NDLI: The genetic landscape of infantile spasms.

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The genetic landscape of infantile spasms.

Content Provider	Semantic Scholar
Author	Michaud, Jacques Loic Marie Lachance, Mathieu Hamdan, Fadi Carmant, Lionel Lortie, Anne Diadori, Paola Major, Philippe Meijer, Inge Anita Lemyre, Emmanuelle Cossette, Patrick Mefford, Heather C. Rouleau, Guy A. Rossignol, E. López Durán
Copyright Year	2014
Abstract	Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in ∼40% of patients. We hypothesized that unexplained IS cases represent a large collection of rare single-gene disorders. We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n = 44) followed by targeted sequencing of 35 known epilepsy genes (n = 8) or whole-exome sequencing (WES) of familial trios (n = 18) to search for rare inherited or de novo mutations. aCGH analysis revealed de novo variants in 7% of patients (n = 3/44), including a distal 16p11.2 duplication, a 15q11.1q13.1 tetrasomy and a 2q21.3-q22.2 deletion. Furthermore, it identified a pathogenic maternally inherited Xp11.2 duplication. Targeted sequencing was informative for ARX (n = 1/14) and STXBP1 (n = 1/8). In contrast, sequencing of a panel of 35 known epileptic encephalopathy genes (n = 8) did not identify further mutations. Finally, WES (n = 18) was very informative, with an excess of de novo mutations identified in genes predicted to be involved in neurodevelopmental processes and/or known to be intolerant to functional variations. Several pathogenic mutations were identified, including de novo mutations in STXBP1, CASK and ALG13, as well as recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). In addition, WES identified 1-3 de novo variants in 64% of remaining probands, pointing to several interesting candidate genes. Our results indicate that IS are genetically heterogeneous with a major contribution of de novo mutations and that WES is significantly superior to targeted re-sequencing in identifying detrimental genetic variants involved in IS.
Starting Page	175
Ending Page	179
Page Count	5
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PubMed reference number	24781210v1
Alternate Webpage(s)	https://doi.org/10.1093/hmg/ddu199
DOI	10.1093/hmg/ddu199
Journal	Human molecular genetics
Volume Number	23
Issue Number	18
Language	English
Access Restriction	Open
Subject Keyword	16p11.2 Biopolymer Sequencing Brain Diseases CASK gene CDISC Subject Level Analysis Dataset Candidate Disease Gene Crossbreeding De novo mutation Deletion Mutation Epilepsy Gene Duplication Abnormality Genetic Heterogeneity Maternal Inheritance PNPO gene Patients Spasm Tetrasomy Viral sequencing:Prid:Pt:Ser:Nom:Sequencing West Syndrome Whole Exome Sequencing Xp11.2
Content Type	Text
Resource Type	Article

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