Zeng Feier, Liu Huan, Xia Xuyang, Shu Yang, Cheng Wei, Xu Heng, Yin Geng, Xie Qibing
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Front Genet. 2022 May 20;13:814786. doi: 10.3389/fgene.2022.814786. eCollection 2022.
Brachydactyly type A1 (BDA1) is an autosomal dominant inherited disease characterized by the shortness/absence of the middle phalanges, which can be induced by mutations in the Indian hedgehog gene (). Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by joint destruction, synovitis, and the presence of autoantibodies. In this study, the proband was diagnosed with both BDA1 and RA. We performed whole-exome sequencing in a four-generation Chinese family to investigate their inherited causal mutation to BDA1. A novel in-frame insertion variant in : NM_002,181.4: c.383_415dup/p.(R128_H138dup) was identified in the BDA1 pedigree. This insertion of 11 amino acids was located in the highly conserved amino-terminal signaling domain of and co-segregated with the disease status. This adds one to the total number of different mutations found to cause BDA1. Moreover, we found a potential causal germline variant in for a molecular biomarker of RA (i.e., a high level of anti-cyclic citrullinated peptide). Collectively, we identified novel variants in for inherited BDA1, which highlights the important role of this gene in phalange development.
A1型短指症（BDA1）是一种常染色体显性遗传病，其特征为中节指骨短小或缺如，可由印度刺猬基因（）突变诱发。类风湿关节炎（RA）是一种慢性全身性自身免疫病，特征为关节破坏、滑膜炎及自身抗体的存在。在本研究中，先证者被诊断同时患有BDA1和RA。我们对一个四代中国家系进行了全外显子组测序，以探究其BDA1的遗传致病突变。在BDA1家系中鉴定出一个新的框内插入变异：NM_002,181.4:c.383_415dup/p.(R128_H138dup)。这11个氨基酸的插入位于的高度保守的氨基末端信号域，且与疾病状态共分离。这使已发现的导致BDA1的不同突变总数增加了一个。此外，我们发现了一个潜在的致病种系变异，可作为RA的分子生物标志物（即高水平的抗环瓜氨酸肽）。总体而言，我们鉴定出了导致遗传性BDA1的新变异，这凸显了该基因在指骨发育中的重要作用。
