca Foulger Source NHS GMS was added to UFM1.
Early onset or syndromic epilepsy v1.190 UBA5 Rebecca Foulger Source NHS GMS was added to UBA5.
Early onset or syndromic epilepsy v1.190 TUBG1 Rebecca Foulger Source NHS GMS was added to TUBG1.
Early onset or syndromic epilepsy v1.190 TUBB4A Rebecca Foulger Source NHS GMS was added to TUBB4A.
Early onset or syndromic epilepsy v1.190 TUBB3 Rebecca Foulger Source NHS GMS was added to TUBB3.
Early onset or syndromic epilepsy v1.190 TUBB2B Rebecca Foulger Source NHS GMS was added to TUBB2B.
Early onset or syndromic epilepsy v1.190 TUBB2A Rebecca Foulger Source NHS GMS was added to TUBB2A.
Early onset or syndromic epilepsy v1.190 TUBA1A Rebecca Foulger Source NHS GMS was added to TUBA1A.
Early onset or syndromic epilepsy v1.190 TSEN54 Rebecca Foulger Source NHS GMS was added to TSEN54.
Early onset or syndromic epilepsy v1.190 TSEN2 Rebecca Foulger Source NHS GMS was added to TSEN2.
Early onset or syndromic epilepsy v1.190 TSC2 Rebecca Foulger Source NHS GMS was added to TSC2.
Early onset or syndromic epilepsy v1.190 TSC1 Rebecca Foulger Source NHS GMS was added to TSC1.
Early onset or syndromic epilepsy v1.190 TRIM8 Rebecca Foulger Source NHS GMS was added to TRIM8.
Early onset or syndromic epilepsy v1.190 TREX1 Rebecca Foulger Source NHS GMS was added to TREX1.
Early onset or syndromic epilepsy v1.190 TMEM70 Rebecca Foulger Source NHS GMS was added to TMEM70.
Early onset or syndromic epilepsy v1.190 TBL1XR1 Rebecca Foulger Source NHS GMS was added to TBL1XR1.
Early onset or syndromic epilepsy v1.190 TBCK Rebecca Foulger Source NHS GMS was added to TBCK.
Early onset or syndromic epilepsy v1.190 TBCD Rebecca Foulger Source NHS GMS was added to TBCD.
Early onset or syndromic epilepsy v1.190 TANGO2 Rebecca Foulger Source NHS GMS was added to TANGO2.
Early onset or syndromic epilepsy v1.190 SYN1 Rebecca Foulger Source NHS GMS was added to SYN1.
Early onset or syndromic epilepsy v1.190 SURF1 Rebecca Foulger Source NHS GMS was added to SURF1.
Early onset or syndromic epilepsy v1.190 SUCLA2 Rebecca Foulger Source NHS GMS was added to SUCLA2.
Early onset or syndromic epilepsy v1.190 STAMBP Rebecca Foulger Source NHS GMS was added to STAMBP.
Early onset or syndromic epilepsy v1.190 STAG1 Rebecca Foulger Source NHS GMS was added to STAG1.
Early onset or syndromic epilepsy v1.190 ST3GAL5 Rebecca Foulger Source NHS GMS was added to ST3GAL5.
Early onset or syndromic epilepsy v1.190 SNORD118 Rebecca Foulger Source NHS GMS was added to SNORD118.
Early onset or syndromic epilepsy v1.190 SMS Rebecca Foulger Source NHS GMS was added to SMS.
Early onset or syndromic epilepsy v1.190 SMARCA2 Rebecca Foulger Source NHS GMS was added to SMARCA2.
Early onset or syndromic epilepsy v1.190 SLC6A8 Rebecca Foulger Source NHS GMS was added to SLC6A8.
Early onset or syndromic epilepsy v1.190 SLC25A12 Rebecca Foulger Source NHS GMS was added to SLC25A12.
Early onset or syndromic epilepsy v1.190 SLC1A4 Rebecca Foulger Source NHS GMS was added to SLC1A4.
Early onset or syndromic epilepsy v1.190 SETBP1 Rebecca Foulger Source NHS GMS was added to SETBP1.
Early onset or syndromic epilepsy v1.190 SEPSECS Rebecca Foulger Source NHS GMS was added to SEPSECS.
Early onset or syndromic epilepsy v1.190 SCO2 Rebecca Foulger Source NHS GMS was added to SCO2.
Early onset or syndromic epilepsy v1.190 SCO1 Rebecca Foulger Source NHS GMS was added to SCO1.
Early onset or syndromic epilepsy v1.190 SCN3A Rebecca Foulger Source NHS GMS was added to SCN3A.
Early onset or syndromic epilepsy v1.190 SAMHD1 Rebecca Foulger Source NHS GMS was added to SAMHD1.
Early onset or syndromic epilepsy v1.190 RTTN Rebecca Foulger Source NHS GMS was added to RTTN.
Early onset or syndromic epilepsy v1.190 RTN4IP1 Rebecca Foulger Source NHS GMS was added to RTN4IP1.
Early onset or syndromic epilepsy v1.190 RORB Rebecca Foulger Source NHS GMS was added to RORB.
Early onset or syndromic epilepsy v1.190 RORA Rebecca Foulger Source NHS GMS was added to RORA.
Early onset or syndromic epilepsy v1.190 ROGDI Rebecca Foulger Source NHS GMS was added to ROGDI.
Early onset or syndromic epilepsy v1.190 RNASET2 Rebecca Foulger Source NHS GMS was added to RNASET2.
Early onset or syndromic epilepsy v1.190 RNASEH2C Rebecca Foulger Source NHS GMS was added to RNASEH2C.
Early onset or syndromic epilepsy v1.190 RNASEH2B Rebecca Foulger Source NHS GMS was added to RNASEH2B.
Early onset or syndromic epilepsy v1.190 RNASEH2A Rebecca Foulger Source NHS GMS was added to RNASEH2A.
Early onset or syndromic epilepsy v1.190 RMND1 Rebecca Foulger Source NHS GMS was added to RMND1.
Early onset or syndromic epilepsy v1.190 RHOBTB2 Rebecca Foulger Source NHS GMS was added to RHOBTB2.
Early onset or syndromic epilepsy v1.190 RFT1 Rebecca Foulger Source NHS GMS was added to RFT1.
Early onset or syndromic epilepsy v1.190 RELN Rebecca Foulger Source NHS GMS was added to RELN.
Early onset or syndromic epilepsy v1.190 RARS2 Rebecca Foulger Source NHS GMS was added to RARS2.
Early onset or syndromic epilepsy v1.190 RALA Rebecca Foulger Source NHS GMS was added to RALA.
Early onset or syndromic epilepsy v1.190 RAB18 Rebecca Foulger Source NHS GMS was added to RAB18.
Early onset or syndromic epilepsy v1.190 RAB11B Rebecca Foulger Source NHS GMS was added to RAB11B.
Early onset or syndromic epilepsy v1.190 QDPR Rebecca Foulger Source NHS GMS was added to QDPR.
Early onset or syndromic epilepsy v1.190 PTS Rebecca Foulger Source NHS GMS was added to PTS.
Early onset or syndromic epilepsy v1.190 PTPN23 Rebecca Foulger Source NHS GMS was added to PTPN23.
Early onset or syndromic epilepsy v1.190 PTEN Rebecca Foulger Source NHS GMS was added to PTEN.
Early onset or syndromic epilepsy v1.190 PSAP Rebecca Foulger Source NHS GMS was added to PSAP.
Early onset or syndromic epilepsy v1.190 PRMT7 Rebecca Foulger Source NHS GMS was added to PRMT7.
Early onset or syndromic epilepsy v1.190 PRICKLE1 Rebecca Foulger Source NHS GMS was added to PRICKLE1.
Early onset or syndromic epilepsy v1.190 PPT1 Rebecca Foulger Source NHS GMS was added to PPT1.
Early onset or syndromic epilepsy v1.190 PPP3CA Rebecca Foulger Source NHS GMS was added to PPP3CA.
Early onset or syndromic epilepsy v1.190 POMT1 Rebecca Foulger Source NHS GMS was added to POMT1.
Early onset or syndromic epilepsy v1.190 POMGNT1 Rebecca Foulger Source NHS GMS was added to POMGNT1.
Early onset or syndromic epilepsy v1.190 PMM2 Rebecca Foulger Source NHS GMS was added to PMM2.
Early onset or syndromic epilepsy v1.190 PLAA Rebecca Foulger Source NHS GMS was added to PLAA.
Early onset or syndromic epilepsy v1.190 PIK3R2 Rebecca Foulger Source NHS GMS was added to PIK3R2.
Early onset or syndromic epilepsy v1.190 PIK3CA Rebecca Foulger Source NHS GMS was added to PIK3CA.
Early onset or syndromic epilepsy v1.190 PIGW Rebecca Foulger Source NHS GMS was added to PIGW.
Early onset or syndromic epilepsy v1.190 PIGO Rebecca Foulger Source NHS GMS was added to PIGO.
Early onset or syndromic epilepsy v1.190 PIGG Rebecca Foulger Source NHS GMS was added to PIGG.
Early onset or syndromic epilepsy v1.190 PHGDH Rebecca Foulger Source NHS GMS was added to PHGDH.
Early onset or syndromic epilepsy v1.190 PHACTR1 Rebecca Foulger Source NHS GMS was added to PHACTR1.
Early onset or syndromic epilepsy v1.190 PEX7 Rebecca Foulger Source NHS GMS was added to PEX7.
Early onset or syndromic epilepsy v1.190 PEX6 Rebecca Foulger Source NHS GMS was added to PEX6.
Early onset or syndromic epilepsy v1.190 PEX3 Rebecca Foulger Source NHS GMS was added to PEX3.
Early onset or syndromic epilepsy v1.190 PEX2 Rebecca Foulger Source NHS GMS was added to PEX2.
Early onset or syndromic epilepsy v1.190 PEX19 Rebecca Foulger Source NHS GMS was added to PEX19.
Early onset or syndromic epilepsy v1.190 PEX13 Rebecca Foulger Source NHS GMS was added to PEX13.
Early onset or syndromic epilepsy v1.190 PEX12 Rebecca Foulger Source NHS GMS was added to PEX12.
Early onset or syndromic epilepsy v1.190 PEX10 Rebecca Foulger Source NHS GMS was added to PEX10.
Early onset or syndromic epilepsy v1.190 PEX1 Rebecca Foulger Source NHS GMS was added to PEX1.
Early onset or syndromic epilepsy v1.190 PET100 Rebecca Foulger Source NHS GMS was added to PET100.
Early onset or syndromic epilepsy v1.190 PDHX Rebecca Foulger Source NHS GMS was added to PDHX.
Early onset or syndromic epilepsy v1.190 PDHA1 Rebecca Foulger Source NHS GMS was added to PDHA1.
Early onset or syndromic epilepsy v1.190 PCDH12 Rebecca Foulger Source NHS GMS was added to PCDH12.
Early onset or syndromic epilepsy v1.190 PCCB Rebecca Foulger Source NHS GMS was added to PCCB.
Early onset or syndromic epilepsy v1.190 PCCA Rebecca Foulger Source NHS GMS was added to PCCA.
Early onset or syndromic epilepsy v1.190 PAH Rebecca Foulger Source NHS GMS was added to PAH.
Early onset or syndromic epilepsy v1.190 PAFAH1B1 Rebecca Foulger Source NHS GMS was added to PAFAH1B1.
Early onset or syndromic epilepsy v1.190 PACS2 Rebecca Foulger Source NHS GMS was added to PACS2.
Early onset or syndromic epilepsy v1.190 PACS1 Rebecca Foulger Source NHS GMS was added to PACS1.
Early onset or syndromic epilepsy v1.190 OTUD6B Rebecca Foulger Source NHS GMS was added to OTUD6B.
Early onset or syndromic epilepsy v1.190 OPHN1 Rebecca Foulger Source NHS GMS was added to OPHN1.
Early onset or syndromic epilepsy v1.190 OCLN Rebecca Foulger Source NHS GMS was added to OCLN.
Early onset or syndromic epilepsy v1.190 NTRK2 Rebecca Foulger Source NHS GMS was added to NTRK2.
Early onset or syndromic epilepsy v1.190 NSDHL Rebecca Foulger Source NHS GMS was added to NSDHL.
Early onset or syndromic epilepsy v1.190 NSD1 Rebecca Foulger Source NHS GMS was added to NSD1.
Early onset or syndromic epilepsy v1.190 NRXN1 Rebecca Foulger Source NHS GMS was added to NRXN1.
Early onset or syndromic epilepsy v1.190 NPRL3 Rebecca Foulger Source NHS GMS was added to NPRL3.
Early onset or syndromic epilepsy v1.190 NHLRC1 Rebecca Foulger Source NHS GMS was added to NHLRC1.
Early onset or syndromic epilepsy v1.190 NGLY1 Rebecca Foulger Source NHS GMS was added to NGLY1.
Early onset or syndromic epilepsy v1.190 NDUFV1 Rebecca Foulger Source NHS GMS was added to NDUFV1.
Early onset or syndromic epilepsy v1.190 NDUFS8 Rebecca Foulger Source NHS GMS was added to NDUFS8.
Early onset or syndromic epilepsy v1.190 NDUFS4 Rebecca Foulger Source NHS GMS was added to NDUFS4.
Early onset or syndromic epilepsy v1.190 NDUFAF5 Rebecca Foulger Source NHS GMS was added to NDUFAF5.
Early onset or syndromic epilepsy v1.190 NDUFAF2 Rebecca Foulger Source NHS GMS was added to NDUFAF2.
Early onset or syndromic epilepsy v1.190 NDUFA10 Rebecca Foulger Source NHS GMS was added to NDUFA10.
Early onset or syndromic epilepsy v1.190 NDUFA1 Rebecca Foulger Source NHS GMS was added to NDUFA1.
Early onset or syndromic epilepsy v1.190 NDE1 Rebecca Foulger Source NHS GMS was added to NDE1.
Early onset or syndromic epilepsy v1.190 NARS2 Rebecca Foulger Source NHS GMS was added to NARS2.
Early onset or syndromic epilepsy v1.190 NAGA Rebecca Foulger Source NHS GMS was added to NAGA.
Early onset or syndromic epilepsy v1.190 MTR Rebecca Foulger Source NHS GMS was added to MTR.
Early onset or syndromic epilepsy v1.190 MTHFR Rebecca Foulger Source NHS GMS was added to MTHFR.
Early onset or syndromic epilepsy v1.190 MPDU1 Rebecca Foulger Source NHS GMS was added to MPDU1.
Early onset or syndromic epilepsy v1.190 MOCS2 Rebecca Foulger Source NHS GMS was added to MOCS2.
Early onset or syndromic epilepsy v1.190 MOCS1 Rebecca Foulger Source NHS GMS was added to MOCS1.
Early onset or syndromic epilepsy v1.190 MMADHC Rebecca Foulger Source NHS GMS was added to MMADHC.
Early onset or syndromic epilepsy v1.190 MMACHC Rebecca Foulger Source NHS GMS was added to MMACHC.
Early onset or syndromic epilepsy v1.190 MLC1 Rebecca Foulger Source NHS GMS was added to MLC1.
Early onset or syndromic epilepsy v1.190 MFSD8 Rebecca Foulger Source NHS GMS was added to MFSD8.
Early onset or syndromic epilepsy v1.190 MED12 Rebecca Foulger Source NHS GMS was added to MED12.
Early onset or syndromic epilepsy v1.190 MAP2K2 Rebecca Foulger Source NHS GMS was added to MAP2K2.
Early onset or syndromic epilepsy v1.190 MAP2K1 Rebecca Foulger Source NHS GMS was added to MAP2K1.
Early onset or syndromic epilepsy v1.190 MAGI2 Rebecca Foulger Source NHS GMS was added to MAGI2.
Early onset or syndromic epilepsy v1.190 MAF Rebecca Foulger Source NHS GMS was added to MAF.
Early onset or syndromic epilepsy v1.190 MACF1 Rebecca Foulger Source NHS GMS was added to MACF1.
Early onset or syndromic epilepsy v1.190 LYST Rebecca Foulger Source NHS GMS was added to LYST.
Early onset or syndromic epilepsy v1.190 LIAS Rebecca Foulger Source NHS GMS was added to LIAS.
Early onset or syndromic epilepsy v1.190 KRAS Rebecca Foulger Source NHS GMS was added to KRAS.
Early onset or syndromic epilepsy v1.190 KIF5C Rebecca Foulger Source NHS GMS was added to KIF5C.
Early onset or syndromic epilepsy v1.190 KIF2A Rebecca Foulger Source NHS GMS was added to KIF2A.
Early onset or syndromic epilepsy v1.190 KIF1A Rebecca Foulger Source NHS GMS was added to KIF1A.