The genetic landscape of infantile spasms

Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in ∼40 % of patients. Wehypothesized that unexplained IS cases represent a large collection of rare single-gene disorders.We inves-tigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n 5 44) fol-lowed by targeted sequencing of 35 known epilepsy genes (n 5 8) or whole-exome sequencing (WES) of familial trios (n 5 18) to search for rare inherited ordenovomutations. aCGHanalysis revealeddenovo variants in 7%of patients (n5 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 forARX (n5 1/14)andSTXBP1 (n 5 1/8). Incontrast, sequencingofapanelof35knownepileptic encephalopathygenes (n 5 8)didnot identify furthermutations.Finally,WES(n5 18)wasvery informative,with an excess of de novomutations 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 novomutations 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 toseveral interestingcandidategenes.Our results indicate that ISaregeneticallyheterogeneouswitha majorcontributionofdenovomutationsandthatWESissignificantlysuperior to targetedre-sequencing in iden-tifying detrimental genetic variants involved in IS