Publication Date:
2014-08-22
Description:
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.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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