Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin
Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin
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DOI：
10.1172/jci84457
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发表时间：
2016-02-01
影响因子：
15.9
通讯作者：
Lupski, James R.
中科院分区：
文献类型：
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作者：
Bayram, Yavuz;Karaca, Ender;Lupski, James R.
背景。关节挛缩被定义为 2 个或多个身体部位的先天性关节挛缩，是一种临床体征，而不是特定的疾病诊断。迄今为止，已描述了超过 400 种与关节弯曲有关的不同疾病，并且超过 220 个基因的变异与这些疾病相关。然而，在绝大多数这些病例中，潜在的分子病因学仍然未知。方法。我们对来自 48 个不同家族的 52 名具有关节弯曲临床表现的患者进行了全外显子组测序 (WES)。 结果。来自 17 个家族的受影响个体 (35.4%) 存在已知关节弯曲相关基因的变异，包括胆碱能 γ 烟碱受体 (CHRNG，6 名受试者) 和内皮素转换酶样 1 (ECELI，4 名受试者) 的纯合变异。在 3 个家族 (6.2%) 中鉴定出候选关节弯曲病致病基因（原纤维蛋白 3 [FBN3]、肌球蛋白 IXA [MY09A] 以及含有 3 [PSD3] 的 pleckstrin 和 Sec7 结构域）的有害变异。此外，在关节弯曲相关基因中具有纯合突变的 8 个家族中，我们在候选基因（肌球蛋白结合蛋白 C，快速型（MYBPC2] 和液泡蛋白分选 8 [VPS8]，2 个家族，4.2%）或另一个疾病相关基因（6 个家族，12.5%）中鉴定出具有纯合或复合杂合变异的第二个位点，表明潜在的突变负担有助于结论：在 58.3% 的家族中，关节弯曲的表现可以通过分子诊断来解释；然而，这 20 个不相关的受试者中只有 5 个的临床表现与肌营养不良症一致；我们的结果表明，更多地使用全基因组技术将为更好地了解疾病的遗传模型和分子机制提供机会。这项工作得到了美国国家人类基因组研究所 (NHGRI)/国家心肺和血液研究所 (NHLBI) 向贝勒-霍普金斯孟德尔基因组学中心拨款 U54HG006542 和美国国家神经疾病和中风研究所 (NINDS) 向 J.R. Lupski 拨款 RO1NS058529 的部分支持。
BACKGROUND. Arthrogryposis, defined as congenital, joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases.METHODS. We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families.RESULTS. Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic gamma nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECELI, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MY09A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type (MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression.CONCLUSION. In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis.FUNDING. This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant RO1NS058529 to J.R. Lupski.