Journal Article

The genetic landscape of infantile spasms

Jacques L. Michaud, Mathieu Lachance, Fadi F. Hamdan, Lionel Carmant, Anne Lortie, Paola Diadori, Philippe Major, Inge A. Meijer, Emmanuelle Lemyre, Patrick Cossette, Heather C. Mefford, Guy A. Rouleau and Elsa Rossignol

in Human Molecular Genetics

Volume 23, issue 18, pages 4846-4858
Published in print September 2014 | ISSN: 0964-6906
Published online April 2014 | e-ISSN: 1460-2083 | DOI:
The genetic landscape of infantile spasms

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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.

Journal Article.  7534 words.  Illustrated.

Subjects: Genetics and Genomics

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