The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
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DOI：
10.1016/j.ajhg.2019.05.015
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发表时间：
2019-07-03
影响因子：
9.8
通讯作者：
Lupski, James R.
中科院分区：
文献类型：
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作者：
Pehlivan, Davut;Bayram, Yavuz;Lupski, James R.
关节弯曲是一种临床发现，在超过400种孟德尔疾病中作为神经肌肉疾病的特征或全身性疾病的一部分存在。由于遗传和表型的异质性，潜在的分子病因学在很大程度上仍然未知。我们应用外显子组测序（ES）在一个队列的89个家庭的临床症状关节弯曲。其他分子技术，包括阵列比较基因组杂交（aCGH）和液滴数字PCR（ddPCR）进行的个人谁被发现有致病性拷贝数变异（CNVs）和嵌合体，分别。65.2%（58/89）的家系建立了分子诊断。58个家庭中有11个（19.0%）表现出在一个以上的基因座致病变异的潜在参与的证据，可能是由于缺乏杂合性（AOH）的负担，由于身份的血统（IBD）。RYR 3、MYOM 2、ERGIC 1、SPTBN 4和ABCA 7代表在两个或多个家族中鉴定的基因，其突变可能是关节弯曲症的病因。我们还提供了证据表明，CNVs参与关节弯曲的病因学，以及同一基因中的单等位基因和双等位基因变体引起相似或不同的综合征。我们能够在20个接受再分析的家庭中确定9个的分子病因。总之，我们的数据从家庭为基础的ES进一步描绘的分子病因学关节弯曲，产生了几个候选的疾病相关基因，并提供证据的突变负担的生物途径或网络。我们的研究还强调了重新分析未解决的诊断与测序大家庭成员的个人的重要性。
Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.