Abstract：
Arthrogryposis is a consequence of reduced fetal movements and arises due to environmental factors or underlying genetic defects, with extensive genetic heterogeneity. In many instances, the genes responsible are involved in neuromuscular function. Missense variants in the gene encoding embryonic myosin heavy chain (MYH3) usually cause distal arthrogryposis. Recently, mono-allelic or bi-allelic MYH3 variants have been associated with contractures, pterygia, and spondylocarpotarsal fusion syndrome 1 (CPSFS1A and CPSFS1B). Here we describe three fetuses presenting in the second trimester with a lethal form of arthrogryposis and pterygia and harbouring bi-allelic variants in MYH3. One proband was compound heterozygous for a missense change and an extended splice site variant, a second proband had a homozygous frameshift variant, and a third proband was homozygous for a nonsense variant. Minigene assays performed on the first fetus showed that the missense and extended splice site variants resulted in aberrant splicing, likely resulting in near complete loss of full-length MYH3 transcript. This study shows that loss of MYH3 is associated with a lethal arthrogryposis phenotype and highlights the utility of minigene assays to assess splicing.
摘要：
关节病是胎儿运动减少的结果，是由于环境因素或潜在的遗传缺陷而引起的。具有广泛的遗传异质性。在许多情况下,负责的基因与神经肌肉功能有关。编码胚胎肌球蛋白重链（MYH3）的基因中的错义变异通常会引起远端关节发育不良。最近,单等位基因或双等位基因MYH3变体与挛缩相关，翼状突起,和脊骨融合综合征1（CPSFS1A和CPSFS1B）。在这里，我们描述了三个在妊娠中期出现的胎儿，它们具有致命的节理和翼状突起，并在MYH3中具有双等位基因变体。一个先证是错义变化和扩展剪接位点变体的复合杂合，第二个先证者有纯合移码变体，第三个先证者是纯合的无义变体。对第一个胎儿进行的Minigene分析显示，错义和扩展的剪接位点变异导致异常剪接，可能导致全长MYH3转录物几乎完全丢失。这项研究表明，MYH3的丢失与致死性关节炎表型有关，并强调了小基因测定评估剪接的实用性。
