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Early infantile-onset epileptic encephalopathy 28 due to a homozygous microdeletion involving the WWOX gene in a region of uniparental disomy.

ABSTRACT: The genetic etiologies of many rare disorders, including early infantile epileptic encephalopathies, are largely undiagnosed. A 6-year-old girl was admitted to the National Institutes of Health Undiagnosed Diseases Program with profound intellectual disability, infantile-onset seizures, chronic respiratory failure, facial dysmorphisms, skeletal abnormalities, and atrial septum defect. A large region of homozygosity was discovered on chromosome 16, spanning 16q22.1-16q24.3' caused by uniparental disomy (UPD) that included a maternally inherited homozygous microdeletion covering exon 6 of WWOX (NM_016373.3). mRNA expression analysis revealed that the deletion led to nonsense-mediated decay of the NM_016373.3 transcript; the exon 6 of an alternative transcript (NM_130791.3), lacking the short-chain dehydrogenase, was utilized. The microdeletion in WWOX explains the seizures and intellectual disability, while pathogenic variants in another gene, HSPG2, are likely responsible for the patient's skeletal abnormalities. This report describes a rare autosomal recessive disorder with multiple genetic etiologies, one of which involves UPD.

SUBMITTER: Davids M

PROVIDER: S-EPMC6296882 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Early infantile-onset epileptic encephalopathy 28 due to a homozygous microdeletion involving the WWOX gene in a region of uniparental disomy.

Davids Mariska M Markello Thomas T Wolfe Lynne A LA Chepa-Lotrea Xenia X Tifft Cynthia J CJ Gahl William A WA Malicdan May Christine V MCV

Human mutation 20181118 1

The genetic etiologies of many rare disorders, including early infantile epileptic encephalopathies, are largely undiagnosed. A 6-year-old girl was admitted to the National Institutes of Health Undiagnosed Diseases Program with profound intellectual disability, infantile-onset seizures, chronic respiratory failure, facial dysmorphisms, skeletal abnormalities, and atrial septum defect. A large region of homozygosity was discovered on chromosome 16, spanning 16q22.1-16q24.3' caused by uniparental ...[more]

PMID: 30362252

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Project description:Objective:Epileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic-based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high-throughput next-generation sequencing (NGS) was used to investigate the genetic causes of non-syndromic cryptogenic neonatal/infantile EE (NIEE). Methods:We have selected a cohort of 31 patients with seizure cryptogenic NIEE and seizure onset before 24 months. All investigations including metabolic work-up, were negative. Using NGS, we distinguished a panel of 430 epilepsy-associated genes by NGS was utilized to identify possible pathogenic variants in the patients. Segregation analysis and multiple silico analysis prediction tools were used for pathogenicity assessment. The identified variants were classified as "pathogenic," "likely pathogenic" and "uncertain significance," according to the American College of Medical Genetics (ACMG) guidelines. Results:Pathogenic or likely pathogenic variants were identified in six genes (ALG13 [1], CDKL5 [2], KCNQ2 [2], PNPO [1], SCN8A [1], SLC9A6 [2]) in 9 NIEE patients (9/31; 29%). Variants of uncertain significance (VUS) were found in DNM1 and TUBA8 in 2 NIEE patients (2/31; 6%). Most phenotypes in our cohort matched with those reported cases. Significance:The diagnostic rate (29%) of pathogenic and likely pathogenic variants was comparable to the recent studies of early-onset epileptic encephalopathy, indicating that gene panel analysis through NGS is a powerful tool to investigate cryptogenic NIEE in patients. Six percent of patients had neurometabolic disorders. Some of our diagnosed cases illustrated that successful molecular investigation may allow a better treatment strategy and avoid unnecessary and even invasive investigations. Functional analysis could be performed to further study the pathogenicity of the VUS identified in DNM1 and TUBA8.

Dataset Information

Early infantile-onset epileptic encephalopathy 28 due to a homozygous microdeletion involving the WWOX gene in a region of uniparental disomy.

Publications

Early infantile-onset epileptic encephalopathy 28 due to a homozygous microdeletion involving the WWOX gene in a region of uniparental disomy.

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