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Abstract：
Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3, encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype. Initial whole-exome sequencing (WES) showed that all five were heterozygous for one of two independent splice-site variants in MYH3. Despite evidence indicating that three of the five individuals shared two allelic haplotypes encompassing MYH3, no second variant could be located in the WES datasets. Subsequent genome sequencing of these three individuals demonstrated a variant altering a 5\' UTR splice donor site (rs557849165 in MYH3) not represented by exome-capture platforms. When the cohort was expanded to 16 SCTS-affected individuals without FLNB mutations, nine had truncating mutations transmitted by unaffected parents, and six inherited the rs557849165 variant in trans, an observation at odds with the population allele frequency for this variant. The rs557849165 variant disrupts splicing in the 5\' UTR but is still permissive of MYH3 translational initiation, albeit with reduced efficiency. Although some MYH3 variants cause dominant SCTS, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. These observations make genetic diagnosis challenging in the context of simplex presentations of the disorder.
摘要：
脊骨滑膜综合征（SCTS）的特征是椎间融合以及腕骨和骨的融合。FLNB的双等位基因突变在一些家庭中导致这种情况，而MYH3中编码胚胎重链肌球蛋白3的单等位基因变体与该疾病的主要遗传形式有关。这里,假设来自三个家庭的5名无FLNB突变的个体由于表型的同胞复发而受到隐性SCTS的影响.初始全外显子组测序(WES)显示,对于MYH3中的两个独立剪接位点变体之一,所有五个都是杂合的。尽管有证据表明五个个体中的三个共享包含MYH3的两个等位基因单倍型,但在WES数据集中没有第二变体。这三个个体的随后基因组测序显示了一种变体，该变体改变了外显子组捕获平台未代表的5'UTR剪接供体位点（MYH3中的rs557849165）。当队列扩展到16个没有FLNB突变的受SCTS影响的个体时，有9个突变是由未受影响的父母传播的，六个继承了rs557849165变体，与该变体的群体等位基因频率不一致的观察结果。rs557849165变体破坏5'UTR中的剪接，但仍允许MYH3翻译起始，尽管效率降低。尽管一些MYH3变体引起显性SCTS,这些数据表明其他(特别是截断变体)没有，除了在第二个低态等位基因的复合杂合性的情况下。这些观察结果使遗传诊断在该疾病的单纯形表现的背景下具有挑战性。
