BACKGROUND Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs. METHODS We performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases. RESULTS We identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs. CONCLUSIONS Disruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.

中文翻译：

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罕见拷贝数变化会影响神经发育障碍中的突触基因DMXL2。

背景技术超罕见的遗传变异，包括影响重要的剂量敏感性基因的非经常性拷贝数变异（CNV），是神经发育障碍（NDD）的病因的重要贡献者。将基于家族的全基因组测序（WGS）与详细的表型数据配对，可以实现NDD中的新型基因关联。方法我们对来自三代家庭的六名成员进行了WGS，其中三人各自具有一系列暗示NDD的特征。CNV和序列水平的变体已被识别，并在疾病和对照数据库中进行了进一步的研究。结果我们在15q21处发现了一个新的252kb缺失，该缺失与突触基因DMXL2和基因GLDN重叠。微缺失在受NDD影响的个体中分离。还发现了可能还涉及的其他罕见的遗传和从头序列序列变体，包括GRIK5中的错义变化。在具有一系列NDD的其他不相关个体中发现了影响DMXL2的多个CNV和功能丧失的序列变体。结论DMXL2的破坏可能导致包括自闭症谱系障碍在内的NDD。对私有变体的可靠解释需要采用多方面的方法，其中要包含多代谱系以及全基因组范围和人口规模的数据。