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

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.

研究提示，自闭症谱系障碍（Autism Spectrum Disorder, ASD）多发家系中的罕见遗传性变异在ASD的遗传病因学中发挥重要作用。为进一步探究罕见遗传性变异的作用，我们对2个各包含3名受累同胞的家系开展了全外显子组测序（Whole-Exome Sequencing, WES）。本研究还针对日本人群开展了两阶段随访病例-对照研究。对6名受累同胞进行全外显子组测序后，共鉴定出6种全新的罕见错义变异。在上述变异中，CLN8 R24H在1个家系中由3名受累同胞从患病父亲处继承获得，因此与ASD共分离。在随访研究的第一阶段，我们对241名患者与667名对照（新潟队列）中经全外显子组测序鉴定出的6种全新罕见错义变异进行了基因分型。仅CLN8 R24H在患者中的突变等位基因频率（1/482）高于对照人群（1/1334）。在第二阶段，我们对该变异进行了进一步基因分型，但在309名患者与350名对照（名古屋队列）中未检测到该变异。合并新潟与名古屋队列样本后，未发现显著关联（优势比=1.8，95%置信区间=0.1~29.6）。上述结果表明，CLN8 R24H至少在部分自闭症谱系障碍患者中参与了ASD的遗传病因过程。