虽然在许多家庭中孤独症的可遗传性很明显，但人们找到的可遗传突变并不多。这主要是因为孤独症相关突变非常多样，让人很难建立起清晰的遗传模式。此前人们鉴定了一些与孤独症有关的de novo拷贝数突变和点突变，现在，波士顿儿童医院的研究人员对大量中东地区和美国的孤独症家庭进行了全外显子组测序，发现一些涉及严重遗传学综合症的基因上带有会引发孤独症的隐性突变。文章于一月二十三日发表在Cell旗下的Neuron杂志上。
波士顿儿童医院的研究者们最初是在三个中东大家庭中寻找隐性致病突变，这些家庭中都有两个以上患有孤独症谱系障碍ASD的儿童。隐性致病突变意味着，当基因上两个等位基因都发生突变才会致病。
“在美国家庭中鉴定可遗传的致病突变并不理想，因为美国家庭的规模往往太小，”文章的资深作者Walsh说。这项研究中三个中东家庭的父母都是堂兄妹，这是中东地区的传统，这样的家庭大大有助于检测可遗传突变。研究人员在上述家庭中发现，从未与孤独症关联的三个基因上存在隐性突变。这些基因涉及了一些严重的遗传学综合症，这类综合症往往包括孤独症行为或智力缺陷，但并非是主要症状。
在此基础上，研究人员对163个中东地区的孤独症家庭进行了全外显子测序，发现在基因AMT、PEX7、SYNE1、VPS13B、PAH和POMGNT1上都存在双等位基因突变（biallelic mutation）。此后，他们又分析了612个美国孤独症家庭的全外显子测序数据，发现上述突变中的一些也同样存在于美国孤独症家庭。这些基因大多与一些代谢或遗传学综合症有关，其上的隐性突变比较温和，使蛋白部分丧失功能。
“这是首次将这些基因与孤独症联系起来，”文章的共同第一作者Chahrour说（另一位第一作者是Timothy W. Yu）。“一般检测方法难以发现AMT和PEX7上的这种隐性突变，只是在全外显子组测序时才浮出水面。”
同期Neuron杂志上还有另一项孤独症研究，麻省总医院和Broad研究所的研究人员在Mark Daly领导下，对933位患者的基因组和869例对照进行了外显子测序，以检测使基因功能完全丧失的隐性突变。
“这两项研究相互补充，共同说明了隐性突变对孤独症的重要性”Yu说。“基因组测序将大大帮助人们鉴别更多这类突变，因为用其他方法很难对许多罕见综合症进行这类分析。”
Using Whole-Exome Sequencing to Identify Inherited Causes of Autism
Timothy W. Yusend, Maria H. Chahrour, Tawfeg Ben-Omran, Ahmad S. Teebi, Lihadh Al-Gazali, Valsamma Eapen, Christine R. Stevens, Leonard Rappaport, Stacey B. Gabriel, Kyriacos Markianos, Matthew W. State, Michael E. Greenberg, Hisaaki Taniguchi, Nancy E. Braverman, Eric M. Morrow, Christopher A. Walsh
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
文献链接：Using Whole-Exome Sequencing to Identify Inherited Causes of Autism
Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders
Elaine T. Lim, Soumya Raychaudhuri, Stephan J. Sanders, Christine Stevens, Eric Boerwinkle, Joseph D. Buxbaum, Edwin H. Cook, Richard A. Gibbs, Gerard D. Schellenberg, James S. Sutcliffe, Bernie Devlin, Kathryn Roeder, Mark J. Daly
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.
