Abstract：
Arthrogryposis is a clinical feature defined by congenital joint contractures in two or more different body areas which occurs in between 1/3000 and 1/5000 live births. Variants in multiple genes have been associated with distal arthrogryposis syndromes. Heterozygous variants in MYH3 have been identified to cause the dominantly-inherited distal arthrogryposis conditions, Freeman-Sheldon syndrome, Sheldon-Hall syndrome, and multiple pterygium syndrome. In contrast, MYH3 variants underlie both dominantly and recessively inherited Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterized by extensive bony abnormalities in addition to congenital contractures. Here we report two affected sibs with distal arthrogryposis born to unaffected, distantly related parents. Sequencing revealed that both sibs were homozygous for two ultra-rare MYH3 variants, c.3445G>A (p.Glu1149Lys) and c.4760T>C (p.Leu1587Pro). Sequencing and deletion/duplication analysis of 169 other arthrogryposis genes yielded no other compelling candidate variants. This is the first report of biallelic variants in MYH3 being implicated in a distal arthrogryposis phenotype without the additional features of CPSFS. Thus, akin to CPSFS, both dominant and recessively inherited distal arthrogryposis can be caused by variants in MYH3.
摘要：
关节病是一种临床特征，由两个或多个不同身体区域的先天性关节挛缩定义，发生在1/3000至1/5000活产中。多个基因的变异与远端关节炎综合征有关。MYH3中的杂合变体已被鉴定为导致显性遗传的远端关节病，Freeman-Sheldon综合征,Sheldon-Hall综合征,和多发性翼状胬肉综合征.相比之下,MYH3变体是显性和隐性继承的挛缩的基础，翼状突起,和脊椎腕骨融合综合征（CPSFS），其特征是除先天性挛缩外还存在广泛的骨异常。在这里，我们报告了两个受影响的同胞，其远端关节病生来未受影响，远亲的父母。测序显示，两个同胞都是纯合的两个超稀MYH3变体，c.3445G>A（p。Glu1149Lys）和c.4760T>C（p。Leu1587Pro）。对169个其他节理基因的测序和缺失/重复分析未产生其他令人信服的候选变体。这是有关MYH3中的双等位基因变体与远端关节病表型有关的第一份报告，而没有CPSFS的其他特征。因此，类似于CPSFS，显性和隐性遗传的远端关节病均可由MYH3变异引起。
