title: Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population.
abstract: Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1-29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Psychiatry, Center for Transdisciplinary Research, Niigata University, Niigata, Japan.
authors: Jun
authors: J
authors: Egawa
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Division of Medical Education, Comprehensive Medical Education Center, School of Medicine, Faculty of Medicine, Niigata University, Niigata, Japan.
authors: Yuichiro
authors: Y
authors: Watanabe
authors: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Chenyao
authors: C
authors: Wang
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Emiko
authors: E
authors: Inoue
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Atsunori
authors: A
authors: Sugimoto
authors: Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors: Toshiro
authors: T
authors: Sugiyama
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Hirofumi
authors: H
authors: Igeta
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Oojima Hospital, Sanjo, Niigata, Japan.
authors: Ayako
authors: A
authors: Nunokawa
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Health Administration Center, Headquarters for Health Administration, Niigata University, Niigata, Japan.
authors: Masako
authors: M
authors: Shibuya
authors: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Itaru
authors: I
authors: Kushima
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Naoki
authors: N
authors: Orime
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Taketsugu
authors: T
authors: Hayashi
authors: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Takashi
authors: T
authors: Okada
authors: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Yota
authors: Y
authors: Uno
authors: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Norio
authors: N
authors: Ozaki
authors: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Toshiyuki
authors: T
authors: Someya
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D035781:Siblings