Dataset Information

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy.

ABSTRACT: Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.

SUBMITTER: Ostrander BEP

PROVIDER: S-EPMC6089881 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy.

Ostrander Betsy E P BEP Butterfield Russell J RJ Pedersen Brent S BS Farrell Andrew J AJ Layer Ryan M RM Ward Alistair A Miller Chase C DiSera Tonya T Filloux Francis M FM Candee Meghan S MS Newcomb Tara T Bonkowsky Joshua L JL Marth Gabor T GT Quinlan Aaron R AR

NPJ genomic medicine 20180813

Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis ...[more]

PMID: 30109124

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Project description:BackgroundSCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations.MethodsTo identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained.ResultsA heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence.ConclusionsOur findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.

Dataset Information

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy.

Publications

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy.

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