The genetic landscape of infantile spasms.
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.
Department of Pediatrics and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada, CHU Ste-Justine Research Center, Montréal, QC, Canada.
Jacques L
JL
Michaud
CHU Ste-Justine Research Center, Montréal, QC, Canada.
Mathieu
M
Lachance
CHU Ste-Justine Research Center, Montréal, QC, Canada.
Fadi F
FF
Hamdan
Department of Pediatrics and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada, CHU Ste-Justine Research Center, Montréal, QC, Canada.
Lionel
L
Carmant
Department of Pediatrics and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada, CHU Ste-Justine Research Center, Montréal, QC, Canada.
Anne
A
Lortie
Department of Pediatrics and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada, CHU Ste-Justine Research Center, Montréal, QC, Canada.
Paola
P
Diadori
Department of Pediatrics and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada, CHU Ste-Justine Research Center, Montréal, QC, Canada.
Philippe
P
Major
CHU Ste-Justine Research Center, Montréal, QC, Canada.
Inge A
IA
Meijer
Department of Pediatrics and CHU Ste-Justine Research Center, Montréal, QC, Canada.
Emmanuelle
E
Lemyre
Department of Neurosciences, Université de Montréal, Montréal, QC, Canada, CHUM, Montréal, QC, Canada.
Patrick
P
Cossette
Department of Pediatrics, University of Washington, Seattle, WA, USA and.
Heather C
HC
Mefford
Department of Neurosciences, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
Guy A
GA
Rouleau
Department of Pediatrics and Department of Neurosciences, Université de Montréal, Montréal, QC, Canada, CHU Ste-Justine Research Center, Montréal, QC, Canada, elsa.rossignol@umontreal.ca.
Elsa
E
Rossignol
D002675:Child, Preschool; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002877:Chromosomes, Human / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology; D058670:Tetrasomy