X chromosome exome sequencing reveals a novel <i>ALG</i><i>13</i> mutation in a nonsyndromic intellectual disability family with multiple affected male siblings

Bissar-Tadmouri, Nesrine; Donahue, W.; Nelson, Stanley F.; Bayrak-Toydemir, Pınar; Kantarci, Sibel

doi:10.1002/ajmg.a.36233

Cited by 29 publications

(28 citation statements)

References 25 publications

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“…Similar cases of males with ALG13 mutations transmitted from their unaffected mothers have been reported. 20 We therefore considered this variant, which was predicted to have altered splicing, to be possibly causative.…”

Section: Resultsmentioning

confidence: 99%

Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

Zhou

Zhang

et al. 2018

Genes Brain and Behavior

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Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty-three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox-Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype-phenotype correlations would provide insights into the underlying pathogenic mechanisms.

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Section: Resultsmentioning

confidence: 99%

Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

Zhou

Zhang

et al. 2018

Genes Brain and Behavior

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“…Transferrin isoelectric focusing showed increased asialo-and disialotransferrin fractions. Two other missense mutations were found in four brothers affected with intellectual disability and in a male patient with ISs and optic nerve atrophy (15,16). 10A1280 was the only patient with the p.Asn107Ser in whom transferrin glycosylation was assayed.…”

Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome

et al. 2015

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Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.

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“…To date, this is the only CDG reported due to a variant in ALG13. Bissar-Tadmouri et al (2014) identified a novel missense variant, 3221A>G in ALG13 (p.Y1074C), that segregated with a non-syndromic X-linked intellectual disability disorder family with four affected boys. No additional clinical information was provided in the report.…”

Section: Introductionmentioning

confidence: 99%

Girls with Seizures Due to the c.320A>G Variant in ALG13 Do Not Show Abnormal Glycosylation Pattern on Standard Testing

2015

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A girl with early onset severe epilepsy, developmental delay, intellectual disability, visual maturation delays, and feeding problems was without a diagnosis despite an extensive genetic and metabolic evaluation. She initially manifested infantile spasms which responded to high-dose ACTH. Seizures seemed to resolve, but then at age 5, she developed complex partial seizures resistant to antiepileptics that responded to a ketogenic diet. Additional features included visual impairment, hypotonia, reflux, and severe feeding problems requiring a G-tube. She was referred to the Geisinger Health System whole-genome sequencing clinical research program. A variant in the X-linked gene ALG13 (c.320A->G p. 107 N->S) was identified. Four additional girls from three published exome sequencing studies were found to have the identical c.320A>G variant in ALG13. All presented with early onset severe epilepsy and intellectual disability. Three of the five exhibited visual impairment and possible developmental regression. A boy with a variant in ALG13 presented with a severe congenital disorder of glycosylation type Is. Glycosylation studies in the case reported here were normal; none of the other girls reported in the literature have had glycosylation studies. X-inactivation studies have not been done. The N107 residue and the surrounding region - MNNHQ - are highly conserved across species and are found in a presumed functional domain of this glycotransferase superfamily. The consistent clinical presentation of a severe phenotype in girls coupled with identical variants in an X-linked gene strongly suggests a critical position effect. Negative glycosylation studies in one individual suggest the possibility of a new mechanism requiring investigation.

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X chromosome exome sequencing reveals a novel ALG13 mutation in a nonsyndromic intellectual disability family with multiple affected male siblings

Cited by 29 publications

References 25 publications

Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

Whole‐exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome

Girls with Seizures Due to the c.320A>G Variant in ALG13 Do Not Show Abnormal Glycosylation Pattern on Standard Testing

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