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| Early onset or syndromic epilepsy v9.82 | CRIPT |
Ida Ertmanska gene: CRIPT was added gene: CRIPT was added to Early onset or syndromic epilepsy. Sources: Literature Q3_26_promote_green tags were added to gene: CRIPT. Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRIPT were set to 24389050; 27250922; 36630262; 37013901 Phenotypes for gene: CRIPT were set to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 Review for gene: CRIPT was set to GREEN Added comment: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature |
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| Early onset or syndromic epilepsy v9.32 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation of p.Phe247_Ala286del. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). |
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| Early onset or syndromic epilepsy v9.32 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). |
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| Early onset or syndromic epilepsy v9.32 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). |
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| Early onset or syndromic epilepsy v8.89 | PRMT9 |
Achchuthan Shanmugasundram gene: PRMT9 was added gene: PRMT9 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: PRMT9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRMT9 were set to 41260215 Phenotypes for gene: PRMT9 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: PRMT9 was set to GREEN Added comment: PMID:41260215 (2025) reported the identification of biallelic loss-of-function variants in PRMT9 gene in 35 individuals from 26 unrelated families primarily presenting with a neurodevelopmental disorder characterised by global developmental delay, learning disabilities, mild to severe intellectual disability, autism spectrum disorder, epilepsy, and hypotonia. There were 26 different variants identified in total which included frameshifting indels, nonsense variants, missense variants, and two copy-number variants. Clinical examinations revealed that 14 individuals developed epilepsy, which was suspected in one other individual. Functional evidence available from skin fibroblasts derived from affected individuals showed reduced expression at the RNA and/or protein level and subsequent aberrant methylation activity. Transcriptomic analysis of fibroblasts from affected individuals indicated differential expression of genes related to intellectual disability, autism, and cilia, suggesting a role of PRMT9 during ciliogenesis. Under ciliogenesis conditions, the skin-derived fibroblasts exhibited anomalies in the length of primary cilia but normal amounts of cilia. In addition, a prmt9 knockout zebrafish model displayed abnormal social preference in adult animals. This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 09 January 2026), but has been associated with 'Limited' rating on the DD panel in Gene2Phenotype. Sources: Literature |
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| Early onset or syndromic epilepsy v8.37 | KCND3 |
Ida Ertmanska changed review comment from: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy: PMID: 26189493 Smets et al., 2015 Male patient, Belgian, non-consanguineous parents. Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9. Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction. PMID: 28947073 Huin et al., 2017 Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease. 11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported. 5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients. PMID: 32823520 Pollini et al. 2020 Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine. Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy. Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES. PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported. PMID: 32921676 Nakajima et al., 2020 Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious. Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal. Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome. Supporting evidence: https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis) International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy. KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. Sources: Literature; to: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy: PMID: 26189493 Smets et al., 2015 Male patient, Belgian, non-consanguineous parents. Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9. Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction. PMID: 28947073 Huin et al., 2017 Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease. 11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported. 5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients. PMID: 32823520 Pollini et al. 2020 Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine. Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy. Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES. PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported. PMID: 32921676 Nakajima et al., 2020 Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious. Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal. Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome. Supporting evidence: https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis) International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy. Functional evidence: PMID: 39562497 Hung et al., 2025 A mouse model with a p.Phe227del-equivalent Kcnd3 knock-in displayed defects in motor coordination and balance, neuroinflammation, trafficking defect due to accumulation in the golgi apparatus, and a transcriptional effect: downregulation of genes involved in neurogenesis. Meanwhile, Kcnd3 knockout mice showed no observable phenotype. This evidence suggests a dominant negative effect of the mutation, and supports the association of KCND3 and neurodevelopmental disorders. KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy. Sources: Literature |
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| Early onset or syndromic epilepsy v8.8 | CRNKL1 |
Achchuthan Shanmugasundram gene: CRNKL1 was added gene: CRNKL1 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013 Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: CRNKL1 was set to GREEN Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients). Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes. This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype. Sources: Literature |
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| Early onset or syndromic epilepsy v4.129 | PIGM |
Sarah Leigh changed review comment from: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition. To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations. Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100).; to: A single PIGM variant (NM_145167.2(PIGM):c.-270C>G)(rs587776528) has been associated with Glycosylphosphatidylinositol deficiency, (OMIM:610293) and as limited Gen2Phen gene for the same condition. To date, this variant has only been reported in people of Arab or Turkish descent. Microsatellite- and SNP-based haplotypes encompassing PIGM reported in PMID:19168132, suggested that a founder effect in the two families (one Arab and one Turkish) was unlikely. However, subsequent occurrences of the variant in two additional unrelated Arab families (PMID: 31445883) might suggest that this variant is confined within the Middle Eastern populations. Functional studies have shown that this variant reduces transcription of PIGM and blocks mannosylation of glycosylphosphatidylinositol anchor (PMID: 16767100). Absence seizures were apparent in 5/7 individuals from 5/6 families with OMIM:610293 biallelic for rs587776528 (table 1, PMID: 31445883). |
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| Early onset or syndromic epilepsy v4.62 | KDM6B |
Hannah Robinson gene: KDM6B was added gene: KDM6B was added to Early onset or syndromic epilepsy. Sources: NHS GMS Mode of inheritance for gene: KDM6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KDM6B were set to PMID: 37196654 Phenotypes for gene: KDM6B were set to Global developmental delay; Intellectual disability; Hypotonia; Joint hypermobility; seizures; Overgrowth Penetrance for gene: KDM6B were set to Incomplete Review for gene: KDM6B was set to GREEN gene: KDM6B was marked as current diagnostic Added comment: Information from Rots et al. 2023 (PMID:37196654): According to OMIM, heterozygous variants in KDM6B cause “neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities.” Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). In this cohort, 9/69 (13%) of individuals had seizures. The majority of individuals had de novo variants but 9/85 individuals inherited the variant (five maternal, four paternal) from a mildly affected (developmental delay [DD], learning problems, autism spectrum disorder [ASD]) or clinically unaffected parent. Sources: NHS GMS |
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| Early onset or syndromic epilepsy v2.547 | PPFIBP1 |
Konstantinos Varvagiannis gene: PPFIBP1 was added gene: PPFIBP1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPFIBP1 were set to 35830857; 30214071 Phenotypes for gene: PPFIBP1 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision Penetrance for gene: PPFIBP1 were set to Complete Review for gene: PPFIBP1 was set to GREEN Added comment: Consider inclusion with green rating in the ID, epilepsy as well as other likely relevant gene panels (microcephaly, white matter disorders, corpus callosum abnormalities, intracerebral calficication disorders, malformations of cortical development, hereditary spastic paraplegia, growth failure in early childhood, etc) based on the summary below. ---- Rosenhahn et al (2022 - PMID: 35830857) describe the phenotype of 16 individuals - belonging to 12 unrelated families - with biallelic PPFIBP1 pathogenic variants. Most (14/16) were born to consanguineous parents. One of these families was previously reported by Shaheen et al (2019 - PMID: 30214071) who first identified PPFIBP1 as a candidate gene for congenital microcephaly. In the current study, Rosenhahn also identified a fetus homozygous for a missense variant and similar features. All individuals presented global DD/ID (16/16 - in 15 cases profound/severe) and epilepsy (16/16 - onset 1d-4y / median 2m - focal seizures in 11/16, epileptic spams in 7/16, generalized onset in 7/16, myoclonic in 6/16 - drug-resistant : 13/16). Almost all (15/16) had microcephaly, commonly congenital (9/16) and progressive (11/16). Other neurological findings included hypertonia (10/16), spastic tetraplegia (6/16), hypotonia (5/16), dystonic movements (3/16) or nystagmus (4/16). Brain abnormalities were identified in all investigated with MRI and included leukoencephalopathy (11/14) mostly periventricular, abnormal cortex morphology (7/14 - polymicrogyria 1, increased cortical thickness 4, pachygyria 3), cortical atrophy, corpus callosum hypoplasia (7/14). Intracranial calcifications were identified in all (9/9) investigated with CT scan. Abnormal growth was reported for several (SGA in 9/16, FTT 8/16, short stature 7/16) often associated with feeding difficulties (7/16). Other features incl. abnormal hearing (4/16), congenital heart defects (7/16), ophthalmologic findings (8/16), undescended testes (3/10). There were no overlapping facial features. The fetus displayed similar features incl. SGA, microcephaly, intracranial calcifications. Investigations incl. exome/genome sequencing (singleton or trio) with Sanger for confirmation/segregation of variants where necessary. Variable previous investigations incl. metabolic screening, TORCH screening, chromosomal studies (CMA) are mentioned in the supplement and were non-diagnostic. Additional candidate variants were identified in few cases although cases with plausible dual diagnoses (e.g. ind14) were not included in the overall phenotypic description. 9 pLoF variants (nonsense, frameshift, 1 splicing) predicted to lead to NMD were identified. There were no functional studies performed. The missense variant c.2177G>T / p.Gly726Val (NM_003622.4) was predicted deleterious by in silico tools while the AA change causing severe steric problems upon modelling. PPFIBP1 encodes PPFIA-binding protein 1 also known as liprin-β1. As the authors discuss: The liprin family of proteins comprises liprins α1 to 4 and liprin β1 and β2 in mammals. Liprin β1 is known to homodimerize and heterodimerize with α-liprins. In fibroblast cultures liprins β1 and α1 colocalize to cell membrane and periphery of focal adhesions. Members of the liprin-α fam. are scaffold proteins playing a role in synapse formation/signaling and axonal transport. A ko model of the PPFIBP1 ortholog in C.elegans displayed abnormal locomotion behavior. In Drosophila, null-allele mutants resulted in altered axon outgrowth and synapse formation of R7 photoreceptors and reduced neuromuscular junction size (Refs provided in article). Using a PPFIBP1/hlb-1 ko C.elegans model the authors demonstrated defects in spontaneous and light-induced behavior. Sensitivity of the worms to an acetylcholinesterase inhibitor (aldicarb) was suggestive of a presynaptic defect. ---- There is currently no PPFIBP1 - associated phenotype in OMIM / G2P. SysNDD lists PPFIBP1 among the ID genes (limited evidence based on the 3 sibs reported by Shaheen et al, 2019 - PMID: 30214071). In PanelApp Australia the gene is listed with green rating for ID, epilepsy, microcephaly based on the medRxiv pre-print. Sources: Literature |
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| Early onset or syndromic epilepsy v2.536 | ASXL3 |
Dmitrijs Rots gene: ASXL3 was added gene: ASXL3 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ASXL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ASXL3 were set to 35172777; 27901041; 34436830 Phenotypes for gene: ASXL3 were set to Bainbridge-Ropers syndrome Penetrance for gene: ASXL3 were set to Complete Review for gene: ASXL3 was set to GREEN Added comment: In a review by Kuechler et al., seizures were reported in 3/15 cases. Additionally Khan et al., report a case with seizure onset since birth. In a description of novel 45 cases and review of previous 45 (n=90) by Schirwani et al., seizures were reported in 28/77 cases. Enough evidence for green rating also on this panel. Sources: Literature |
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| Early onset or syndromic epilepsy v2.518 | PABPC1 |
Konstantinos Varvagiannis gene: PABPC1 was added gene: PABPC1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PABPC1 were set to 35511136 Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures Penetrance for gene: PABPC1 were set to unknown Review for gene: PABPC1 was set to AMBER Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1. Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible. All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del). Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date). PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory. To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes. Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect. While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence. Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding. In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules. In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below). Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype. Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed. Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194). Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia). Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants). Sources: Literature |
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| Early onset or syndromic epilepsy v2.518 | GLRA2 |
Konstantinos Varvagiannis gene: GLRA2 was added gene: GLRA2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: GLRA2 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: GLRA2 were set to 20531469; 20479760; 26370147; 28588452; 35294868 Phenotypes for gene: GLRA2 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Microcephaly; Abnormality of eye movement Penetrance for gene: GLRA2 were set to unknown Mode of pathogenicity for gene: GLRA2 was set to Other Review for gene: GLRA2 was set to AMBER Added comment: Heterozygous or hemizygous pathogenic GLRA2 variants cause Intellectual developmental disorder, X-linked, syndromic, Pilorge type (# 301076) as summarized in a recent OMIM entry. The phenotype is characterized by DD with variably impaired intellectual development, behavioral abnormalities (autistic features in some), variable ocular findings (nystagmus, strabismus, oculomotor apraxia) and seizures in some [ 6/13 in Ref4 ]. GLRA2 encodes the α2 subunit that is expressed in embryonic and perinatal CNS with expression decreasing after birth. Animal models support the role of the gene in CNS. Studies have been performed for several of the variants reported to date (in all cases missense and a htz deletion of the last 2 exons). As summarized by OMIM, most affected females carry de novo htz missense GoF variants, and most affected males inherited hemizygous LoF ones. XCI has not been studied in most htz (affected/unaffected) females (with the exception of the del in Ref2, see also Ref3). Details provided below. (Note: Most articles refer to variants using HGVS nomenclature while few without incl. the signal peptide eg. p.Arg350Leu corresponding to Arg323Leu). Consider inclusion in the current panel with amber/green rating. [1]---- Piton et al (2011 - PMID: 20479760) sequenced 111 X-linked synaptic genes in a cohort of 142 individuals with ASD and identified a female (S00125) harboring Arg350Leu (NM_002063 chrX:14618871 G/T), inherited from her mother (no clinical information provided). Functional evaluation of the variant was performed in a later publication (Ref3), providing additional clinical details on the proband. [2]---- Pilorge et al (2016 - PMID: 26370147) review the role of glycine receptors (GlyRs). These typically consist of pentameric combinations of alpha (α1-α4) and beta (β) subunits and form a pore that controls transmembrane flux of chloride. GlyRs can be formed either as homomers comprising five α subunits or as heteromers of α and β subunits (in 2:3 or 3:2 stoichiometry). Each subunit has an N-terminal extracellular domain with the ligand-binding site and 4 transmembrane domains. GLRA2 encodes the α2 subunit that is expressed in embryonic and perinatal CNS with expression decreasing after birth. The authors discuss the role of glycine as inhibitory neurotransmitter in adult CNS and depolarizing/excitatory action in immature neurons, as well as the role of GlyR α2 in proliferation and neuronal migration during cortical development. The authors previously (2010 - PMID: 20531469) identified a boy with ASD, language delay and low average IQ (verbal 93, performance 75, full-scale IQ 82) harboring a 142 kb microdeletion spanning the last 2 exons of GRLA2 (hg19 - chrX:14693216-14836199). This CNV was confirmed with qPCR and the breakpoints localized to intron 7 after sequencing. Reverse transcription of mRNA from blood revealed presence of a truncated transcript in the child suggestive of little or no NMD. In the mother, the non-truncated transcript was amplified. Further it was shown that the product leaded to incorporation of intron 7, with inclusion of 5 residues followed by a stop codon. The mother had a normal, non-skewed XCI. Previous testing had excluded an FMR1 expansion. Screening of 400 males with ASD identified a further male with de novo missense SNV (NM_002063.3:c.458G>A / p.Arg153Gln). This child had non-syndromic autism, severe language delay, mild ID (fs IQ 63) and GTC seizures with onset at 18y. Previous testing incl. a normal karyotype, FMR1 analysis, and CMA. The boy had an older sister with ASD, not harboring the same GLRA2 variant (interpreted in the context of intrafamilial genetic heterogeneity for ASD). The authors also studied a dn missense variant (NM_001118886.1:c.407A>G / p.Asn136Ser) previously reported in a proband with autism (11842.p2 - Iossifov et al, 2014 - PMID: 25363768). In vitro studies demonstrated that the 3 aforementioned variants impaired GlyR2 α2 function: - The authors generated constructs for wt, the deletion (of last 2 exons) and Arg153Gln and performed co-transfection with EGFP cDNA in Chinese hamster ovary (CHO) cells. While wt and Arg153Gln were observed at the plasma membrane of transfected cells, the del was undetectable at the cell surface and was mislocalized in the cytoplasm (as also expected by loss of the transmembrane domains). - Upon isolation of biotinylated surface receptors and western blot, Arg153Gln was shown to result to 56% decreased surface expression compared to wt, while the intracellular fragment was also reduced by 32% suggesting impaired synthesis or degradation. Asn136Ser had 67% lower surface (and 15% lower intracellular) expression. - Whole-cell patch clamp recordings of transfected CHO cells suggested that the minimum concentration of glycine to evoke whole-cell current was ~100 higher for Arg153Gln compared to wt. High concentrations of glycine were unable to evoke any current in the case of the deletion (due to loss of surface expression). Asn136Ser also reduced glycine sensitivity (14x increase in EC50). Zebrafish studies for glra2 and the del or Arg153Gln variants: Morpholino mediated knockdown of glra2 led to hyperbranching of spinal motor axons compared to ctrls. Co-injection of human wt mRNA with glra2 morpholino, rescued the aberrant branching phenotype which was not the case for the 2 variants. Glra2 ko mouse model (also on chrX): - Mutant mice (Glra2-/Y) had normal adult body, brain weight, were fertile and had a normal lifespan. They displayed no differences in locomotor activity, or social behavior compared to wt. They however exhibited impaired learning and memory in the novel object recognition task (spatial learning and memory in the novel location recognition task and Morris water maze were N). - Long-term potentiation in prefrontal cortex after high frequency stimulation was significantly impaired in mutant mice compared to wt, overall supporting that impaired glycinergic signaling results in abnormal synaptic plasticity in this relevant for ASD region. [3]---- Zhang et al (2017 - PMID: 28588452) determined the functional effects of Arg350Leu which was reported by Piton et al (Arg323Leu without the signal peptide). The authors provide further clinical details on this female with autism, macrocephaly, loss of acquired words, seizures, mild motor delay and hypothyroidism. The mother of the, also carrier of the SNV, was reportedly unaffected. The potency of glycine in activating recombinant homomeric α2 and heteromeric α2β receptors was examined by whole-cell patch-clamp recording (HEK293 cells). In homo-/ and heteromeric receptors this variant resulted in small decrease in glycine sensitivity with peak currents not significantly different compared to wt (the latter suggestive of normal surface expression). This variant resulted in prolonged inhibitory postsynaptic currents (IPSCs) with ~2-fold slower rise and decay times, while IPSC amplitude did not differ significantly. Overall, the slowed decay times, prolongation of active periods and small but significantly increased conductance of mutant channels suggested that this variant exerts a gain-of-function effect. The authors briefly cite a study by Cotton et al (2015, PMID: 25381334) providing evidence that GLRA2 escapes XCI in the vast majority of tissues and brain. [4]---- Marcogliese et al (2022 - PMID: 35294868) functionally tested the effects of missense DNM observed in individuals with ASD diagnosis in Drosophila. The authors generated TG4 (MiMIC cassette) fly mutants for candidate ASD genes (creating LoF alleles for the respective genes). Using a GAL4/UAS system with human cDNA constructs for reference/variants they performed the rescue/overexpression assays to study the functional consequences. Flies expressing human ref GLRA2 cDNA failed to copulate but exhibited normal movement. Flies for Asn136Ser (a variant reported by Iossifov et al, 2014 - PMID: 25363768) copulated similar to the TG4 mutant providing evidence for a LoF effect of this variant. Upon GAL4/UAS expression and co-staining with neuronal (Elav) and glial (Repo) nuclear markers, GLRA2 was shown to be expressed in CNS with expression in a subset of neurons and in some glia. Upon ubiquitous overexpression of human reference or variant cDNA, Asn136Ser also behaved as a LoF allele. Based on the evidence on this gene, and following re-analyses of exome data, GeneMatcher collaborations etc, the authors identified 13 additional unrelated subjects harboring GLRA2 variants (8 females/5 males). These had DD/ID of variable severity (13/13) w/wo autistic features (in 4 or 5), microcephaly (4-5/13 all females), epilepsy (6/13 - both sexes) and ocular manifestations (10/13 - incl. nystagmus, strabismus, etc). Hypotonia/incoordination was observed in 7/13. All females had dn missense variants (8/8, NM_001118886.1:c.887C>T/p.Thr296Met in 6/8, others: c.140T>C/p.Phe47Ser, c.777C>G/p.Ile259Met), while all males had inherited missense SNVs from their unaffected mothers (p.Arg252Cys, p.Ala288Thr, p.Pro396Thr, p.Pro400Leu, p.Arg445Gln). The authors studied an variant which was recurrent in females (Thr296Met) and another found in a male (Arg252Cys). Upon overexpression, the latter behaved - similarly to Asn136Ser - as LoF allele, while Thr296Met did not differ significantly from reference. Structural modeling suggested that Thr296 is adjacent to a residue important for keeping the ion pore in closed conformation. Upon pnr-GAL4 (over)expression in the dorsolateral stripe in the notum, Thr296Met caused lethality, which was not the case for the reference. When expressed at lower levels, Thr296Met formation of melanized nodules in thorax, a phenotype not previously observed upon overexpression of ref/other variants. The authors performed ERGs in fly eyes. They first used a pan-neuronal driver (nSyb-GAL) leading to GLRA2 ref / variant expression in pre-synaptic photoreceptors and post-synaptic neurons. A significant increase of "OFF" transients was observed for Thr296Met, suggesting increase in synaptic transmission and a GoF effect. Expression limited to pre-synaptic photoreceptors (Rh1-GAL4 driver) did not lead to significant differences compared to ref allele, while Arg252Cys was associated with decreased amplitudes of "OFF" transients, suggestive of decreased synaptic transmission and confirming a LoF effect. Marcogliese et al conclude that reduced GLRA2 activity can lead to disease in males but can be tolerated in htz females (as was the case for asymptomatic mothers), while GoF variants leading to overactivation of the channel could be overrepresented in affected females. Sources: Literature |
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| Early onset or syndromic epilepsy v2.452 | GABRD |
Helen Lord changed review comment from: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onse epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4. From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher. The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic. The T291I variant was detected in an aff mother and her aff twin boys. The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients. All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD. The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits. Functional analysis suggests: P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaeed propensity to desensitise - LOF trait. The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait. No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis. The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~). The patient with the LOF variant has ASD, normal intelligence and no seizure history. In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder. One GOF variant was identifed (de novo) in a patient with ASD but no seizures. Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.; to: Screened the GABRD gene in a cohort of 933 individuals with various childhood-onset epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4. From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher. The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic. The T291I variant was detected in an aff mother and her aff twin boys. The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients. All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD. The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits. Functional analysis suggests: P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaesed propensity to desensitise - LOF trait. The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait. No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis. The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~). The patient with the LOF variant has ASD, normal intelligence and no seizure history. In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder. One GOF variant was identifed (de novo) in a patient with ASD but no seizures. Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not. |
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| Early onset or syndromic epilepsy v2.444 | SNIP1 | Sarah Leigh edited their review of gene: SNIP1: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v2.403 | VPS50 |
Konstantinos Varvagiannis gene: VPS50 was added gene: VPS50 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to 34037727 Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum Penetrance for gene: VPS50 were set to Complete Review for gene: VPS50 was set to AMBER Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes. Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports. Sources: Literature |
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| Early onset or syndromic epilepsy v2.402 | PIDD1 |
Konstantinos Varvagiannis changed review comment from: There is enough evidence to include this gene in the current panel with green rating. Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested. The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families]. Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants. Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder. PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage. There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation. Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants. Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26 Evidence so far provided includes: - Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern. - Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability. - Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp] - Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain. - Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD. Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects. There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-relared NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes. Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc. Sources: Literature, Other; to: There is enough evidence to include this gene in the current panel with green rating. Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested. The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families]. Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants. Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder. PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage. There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation. Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants. Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26 Evidence so far provided includes: - Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern. - Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability. - Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp] - Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain. - Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD. Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects. There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes. Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc. Sources: Literature, Other |
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| Early onset or syndromic epilepsy v2.402 | PIDD1 |
Konstantinos Varvagiannis gene: PIDD1 was added gene: PIDD1 was added to Genetic epilepsy syndromes. Sources: Literature,Other Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010 Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum Penetrance for gene: PIDD1 were set to Complete Review for gene: PIDD1 was set to GREEN Added comment: There is enough evidence to include this gene in the current panel with green rating. Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested. The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families]. Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants. Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder. PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage. There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation. Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants. Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26 Evidence so far provided includes: - Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern. - Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability. - Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp] - Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain. - Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD. Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects. There is currently no associated phenotype in OMIM, PanelApp Australia. PIDD1 is listed in the DD panel of G2P (PIDD1-relared NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes. Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc. Sources: Literature, Other |
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| 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 |
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| 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. ----- 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. ----- 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*)]. ----- 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 |
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| 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 |
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| 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 |
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| 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. --- 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: -- 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). -- 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 |
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| 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 |
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| 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 |
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| 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)]. |
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| 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 |
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| 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 |
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| 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. --------- 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). ------- 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). ------- There is no associated phenotype in OMIM/G2P/SysID. ------- 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 |
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| 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 |
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| 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]. ---- 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 |
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| 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). ------------ [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 |
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| 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. ------ 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]. |
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| 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]. ------ 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 |
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| 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). -------- 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 |
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| 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). -------- 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 |
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| 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 |
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| 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)]. |
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| 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. ---- 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 |
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| Early onset or syndromic epilepsy v1.74 | ASAH1 | Rebecca Foulger changed review comment from: PMID:30291339: Ame van der Beek et al (2019) report an additional case of a mild SMA phenotype with NO myoclonic epilepsy due to variants in ASAH1. Ambulatory problems of the 24 year old female began around age 8 years.; to: PMID:30291339: Ame van der Beek et al (2019) report an additional case of a mild SMA phenotype with NO myoclonic epilepsy due to variants in ASAH1. She carried two novel ASAH1 variants (Pro26Arg and c.125+1G>A splice variant leading to an unstable transcript lacking exon 2. Segregation analysis confirmed the parental inheritance and acid ceramidase activity was deficient in functional tests. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.35 | ZNF142 |
Konstantinos Varvagiannis gene: ZNF142 was added gene: ZNF142 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF142 were set to 31036918 Phenotypes for gene: ZNF142 were set to Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia Penetrance for gene: ZNF142 were set to Incomplete Review for gene: ZNF142 was set to AMBER Added comment: Khan et al. (2019 - PMID: 31036918) describe the phenotype of 7 females from 4 families, harboring biallelic likely pathogenic ZNF142 variants. Overlapping features included cognitive impairment (ID in 6/7 from 3 families, borderline intellectual functioning was reported one occasion), speech impairement and motor impairment (7/7), and variably penetrant seizures (5/7), tremor (4/7) and dystonia (3/7). Most individuals (5/7) had experienced at least one episode of seizures (tonic-clonic) though seizures were recurrent in 3 sibs. Other disorders with ID (eg. Angelman syndrome, Rett syndrome, chromosomal disorders) or movement disorders as a feature were previously ruled out for many subjects. 6 individuals were homozygous or compound heterozygous for LoF (stopgain or frameshift) variants. One individual harbored 2 missense SNVs in the compound heterozygous state. Variants reported include (NM_001105537.2): c. 817_818delAA (p.Lys273Glufs*32), c.1292delG (p.Cys431Leufs*11), c.3175C>T (p.Arg1059*), c.4183delC (p.Leu1395*), c.3698G>T (p.Cys1233Phe), c.4498C>T (p.Arg1500Trp) with the LoF variants predicted to result in NMD. Expression or functional studies were not carried out. ZNF142 encodes a C2H2 domain-containing transcription factor. Mutations in other zinc finger proteins (ZNF/zfp) have been reported in several neurodevelopmental disorders impacting the CNS (eg. ZBTB20 and ZBTB11 heterozygous and biallelic mutations, respectively) and/or presenting with movement disorders among their manifestations (eg. YY1). As the authors comment, homozygous ablation of the orthologous (Zfp142) locus in mice results in behavioral and neurological phenotypes [MGI ref.ID: J:211773 cited - http://www.informatics.jax.org/marker/reference/J:211773 (though Zfp142 or its locus do not seem to appear in the list)]. ZNF142 is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. It is not associated with any phenotype in OMIM, nor in G2P. As a result, this gene can be considered for inclusion in the current panel as probably as amber (seizures in 5/7 individuals, though many had a single occurrence) or green. Sources: Literature |
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| Early onset or syndromic epilepsy v1.35 | ACTL6B |
Konstantinos Varvagiannis gene: ACTL6B was added gene: ACTL6B was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ACTL6B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACTL6B were set to 31031012; 30656450; 26539891; 27171548; 30237576 Phenotypes for gene: ACTL6B were set to Global developmental delay; Intellectual disability; Seizures; Spasticity Penetrance for gene: ACTL6B were set to Complete Review for gene: ACTL6B was set to GREEN Added comment: Epilepsy is a typical feature in individuals with biallelic pathogenic ACTL6B variants, though it is uncommon for the dominant phenotype (only a single individual with seizures probably reported). Intellectual disability is a prominent feature of the ACTL6B-related disorder, whether this is secondary to biallelic mutations (leading to loss-of-function) or monoallelic ones (probably by a gain-of-function mechanism). Biallelic ACTL6B mutations: Bell et al. (2019 - PMID: 31031012) report on 11 individuals from 10 families with biallelic variants, adding to 3 individuals from 2 families, recently reported in detail by Fichera et al. (2019 - PMID: 30656450). Previous reports by Karaca et al. (1 individual - 2015 - PMID: 26539891), Sajan et al. (1 individual - 2017 - PMID: 27171548), Maddirevula et al. (2019 - PMID: 30237576) are summarized by Fichera et al. Overlapping features include global DD/ID, epileptic encephalopathy and spasticity. Monoallelic ACTL6B mutations: Bell et al. (2019 - PMID: 31031012) report on 10 individuals with de novo pathogenic variant, namely a recurrent missense one (9/10 - NM_016188.4:c.1027G>A or p.Gly343Arg) as well as a further missense SNV (c.230A>G or p.Asp77Gly) on one occasion. Features included hypotonia, DD and ID, stereotypic movements, and some possibly suggestive features (wide mouth, diastema, bulbous nose). ACTL6B (also known as BAF53B) encodes a subunit of the neuron-specific chromatin remodeling complex nBAF. Some ACTL6B-related phenotypic features were somewhat overlapping to those of other "BAFopathies" (notably Nicolaides-Baraitser and Cofin Siris syndrome - eg. DD/ID, seizures in the recessive type, short phalanges in the dominant one) though others (eg. hair or digital abnormalities) were not observed. Actl6b knock-out mouse neurons show deficits in dendrite development (cited: Wu et al. 2007 - PMID: 17920018). Additional previous studies have shown deficit in dendritic spine and synapse function in Actl6b KO mice, associated with impaired long-term memory and poor survival (cited: Vogel-Ciernia et al. 2013 - PMID: 23525042). Bell et al. provide evidence for profound deficits in dendrite develpment in engineered knock-out of ACTL6B in wt human neurons, similar to what was observed in 2 individuals with biallelic mutation. The deficits were reversed upon bi-allelic repair to wild-type or exogenous ACTL6B expression. Additional studies suggested alteration of genomic binding of the BAF complex and transcriptional dysregulation of genes, among other involved in dendrite development. Loss of ACTL6B function probably explains the recessive phenotype, while a gain-of-function effect is presumed for the dominant one (though the exact mechanism is not known). --- ACTL6B is included in gene panels for ID offered by some diagnostic laboratories. It is part of the DD panel of G2P, associated with "Unspecified Neurodevelopmental Disorder" (monoallelic variants - disease confidence : probable). --- As a result ACTL6B can be considered for inclusion in the current panel as green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v1.35 | SNAP25 |
Konstantinos Varvagiannis gene: SNAP25 was added gene: SNAP25 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006 Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330 Penetrance for gene: SNAP25 were set to Complete Review for gene: SNAP25 was set to GREEN Added comment: Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below): - Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent. - DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants. - Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant - Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant - Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant - Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported). Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified). SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID. SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.). Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988]. Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants. Animal models discussed: - Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238). - In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548). - Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108). - Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335). In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable). This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). As a result SNAP25 can be considered for inclusion in the epilepsy and ID panels as green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v1.35 | P4HTM |
Konstantinos Varvagiannis gene: P4HTM was added gene: P4HTM was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: P4HTM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: P4HTM were set to 30940925 Phenotypes for gene: P4HTM were set to Central hypotonia; Muscular hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Hypoventilation; Sleep apnea; Dysautonomia Penetrance for gene: P4HTM were set to Complete Review for gene: P4HTM was set to GREEN Added comment: Gene added in the ID panel. Epilepsy is a feature of the disorder. ----- Rahikkala et al. (2019 - PMID: 30940925) report on 13 individuals from 5 families with biallelic pathogenic P4HTM variants. 6 of these individuals from a large consanguineous family from Finland were previously reported by the same group, although studies at the time had revealed a 11.5 Mb region of homozygosity with 3 genes within this interval considered to be candidate for the patients' phenotype (P4HTM, TKT, USP4) [Kaasinen et al. - PMID: 25078763]. Common features included Hypotonia (13/13), DD and ID (the latter present in 12/13 individuals with appropriate age for evaluation) and Eye Abnormalities, reason why the acronym HIDEA is suggested for the disorder. Epilepsy was observed in 10 individuals (10/13). Hypoventilation, sleep apnea and dysautonomia were additional features reported. Muscle biopsies from 4 individuals had variable findings suggestive of disruption of normal mitochondrial function. Finnish patients were homozygous for a SNV - possibly a founder variant in this population - predicted to lead to a missense change in the canonical transcript (NM_177938.2:c.1073G>A) but causing an in-frame loss of the complete exon 6 of another transcript (NM_177939.2). The latter transcript (encoding a 502 aa protein) is the prevalent one in fibroblasts/myoblasts instead of the canonical one (563 aa). It is not known whether the canonical transcript is the prevalent in brain tissue although northern blot analysis in a previous study suggested presence of a 2.3 kb mRNA in brain instead of a 1.8 kb observed in other tissues, a finding which may be suggestive of expression of the canonical transcript. [Reviewer's note: In gnomAD based on the pext values from the GTEx, the noncanonical transcript appears to be prevalent in brain regions - https://gnomad.broadinstitute.org/gene/ENSG00000178467] All variants reported affected both transcripts. All 5 variants have been submitted to LOVD ( https://databases.lovd.nl/shared/variants/P4HTM?search_var_status=%3D%22Marked%22%7C%3D%22Public%22 - first author appearing as the submitter). Overexpression of wt and 3 mutants (His161Pro, Gln352*and Exon6del) in insect cells followed by analysis with SDS-PAGE and western blot revealed severly reduced/abolished fraction of soluble protein for the 3 studied variants suggesting improper protein folding. Knockout of the gene in mice leads to retinal defects and/or visual impairment in line with eye abnormalites (nystagmus, strabismus, achromic retinal fundi or cortical blindness) being a prominent feature in affected individuals. Mouse studies suggest that this gene is also important for renal function, although kidney problems were not reported in any affected individual. Overall loss-of-function is suggested to be the underlying mechanism. P4HTM is not associated with any phenotype in OMIM, nor in G2P. This gene is not (at least commonly) included in gene panels for ID offered by diagnostic laboratories. As a result P4HTM can be considered for inclusion in the ID and epilepsy panels probably as green (several affected individuals) or amber. Sources: Literature |
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| Early onset or syndromic epilepsy v1.31 | KMT2E |
Konstantinos Varvagiannis gene: KMT2E was added gene: KMT2E was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: KMT2E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KMT2E were set to https://doi.org/10.1101/566091 Phenotypes for gene: KMT2E were set to Global developmental delay; Intellectual disability; Autism; Seizures; Abnormality of skull size Penetrance for gene: KMT2E were set to unknown Review for gene: KMT2E was set to GREEN Added comment: Gene added in the ID panel (comments below). Epilepsy was a feature in - at least - 11 individuals (with all categories of variants : 4 with truncating, 3 with CNVs, 4 with missense SNVs). As a result this gene can be considered for inclusion in the current panel as green (or amber). From the ID panel : In a collaborative study, O'Donnell-Luria et al. (2019 - https://doi.org/10.1101/566091 - DDD study among the co-authors) report on 38 individuals from 36 families with heterozygous KMT2E variants. Some of these individuals were previously included in previous publications. Developmental delay, intellectual disability, epilepsy and ASD were among the features reported, albeit of variable degree and not universal. 34 of 38 individuals had SNVs or indel variants in KMT2E and 4 individuals had CNVs spanning KMT2E (in one case intragenic, in 3 further as a contiguous gene deletion). For 26 (of 38 individuals) the variant had arisen as a de novo event while in some cases parental sample(s) was/were unavailable to confirm the de novo occurrence or origin (from a reportedly affected parent). The variant in one family was inherited from a parent for whom information on affected/unaffected status was unavailable. As for the variants reported: 30 were protein-truncating (of which 23 predicted to produce transcripts subject to NMD). 4 were missense. 4 were CNVs (de novo deletions, of which 1 intragenic). Truncating variants and deletions of KMT2E suggest haploinsufficiency as the underlying mechanism for this category of variants (KMT2E has a pLI of 1 in gnomAD). However, the somewhat different phenotype related to missense variants (degree of ID, epilepsy in all, microcephaly in some versus macrocephaly in subjects with truncating variants) may suggest a different mechanism for these variants eg. gain of function or dominant negative effect. There was no clustering observed for the missense variants reported. Expressivity of certain features may be variable between males and females. As the authors note : KMT2E encodes a member of the lysine N-methyltransferase 2 family, a family of enzymes with critical role in H3K4 methylation. It is highly expressed in brain, particularly during fetal development. Several monogenic neurodevelopmental disorders due to impaired regulation of H3K4 methylation are known (eg. due to KMT2D/C/B/A mutations, etc). Studies suggest that KMT2E may lack intrinsic methyltransferase activity although it may have an indirect effect on H3K4 methylation. In contrast to other members of the KMT2 family functioning as global activators of open chromatin, KMT2E is believed to be a repressor (although it's function in gene transcription regulation needs to be clarified). A neurological phenotype of Kmt2e (Mll5) deficiency mouse models has not been reported (features included growth restriction, impaired hematopoiesis, etc). KMT2E is not associated with any phenotype in OMIM. The gene is included in the DD panel of G2P, associated with Intellectual disability (disease confidence: confirmed / mutation consequence registered in the db : LoF). KMT2E is included in gene panels for ID offered by some diagnostic laboratories (eg. among those participating in the study). As a result, this gene can be considered for upgrade to green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v1.30 | ATN1 |
Konstantinos Varvagiannis gene: ATN1 was added gene: ATN1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATN1 were set to 30827498 Phenotypes for gene: ATN1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Feeding difficulties; Abnormality of the cardiovascular system; Cleft palate; Abnormality of the kidney Penetrance for gene: ATN1 were set to unknown Mode of pathogenicity for gene: ATN1 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: ATN1 was set to GREEN Added comment: Apart from CAG repeat expansions (green in the present panel) seizures have been reported in individuals with mutations in the HX repeat motif (5 unrelated individuals, each with a private variant). As a result, ATN1 can be considered for inclusion in the Epilepsy panel as green (or amber). Copied from the ID panel : Palmer et al. (2019 - PMID: 30827498) report on 8 individuals all harboring de novo missense or insertion variants within a 16-amino-acid HX repeat motif (aa 1150-1065 / 8 HX repeats, where H is histidine and X any amino acid) in exon 7 of ATN1. The specific motif is distal to the Gln-rich region involved in Dentatorubro-pallidoluysian atrophy (caused by polyglutamine expansion in exon 5, due to a probable toxic GoF effect - MIM #125370). None of the subjects reported presented features of the latter disorder. Common features included hypotonia (8/8) , DD and/or ID (8/8). Other frequent features included visual or hearing impairment, seizures (5/8 - in most presenting as neonatal/infantile onset dev. encephalopathy), feeding difficulties/functional GI disorders. Some individuals presented with congenital anomalies eg. cardiac, cleft palate, renal anomalies, anteriorly placed anus. Some facial (eg. presence of tall forehead, bitemporal narrowing, deep set eyes, sparse lateral hair, bulbous nose, open mouth appearance ,etc) or features of the extremities (overlapping fingers/toes) were also common. Converging evidence from the literature suggests that ATN1 is a nuclear transcriptional regulator important in the control of brain and other organ development (PMIDs cited: 17150957, 25519973, 10973986). The gene is widely expressed in various tissues incl. brain, heart, lung, kidney, skeletal muscle. Expression is higher in fetal tissues particularly in brain while the gene is broadly expressed in multiple regions of the adult human brain (PMID: 7485154). All 8 variants were missense SNVs or insertions within the HX repeat motif (aa 1150-1065) and had occurred as de novo events: c.3160C>A or p.His1054Asn, c.3172C>T or p.His1058Tyr, c.3177_3178insAACCTG or p.Ser1059_His1060insAsnLeu, c.3177_3178insGACCTG or p.Ser1059_His1060insAspLeu, c.3178C>T or p.His1060Tyr, c.3184C>G or p.His1062Asp, c.3188T>G or p.Leu1063Arg, c.3185A>G or p.His1062Arg [NM_001007026.1]. NMR studies of 2 commercialy synthesized polypeptides containing residues 1046-1067 of ATN1 and the HX motif suggested disruption in the case of His1060Tyr of the spatial and dynamical synchronization of histidines which is favored by the regularly spaced occurrence of histidines in the wild-type sequence. Under specific conditions introduction of His1060Tyr allowed zinc binding, which was not the case for the wild-type peptide, thus conferring the peptide a novel property (the consequences of which are though unknown). Clustering of the variants and presence of LoF in healthy individuals (eg. in gnomAD db) suggests that haploinsufficiency is unlikely. Similar (HX)n repeat motifs exist in other proteins, among others RERE or AUTS2 which are associated with neurodevelopmental disorders. The authors comment that disruption of the HX motif in RERE has been reported in affected individuals and that mutations occurring in this motif are more likely to be associated with congenital anomalies, compared to mutations in the rest of the protein. As for animal models, Atn1 -/- mice are neurologically normal. Knockdown of the gene in rat neuronal progenitor cells led to anomalies in brain development, though these could be rescued by co-transfection with human ATN1 construct (PMIDs cited: 17150957, 25519973). ------- In OMIM, heterozygous pathogenic CAG trinucleotide expansions in ATN1 are associated with DRPLA (MIM #125370). The gene is not associated with any phenotype in G2P. Sources: Literature |
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| Early onset or syndromic epilepsy v1.13 | LSS |
Konstantinos Varvagiannis gene: LSS was added gene: LSS was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: LSS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LSS were set to 30723320 Phenotypes for gene: LSS were set to Alopecia; Abnormality of the skin; Hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the genital system; Microcephaly Penetrance for gene: LSS were set to unknown Review for gene: LSS was set to AMBER Added comment: Epilepsy was observed in at least 6 individuals from 4 unrelated families (7 different variants). However other individuals with biallelic LSS mutations and primarily neuroectodermal phenotype or others (hypotrichosis or congenital cataract) did not manifest seizures. As a result this gene can be considered for inclusion possibly as amber. Copied from the ID panel (only the relevant publication included here): DD and ID seem to be among the features observed in some individuals with biallelic LSS mutations, although the clinical presentation appears to be highly variable. PMID: 30723320 [Besnrard et al, 2019] reports on 10 individuals from 6 unrelated families with biallelic LSS variants. One additional subject from a seventh family was found to harbor only a missense SNV (in the maternal allele) while the transcript corresponding to the other (/paternal) allele was less expressed upon RNA studies from patient fibroblasts. The allelic imbalance and the phenotypic overlap with the other individuals of the study were thought to be explained by an LSS defect. The phenotype consisted of total alopecia (11/11) with additional dermatological features in most (9/11), hypotonia (7/11), DD with variable degrees of ID (11/11 both), epilepsy (8/11), microcephaly and genital anomalies in few. Cataracts were not noted in any individuals. The authors suggest that the phenotype corresponds to that observed in a neuroectodermal syndrome previously known as APMR (alopecia with mental retardation - other genes or loci earlier proposed). Variants included: 7 missense SNVs, 1 nonsense, 1 frameshift, 2 splice variants (c.1109+2T>C / c.1194+5G>A - using NM_002340.5). Using a minigene assay the latter variants were confirmhed (both) to affect splicing, at least to some important extent. However the splicing defect for one SNV (c.1194+5G>A - skipping of exon 12) was not confirmed upon RNA studies from blood samples of the respective individuals but an allelic balance in favor of the other allele instead (due to presumed utilisation of an alternative splice site, introduction of a premature stop codon and NMD). Allelic imbalance is discussed for the individual with the single LSS variant but not shown. Variants did not show clustering (also upon 3D modelling). Lanosterol synthase converts (S)-2,3-oxidosqualene to lanosterol in the cholesterol biosynthesis pathway. Quantification of cholesterol and its precursors in affected individuals did not however reveal any important imbalance. As most individuals harbored an allele with missense variant, and mice homozygous for an allele with absent LSS activity show variable lethality, residual LSS activity is suggested for the individuals studied. Several other disorders affecting cholesterol biosynthesis present overlapping features eg. DD/ID in Lathosterolosis, Desmosterolosis, Smith-Lemli-Opitz syndrome (in this case also genital anomalies), etc or cutaneous anomalies in others. A neurodevelopmental phenotype in animal models for LSS deficiency is not commented. ----- Based on the discussion of the current article (and OMIM): Earlier studies [PMIDs : 26200341, 29016354 - Zhao et al 2015 and Chen and Liu 2017 respectively] found biallelic missense in individuals with congenital cataracts. DD/ID were not commented/observed. The subject reported by Chen had baldness and genital defects. Shumiya cataract rats due to mutation in Lss gene recapitulate the specific human phenotype [PMID: 16440058 and OMIM]. Cataract was not a feature in any of the individuals of the present study. The corresponding entry for this phenotype in OMIM is Cataract 44 (#616509). PMID: 30401459 [Romano et al, 2018] reported biallelic LSS mutations in 3 unrelated families with hypotrichosis. Intellectual disability was a feature in 2 sibs from 1 non-consanguineous family (among the three). ID was considered to be coincidental by the authors. The respective entry in OMIM is Hypotrichosis 14 (#618275). Sources: Literature |
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| Early onset or syndromic epilepsy v1.13 | ZMIZ1 |
Konstantinos Varvagiannis gene: ZMIZ1 was added gene: ZMIZ1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ZMIZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZMIZ1 were set to 29754769; 18053775; 17967885; 26163108; 27479843 Phenotypes for gene: ZMIZ1 were set to Global developmental delay; Intellectual disability; Feeding difficulties; Growth abnormality; Microcephaly; Abnormality of the skeletal system; Abnormality of the urinary system; Abnormality of the cardiovascular system; Abnormality of head or neck; Seizures Penetrance for gene: ZMIZ1 were set to unknown Review for gene: ZMIZ1 was set to AMBER Added comment: Gene added in the ID panel. Seizures were noted in 3 unrelated individuals (with different variants) of the 19 reported to date. If the proportion of individuals with this feature is sufficient then this gene can be considered for inclusion in this panel. ------- From the ID panel: Carapito et al. (doi.org/10.1016/j.ajhg.2018.12.007 - PMID to add) report on 19 individuals with variants affecting ZMIZ1 (alternative symbols RAI17/KIAA1224/ZIMP10). Features included DD/ID (19/19), feeding difficulties, growth failure, microcephaly and variable congenital malformations. Seizures were noted in 3 unrelated individuals (with different variants). Variants included 6 missense SNVs, 5 frameshift variants, 1 splice site variant, 1 synonymous variant with probable impact on splicing (not studied) and 2 translocations. In all individuals for whom parental studies were possible (n=16), the variants had occurred as de novo events while for 3 sibs harboring a frameshift variant parental samples were unavailable. These subjects however harbored the same variant as a DDD study participant included in the current report. One translocation disrupted only ZMIZ1 while a second [t(X;10)] did not disrupt the coding sequence of any gene but only a distal enhancer 276 kb upstream of ZMIZ1. A previous study had found recurrent SNVs of the same region in ASD subjects and suggested possible interaction with the ZMIZ1 promoter (Liu et al. - PMID: 29754769). The deleterious effect of both translocations was confirmed by quantitative RT-PCR. For 4 missense SNVs as well as a splice variant mRNA levels were similar to controls. The splice site (-2) variant was shown to produce 2 new splicing isoforms from utilization of alternative splice site acceptors. ZMIZ1 belongs to the PIAS-like family of transcriptional coregulators. Five missense variants were located in an alanine rich domain (aa 280-305). Seven other variants were predicted to shorten or remove the C-terminal transactivation domain. This gene enhances - among others - the transcriptional activity of androgen receptor (AR). In vitro studies using HEK293T cell lines supported impaired coactivation of the AR for 3 variants studied. In utero electroporation of pathogenic variants in mouse embryos (E14.5) led to impaired neuronal positioning of the electroporated neurons and disruption of the morphology/polarization. As the authors note previous studies have shown expression of Zimp10 in the developing mouse brain, craniofacial tissue as well as the interdigital region of limbs (PMIDs cited : 18053775 and 17967885) in line with ID, facial phenotype and syndactyly observed in some patients. Finally the authors cite a previous report on an individual with ID due to a translocation [t(10;19)] disrupting both ZMIZ1 and PRR12 (Córdova-Fletes al. - PMID: 26163108). Although disruption of ZMIZ1 is discussed as a cause, PRR12 has recently been proposed as (also) an ID gene (Leduc et al. - PMID: 29556724). [For details see PRR12 in the current panel]. ------------ One of the variants found in 2 unrelated individuals in the aforementioned study [NM_020338.3:c.899C>T or p.(T300M)] has been reported in a further individual investigated for ID in the context of a bigger cohort (Lelieveld et al. - PMID: 27479843). [ Details in the denovo-db : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZMIZ1 ] ------------ ZMIZ1 is not associated with any phenotype in OMIM, nor in G2P. This gene has been included in gene panels for intellectual disability offered by some diagnostic laboratories. ------------ As a result, ZMIZ1 can be considered for inclusion in the ID panel as green. Sources: Literature |
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| Early onset or syndromic epilepsy v1.6 | SLC35A3 |
Konstantinos Varvagiannis gene: SLC35A3 was added gene: SLC35A3 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35A3 were set to 24031089; 28328131; 28777481; 16344554 Phenotypes for gene: SLC35A3 were set to ?Arthrogryposis, mental retardation, and seizures (MIM 615553) Penetrance for gene: SLC35A3 were set to Complete Review for gene: SLC35A3 was set to GREEN Added comment: Biallelic pathogenic variants in SLC35A3 cause Arthrogryposis, mental retardation, and seizures (MIM 615553). -------- Edvardson et al. (PMID: 24031089) report on 8 affected individuals from 3 nuclear Ashkenazi Jewish families. All harbored a nonsense [NM_012243.1:c.514C>T / p.(Gln172*)] as well as a missense variant [NM_012243.1:c.886A>G / p.(Ser296Gly)] in the compound heterozygous state. Most of the parents, who were heterozygous for the one or the other variant, were distantly related. Common features included ASD (8/8), arthrogryposis (8/8), seizures (6/8) and intellectual disability (6/8 - variable degrees). Upon cDNA studies, the (predicted) missense variant led to skipping of exon 8 and there was no normal size transcript (as would be expected for a variant of this type). Introduction of a premature stop codon due to this variant as well instability of the mRNA from the Gln172Ter allele was presumed to lead to absence of functional SLC35A3 protein. Testing of 2045 Ashkenazi Jewish individuals revealed a carrier frequency of 1/205 for the missense variant in this community (with no occurrence of the nonsense variant). SLC35A3 is a nucleotide sugar transporter that transports (uniquely) UDP-N-acetylglucosamine (UDP-GlcNAc) from the cytoplasm where it is synthesized to its site of use in the Golgi. Proper function of such transporters is essential for biosynthesis of glycoproteins, glycolipids and proteoglycans. Although the transport of UDP-GlcNAc is mediated also by other less specific transporters, members of the SLC35 family, reduced transport was shown in patient fibroblasts compared to controls. In addition an abnormal N-glycan profile was shown in patient fibroblasts (but was not the case in serum). Biallelic SLC35A3 mutations in cattle were previously shown to cause a Complex Vertebral Malformation (CVM) syndrome characterized by abnormal growth, vertebral and heart malformations as well as arthrogryposis (Thomsen et al. - PMID: 16344554). Arthrogryposis as well as some skeletal features observed in patients were similar to those of the animal model. -------- Marini et al. (PMID: 28328131) report on 2 sibs compound heterozygous for a missense and a frameshift variant [NM_012243.2:c.73C>T or p.(Arg25Cys) and c.899_900delTTinsA or p.(Leu300Glnfs*6)]. Hypotonia, DD with ID, early-onset seizures and arthrogryposis were features in both. Severe scoliosis was also noted in the younger sib. --------- Edmondson et al. (PMID: 28777481) report on a neonate (follow-up till the 21st day of life) with extensive vertebral anomalies (butterfly vertebrae, hemibertebrae, sagittal clefts, scoliosis), heart defects (PFO, PDA) and arthrogryposis. Presence of hypotonia or other neurologic features (eg. seizures) is not commented on. Conventional caryotype and SNP-array analysis were normal apart from the presence of ROH regions due to parental consanguinity. Exome sequencing revealed only a homozygous missense SNV [c.74G>T or p.(Arg25Leu) - NP_036375.1] which was supported by an abnormal N-glycan profile. As proposed for the bovine model (PMID: 16344554) and discussed in this article, similarity of the skeletal/congenital heart defects with those observed in Alagille syndrome might be due to some of the Notch functions being dependent upon N-acetylglucosamine modification. --------- In ClinVar : There is a further submission of p.Ser296Gly as pathogenic (SCV000699337.1 - 2016) apart from the submission by OMIM (SCV000108589.2 - 2013). The associated condition is Arthrogryposis, mental retardation, and seizures. A frameshift variant [NM_012243.2(SLC35A3):c.680dup (p.Asp227Glufs)- SCV000826704.1 - April 2018] as well as an intragenic deletion [NC_000001.10:g.(?_100472570)_(100477109_?)del (GRCh37) - SCV000837123.1 - June 2018] have both been submitted as pathogenic, associated with Arthrogryposis, mental retardation, and seizures. (Note: due to the different submission dates, one can presume that these variants were found in different individuals). --------- SLC35A3 is not associated with any phenotype in G2P. --------- As a result, this gene can be considered for inclusion in the epilepsy panel probably as green (or amber) [Consider upgrade of this gene to green in other panels (eg. CDGs, arthrogryposis, IEMs) and/or inclusion in other possibly relevant panels.] Sources: Literature |
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| Early onset or syndromic epilepsy v1.6 | SMARCC2 |
Konstantinos Varvagiannis gene: SMARCC2 was added gene: SMARCC2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SMARCC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SMARCC2 were set to 27392482 Phenotypes for gene: SMARCC2 were set to Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck; Seizures Penetrance for gene: SMARCC2 were set to unknown Review for gene: SMARCC2 was set to AMBER Added comment: Gene present in the ID panel : Machol et al. (https://doi.org/10.1016/j.ajhg.2018.11.007) report on 15 unrelated individuals with heterozygous pathogenic SMARCC2 variants. SMARCC2 (BAF170) is one of the subunits of the chromatin remodeling BAF complex and the phenotype of these subjects resembled the phenotype of other "BAFopathies", notably Coffin-Siris and Nicolaides-Baraitser syndrome. DD and/or ID were universal features (a few individuals were too young). Other common features included speech impairment, hypotonia, feeding problems, behavioral anomalies as well as some overlapping facial features (similar to other BAFopathies). ** Seizures were noted in 4/15 individuals. ** 8 missense variants, 1 in-frame deletion, 4 splice-site variants, 1 frameshift and 1 nonsense variant are reported. De novo occurrence was the case for 12 of these variants while for 2 individuals one/both parents were unavailable. One subject with mild DD had inherited a nonsense variant from his affected father (with borderline ID) in whom the mutation had occurred as a de novo event. Several of the missense variants (but not all) clustered in the SANT domain, while individuals with the specific variants seemed to present with a more severe phenotype. The de novo in-frame deletion, which was observed in one mildly affected individual, has been reported once in gnomAD. Exon skipping was demonstrated for 1 splice-site variant while expression studies for another splice-site variant showed reduced mRNA expression. mRNA expression was normal for the in-frame deletion. Similarly to what has been observed in other disorders of this group, some mutations are thought to act through a dominant-negative mechanism. Transcriptome analysis in fibroblasts from affected individuals suggested the presence of a group of differentially expressed genes possibly involved in regulation of neuronal development/function. As the authors note, studies in Smarcc2-deficient mice suggest a role in learning as well as behavioral adaptation (PMID: 27392482). SMARCC2 is not associated with any phenotype in OMIM, nor in G2P. As a result, this gene should be considered for inclusion in this panel as amber (or green). Sources: Literature |
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| Early onset or syndromic epilepsy v1.1 | AIMP2 |
Konstantinos Varvagiannis gene: AIMP2 was added gene: AIMP2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: AIMP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AIMP2 were set to 29215095 Phenotypes for gene: AIMP2 were set to Leukodystrophy, hypomyelinating, 17 (MIM 618006) Penetrance for gene: AIMP2 were set to Complete Review for gene: AIMP2 was set to AMBER Added comment: Biallelic pathogenic variants in AIMP2 cause Leukodystrophy, hypomyelinating, 17 (MIM 618006). 3 individuals from 2 unrelated consanguineous families, of Indian origin have been reported (all in PMID: 29215095). The phenotype consisted of feeding difficulties, lack of development with intellectual disability and seizures (3/3) as well as brain MRI abnormalities (cerebral and cerebellar atrophy, hypo-intensities of the basal ganglia on T2w sequences). Severe microcephaly was observed in 2 patients for whom this information was available (birth measurements not specified). All patients described to date were homozygous for a nonsense variant [NM_006303.3:c.105C>A or p.(Tyr35Ter)] which appears to be a founder mutation in this population. Quantitative reverse transcription PCR demonstrated reduced mRNA levels in peripheral lymphocytes, but this decrease was not significant compared to controls (the authors presume low level of NMD). Previous mouse models provide some - but not substantial - support. The authors note marked similarity with the phenotype associated with AIMP1 (Leukodystrophy, hypomyelinating, 3 - MIM 260600), another auxiliary protein of the macromolecular multienzyme multi-tRNA synthetase complex. AIMP1 is listed in the current panel as green. AIMP2 is not associated with any phenotype in G2P. As a result, this gene can be considered for inclusion in this panel probably as amber. Sources: Literature |
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| Early onset or syndromic epilepsy v1.1 | PAK1 |
Konstantinos Varvagiannis gene: PAK1 was added gene: PAK1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PAK1 were set to 30290153 Phenotypes for gene: PAK1 were set to Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158) Penetrance for gene: PAK1 were set to unknown Mode of pathogenicity for gene: PAK1 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: PAK1 was set to AMBER Added comment: Heterozygous pathogenic PAK1 variants cause Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). Harms et al. (PMID: 30290153) report on two unrelated individuals with de novo missense mutations in PAK1. Common features included developmental delay with associated intellectual disability, seizures, ataxic gait. Postnatal-onset microcephaly as well as some facial features were also common to both subjects. Each patient was found to harbour a (private) de novo missense variant [NM_001128620.1:c.392A>G or p.(Tyr131Cys) - c.1286A>G or p.(Tyr429Cys)]. Expression studies demonstrated similar levels for the mutant and wt transcript and Western blot confirmed similar amounts of protein in patient fibroblasts when compared to controls. Functional studies suggest that gain-of-function is the underlying mechanism for both variants. PAK1 is not associated with any phenotype in G2P. As a result, this gene can be considered for inclusion in this panel as amber. Sources: Literature |
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| Early onset or syndromic epilepsy v0.1488 | MAST1 |
Konstantinos Varvagiannis gene: MAST1 was added gene: MAST1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: MAST1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAST1 were set to 30449657; 23934111 Phenotypes for gene: MAST1 were set to Global developmental delay, Intellectual disability, Abnormality of the corpus callosum, Cerebellar hypoplasia, Abnormality of the cerebral cortex, Seizures; Global developmental delay, Intellectual disability, Microcephaly, Autism, Seizures Penetrance for gene: MAST1 were set to unknown Review for gene: MAST1 was set to GREEN Added comment: PMID: 30449657 reports on 6 unrelated individuals with de novo mutations in MAST1. All these 6 individuals were investigated for a strikingly similar phenotype of enlarged corpus callosum (CC), cerebellar hypoplasia, cortical malformation with associated DD/ID. Seizures were a feature in 2/6 (one further had EEG anomalies without clinical seizures). Three of them harbored an in-frame deletion of 1 amino-acid (3 different indels reported - all in a specific domain) while 3 others had a missense variant (NM_014975.2:c.1549G>A or p.Gly517Ser). Mast1 has embryonic expression in murine models with postnatal decrease. Similarly qPCR of human fetal brain cDNA demonstrated expression at 13 and 22 gestational weeks. A murine model for L278del recapitulated the brain (incl. CC) and cerebellar phenotype while Mast1 knockout mice do not present similar morphological defects. While Western blot in murine brain lysates demonstrated absence of Mast1 in knockout and reduction in the L278del, Mast1 transcript levels for L278del were similar to wildtype. Other Mast proteins (Mast1 & Mast2) were significantly reduced upon western blot while this was not reflected in their mRNA levels, suggesting a dominant-negative effect, at least for the L278del. 4 additional individuals with somewhat different phenotype consisting DD/ID and microcephaly/autism are described in the supplement. All 4 had de novo missense variants but did not display the CC-cerebral and cerebellar anomalies. Four different (additional to Gly517Ser) missense SNVs were observed. Several additional individuals exist in the denovo-db (among others DDD participant DDD4K.02310 published in 28135719, 25666757 - McMichael et al. commented in the article, 27479843, etc.). [http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=Mast1] Epilepsy was a feature in 4/10 individuals (with an additional one with EEG anomalies without clinical seizures). One further individual from PMID:23934111 (in denovo-db) had seizures. As the authors comment (and as evident from the 6+4 reported patients) the related neurodevelopmental phenotype may be more complex. MAST1 is not related to any phenotype in G2P, nor in OMIM. As a result, this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy v0.1113 | DPM1 | Rebecca Foulger commented on gene: DPM1: Kim et al., 2000 (PMID:10642597) report a patient with CDG1E and a homozygous 274C-G transversion in the DPM1 gene (p.R92G). Another unrelated patient was compound heterozygous for the R92G variant and a 13-bp deletion in exon 4 that may result in an unstable transcript. Both patients were recorded with medically intractable seizures | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1095 | MACF1 |
Konstantinos Varvagiannis gene: MACF1 was added gene: MACF1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: MACF1 were set to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia Penetrance for gene: MACF1 were set to unknown Mode of pathogenicity for gene: MACF1 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: MACF1 was set to GREEN Added comment: Dobyns et al. (doi.org/10.1016/j.ajhg.2018.10.019) report on 9 individuals (all unrelated appart from a pair of monozygotic twins) with de novo variants in MACF1. All patients presented lissencephaly and brainstem hypoplasia with associated intellectual disability (9/9) and seizures (9/9). Seven of these individuals had de novo missense variants within the GAR domain and an eighth had a deletion of several exons also spanning this domain and leading to an in-frame deletion. A further ninth patient had a de novo missense variant in the spectrin repeat domain and was found to have similar features although the brainstem dysplasia was rather subtle. 5 missense variants (4 of which in the GAR domain) and an intragenic deletion are reported in total. The variants in the GAR domain were predicted to have important effect in the zinc-binding pocket. The spectrin repeat (SR4) is thought to have an important role for the function of MACF1 and further to neuronal migration. Knockdown of Macf1 in mice has been shown to result in developmental defects similar to the human malformation. The authors note that several high-confidence loss-of-function mutations are listed in ExAC and as a result this type of variants could be non-pathogenic (or lead to neurodevelopmental disorders with reduced penetrance). Still MACF1 has a pLI of 1.0. As for the missense variants, the authors suggest either a gain-of-function or dominant negative mechanism. Caution should be taken when interpreting variants as the ENST00000372915.7 (or MACF1-204) transcript is used for the predicted protein changes, although ENST00000361689.6 or MACF1-203 (corresponding to NM_012090.5) has also been used in some tables or figures. As a result, this gene can be considered for inclusion in this panel probably as green. Sources: Literature, Expert Review |
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| Early onset or syndromic epilepsy v0.914 | FUT8 |
Konstantinos Varvagiannis gene: FUT8 was added gene: FUT8 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Mode of inheritance for gene: FUT8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FUT8 were set to 29304374 Phenotypes for gene: FUT8 were set to Congenital disorder of glycosylation with defective fucosylation, 618005 Penetrance for gene: FUT8 were set to Complete Review for gene: FUT8 was set to GREEN Added comment: PMID: 29304374 reports on 3 unrelated individuals with biallelic pathogenic variants in FUT8. Two of the patients were born to consanguineous parents and were found to be homozygous for stopgain variants (p.Arg239* in one family and p.Arg315* in the other). A third patient was compound heterozygous for a missense as well as a splice variant. All three presented with similar phenotype consisting of polyhydramnios (2 out of 3), IUGR and failure to thrive with short stature (3/3), severe developmental delay (3/3) with microcephaly (3/3) and seizures (3/3). Variable respiratory problems were also noted in all. Western blot demonstrated loss of FUT8 protein expression in one individual homozygous for a stopgain mutation as well as the patient who was compound heterozygous for the missense and the splice variant. The splice variant was further shown to produce a shorter transcript due to lack of exon 9, leading to an in-frame deletion of 59 residues critical for the protein function. Additional studies confirmed the fucosylation defect compared to controls. The authors note that while Fut8 knockout mice are born normal, 70% die within the first 3 days due to severe growth retardation and respiratory deficiency (similarly to what is observed in humans, though to a lesser extent). As a result this gene can be considered for inclusion in this panel probably as green (3 unrelated families, strong additional functional data, consistent phenotype) or amber. Sources: Literature, Expert Review |
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| Early onset or syndromic epilepsy v0.787 | SUCLG1 | Rebecca Foulger Added comment: Comment on publications: PMID:27143079 article is in Chinese. See PMID:26028457 for a description of the same patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.676 | RHOBTB2 |
Konstantinos Varvagiannis gene: RHOBTB2 was added gene: RHOBTB2 was added to Genetic Epilepsy Syndromes. Sources: Expert Review,Literature Mode of inheritance for gene: RHOBTB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508 Phenotypes for gene: RHOBTB2 were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly Penetrance for gene: RHOBTB2 were set to unknown Mode of pathogenicity for gene: RHOBTB2 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: RHOBTB2 was set to GREEN Added comment: PMID: 29276004 reports on 10 unrelated patients with de novo pathogenic missense variants in RHOBTB2. The phenotype in all individuals was compatible with a developmental and epileptic encephalopathy including early-onset seizures, severe intellectual disability, postnatal onset microcephaly (6/10) and movement disorders (8/10). The variants occured as de novo events and clustered within the BTB-domain encoding region (within and between the 2 BTB domains). Three missense variants were recurrent and/or concerned the same residue (p.Arg483His in 4 individuals, Arg511Gln was reported in 2, and Arg511Trp was was found in another 2 individuals). Functional studies in HEK293 cells suggested increased abundance of the mutant protein secondary to decreased proteasome degradation. Using Drosophila as a model organism, altered expression of RhoBTB (the single ortholog of the 3 vertebrate paralogs, closest to RHOBTB2) was shown to result in neurological phenotypes. RhoBTB overexpression in particular was associated with increased bang sensitivity (which was not the case or milder in the case if knockdown of this gene) and impaired performance upon the negative geotaxis assay, similar to the human neurological phenotypes. Altered RhoBTB dosage was shown to be associated with impaired dendrite development. As commented by the authors, these results as well as the clustering of missense variants and the pLI score of 0.51 reported for RHOBTB2 are consistent with altered protein function (due to the missense variants) rather than haploinsufficiency or loss-of-function. PMID: 29768694 describes 3 additional individuals, all found to harbor de novo missense variants again within the BTB-domain encoding region. Two of the variants had been reported in the previous study (Arg511Gln and Arg483His) while the third was a private one (Arg507Cys). The phenotype was similar to the previous descriptions. Functional studies were suggestive of impaired degradation of the mutant protein by the CUL3 complex although this was not secondary to decreased binding with CUL3. PMID: 26740508 (cited by the two aforementioned publications) reports briefly on an individual with de novo missense variant in the same region of RHOBTB2 (Asn510Asp) and Rett-like phenotype. RHOBTB2 is included in gene panels for intellectual disability offered by different diagnostic laboratories. As a result the gene can be considered for inclusion in the intellectual disability and epilepsy panels as green. Sources: Expert Review, Literature |
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| Early onset or syndromic epilepsy v0.505 | VARS |
Konstantinos Varvagiannis gene: VARS was added gene: VARS was added to Genetic Epilepsy Syndromes. Sources: Expert Review,Literature Mode of inheritance for gene: VARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VARS were set to 26539891; 29691655; 30275004 Phenotypes for gene: VARS were set to # 617802. NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND CORTICAL ATROPHY; NDMSCA Penetrance for gene: VARS were set to Complete Review for gene: VARS was set to GREEN Added comment: PMID: 26539891 is the first report on individuals with biallelic pathogenic variants in VARS. 3 individuals from 2 consanguineous families are briefly reported. The phenotype was similar in all 3, consisting of severe developmental delay, microcephaly, seizures and cortical atrophy. Subjects from the first family were homozygous for a missense variant in the tRNA synthetase catalytic domain [p.(L885F)]. The patient from the second family was homozygous for a missense SNV affecting the anticodon-binding domain [p.(R1058Q)]. PMID: 29691655 reports on a further patient born to non-consanguineous parents, with 2 in-trans pathogenic variants in VARS. The phenotype consisted of progressive microcephaly (OFC at birth -2SD, at the age of 2 months -4SD), global developmental delay, seizures and progressive cerebral and cerebellar atrophy. An affected brother presented with more severe phenotype (OFC -6SD at birth and -8SD at 2 months of age), seizures, hearing loss but was deceased and unavailable for genetic testing. cDNA studies demonstrated absence of the reference allele for the missense mutation downstream the splice variant (in line with a reduced or absent mRNA allele harboring the splice variant). Similarly, mRNA expression studies demonstrated 50-60% reduction in the transcripts (due to NMD of the allele with the splice SNV). Western blot showed severe reduction in protein levels (more pronounced compared to what would be expected by mRNA expression) presumably secondary to decreased protein stability due to the missense variant. Severe defects in aminoacylation were further confirmatory of a pathogenic role of these variants. The missense variant was affecting the anticodon-binding domain, important for aminoacylation. PMID: 30275004 reports on 2 siblings with developmental delay, intellectual disability, severe speech impairment and microcephaly, similar to what has been described for the disorder. Clinical findings were somewhat different from previous studies in that microcephaly was acquired, while seizures and cortical atrophy were not part of the phenotype. Both sibs were compound heterozygous for 2 missense variants, though only one of these mutations affected the anticodon binding domain and the other was in the N-terminal region of the protein. Previous metabolic studies and extensive genetic testing (karyotype, CMA, MECP2, FMR1) was normal. Epilepsy was a feature in 4 of the 6 individuals for whom genetic testing was possible (or 5/7 in total). VARS belongs to the family of amino acyl-tRNA synthetases (ARSs). Mutations in several cytoplasmic ARSs are associated with severe neurological manifestations including seizures, intellectual disability associated with microcephaly. VARS is included in gene panels for intellectual disability (but not for epilepsy) offered by different diagnostic labs. As a result this gene can be considered for inclusion in the ID and epilepsy panel as green (or amber). Sources: Expert Review, Literature |
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| Early onset or syndromic epilepsy v0.503 | PIGG |
Konstantinos Varvagiannis gene: PIGG was added gene: PIGG was added to Genetic Epilepsy Syndromes. Sources: Literature,Expert Review Mode of inheritance for gene: PIGG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGG were set to 26996948; 28581210 Phenotypes for gene: PIGG were set to # 616917. MENTAL RETARDATION, AUTOSOMAL RECESSIVE 53; MRT53 Penetrance for gene: PIGG were set to Complete Review for gene: PIGG was set to GREEN Added comment: PMID: 26996948 reports on 5 individuals from 3 families, with biallelic pathogenic variants in PIGG. Individuals from first family, were born to consanguineous parents from Egypt and were homozygous for a stopgain variant [p.(Gln310*)]. The patient from the second family had a rare missense SNV [p.(Arg669Cys)] and a de novo microdeletion affecting PIGG on her other allele. In the third family (consanguineous parents from Pakistan), two affected sibs were found to be homozygous for a splice variant. The phenotype consisted of hypotonia, early-onset seizures and intellectual disability. Ataxia was an additional feature in one of the families. Seizures, were observed in most of patients but do not appear to be a universal feature as they were absent in one of the sibs from the third family (10 years of age), while the other had a single episode by the age of 12 years. In vitro testing of lymphoblastoid cell lines (generated from individuals from the 1st and 3rd family) indicated that the variants abolished completely the function of PIGG, whereas the surface level of GPI anchored proteins was normal. // PMID: 28581210 describes the phenotype of 2 sibs from Palestine, homozygous for a stopgain variant [p.(Trp547*)]. Hypotonia, feeding difficulties, severe non-progressive ataxia (with cerebellar hypoplasia), intellectual disability and seizures were common features. Differences in severity and/or additional features might be explained by other homozygous variants (the girl had a concurrent diagnosis of MCAD deficiency). The authors demonstrated that the PIGG transcript levels were significantly lower (approximately half) in the two siblings compared to their parents, while the transcripts with the mutation in the heterozygous parents were very low due to nonsense-mediated decay. Patient fibroblasts showed decreased surface level of GPI-anchored proteins, in contrast with what was noted in lymphoblastoid cells in the previous study. // As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature, Expert Review |
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