De novo variants in sporadic cases of childhood onset schizophrenia.
Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes.
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Amirthagowri
A
Ambalavanan
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Simon L
SL
Girard
Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD, USA.
Kwangmi
K
Ahn
Department of Medicine, Université de Montréal, Montreal, QC, Canada.
Sirui
S
Zhou
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Alexandre
A
Dionne-Laporte
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Dan
D
Spiegelman
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Cynthia V
CV
Bourassa
Department of Medicine, Université de Montréal, Montreal, QC, Canada.
Julie
J
Gauthier
Department of Medicine, Université de Montréal, Montreal, QC, Canada.
Fadi F
FF
Hamdan
Department of Psychiatry, Université de Montréal, Montreal, QC, Canada.
Lan
L
Xiong
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Patrick A
PA
Dion
Department of Human Genetics, McGill University, Montreal, QC, Canada.|Department of Psychiatry, Douglas Mental Health University Institute, Montreal, QC, Canada.
Ridha
R
Joober
Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD, USA.
Judith
J
Rapoport
Department of Human Genetics, McGill University, Montreal, QC, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.|Montreal Neurological Institute and Hospital, Montreal, QC, Canada.
Guy A
GA
Rouleau
D002648:Child; D059472:Exome; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D039503:Integrin alpha6 / Q000235:genetics; D008297:Male; D009124:Muscle Proteins / Q000235:genetics; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D012561:Schizophrenia, Childhood / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics
C405493:GTF2IRD1 protein, human; C569436:Gpr153 protein, human; C588002:ITGA6 protein, human; D039503:Integrin alpha6; D009124:Muscle Proteins; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled; C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel; D015534:Trans-Activators; C095903:tau-tubulin kinase; D017346:Protein Serine-Threonine Kinases