To investigate the molecular basis of muscle disease and gnathodiaphyseal dysplasia (GDD) in a large kindred with 11 (6 women and 5 men) affected family members.

We performed clinical assessment of 3 patients and collected detailed clinical and family history data on 8 additional patients. We conducted molecular genetic analyses on 5 patients using comprehensive neuromuscular disorder panels, exome sequencing (ES), and targeted testing for specific genetic variants. We analyzed the segregation of the muscle and bone phenotypes with the underlying molecular cause.

The unique clinical presentation of recurrent episodes of rhabdomyolysis associated with muscle cramps, hyperCKemia, muscle hypertrophy, with absent or mild muscle weakness, as well as cemento-osseous lesions of the mandible, with or without bone fractures and other skeletal abnormalities, prompted us to look for the underlying molecular cause of the disorder in this kindred. Molecular testing revealed a missense variant in anoctamin 5 (ANO5) designated as c.1538C>T; p.Thr513Ile, which was previously described in a large kindred with GDD. In silico analysis, searching publicly available databases, segregation analysis, as well as functional studies performed by another group provide strong evidence for pathogenicity of the variant. ES data in the proband excluded the contribution of additional genetic factors.

This report described the coexistence of muscle and bone phenotypes in the same patients with ANO5-related disorder. Our data challenge recent results that suggested complete dichotomy of these phenotypes and the proposed loss-of-function and gain-of-function mechanisms for the skeletal and muscle phenotypes, respectively.

在一个有 11 名（6 名女性和 5 名男性）受累家庭成员的大型亲属中调查肌肉疾病和颌骨发育不良 (GDD) 的分子基础。

我们对 3 名患者进行了临床评估，并收集了另外 8 名患者的详细临床和家族史数据。我们使用综合神经肌肉疾病组、外显子组测序 (ES) 和针对特定遗传变异的靶向测试对 5 名患者进行了分子遗传分析。我们分析了肌肉和骨骼表型与潜在分子原因的分离。

与肌肉痉挛、高CK血症、肌肉肥大、无或轻度肌肉无力以及下颌骨牙骨质病变、伴有或不伴有骨折和其他骨骼异常相关的横纹肌溶解症反复发作的独特临床表现促使我们寻找这种疾病的潜在分子原因。分子测试揭示了 anoctamin 5 ( ANO5 ) 中的错义变体，称为 c.1538C>T；p.Thr513Ile，之前在 GDD 的一个大家族中描述过。在计算机分析中，搜索公开可用的数据库、分离分析以及另一组进行的功能研究为变异的致病性提供了强有力的证据。先证者的 ES 数据排除了其他遗传因素的影响。

该报告描述了 ANO5 相关疾病患者同时存在肌肉和骨骼表型。我们的数据挑战了最近的结果，这些结果表明这些表型的完全二分法以及骨骼和肌肉表型分别提出的功能丧失和功能获得机制。