Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal‐recessive disorder and a distinctive type of osteopetrosis, characterized mainly by skeletal fractures and deformity, osteosclerosis, and sometimes hypotonia, developmental delay, and seizures. Sequence variants in the leucine‐rich repeat kinase 1 (LRRK1) gene underlying OSMD have been reported previously. In the present study, we investigated a 14‐year‐old girl suspected with OSMD in a consanguineous family of Iranian origin segregating the disease in an autosomal‐recessive manner. The patient had severe short stature, multiple sclerotic lesions, sandwich vertebrae, Erlenmeyer flask deformity, and looser zones. The multifocal active bony pathology suggested multifocal bony inflammation or multiple looser fractures. Whole‐exome sequencing followed by Sanger sequencing confirmation revealed a novel homozygous stop gain mutation (c.G2785T, p.E929X) in the LRRK1 gene. This is the first mutation in the LRRK1 gene, underlying OSMD, in the Iranian population and the third case worldwide. The mutation is located in the C terminal of the Roc domain, distinct from domains affected in the previous two LRRK1 mutations. Additionally, a new group of clinical indications different from the two previous cases is discussed.

中文翻译：

---

怀疑患有骨硬化干骺端发育不良的患者的新型纯合 LRRK1 停止增益突变

骨硬化干骺端发育不良 (OSMD) 是一种非常罕见的常染色体隐性遗传疾病，也是一种独特的骨硬化病类型，其主要特征是骨骼骨折和畸形、骨硬化，有时还会出现肌张力减退、发育迟缓和癫痫发作。之前已经报道了 OSMD 基础上的富含亮氨酸重复激酶 1 (LRRK1) 基因的序列变异。在本研究中，我们调查了一名怀疑患有 OSMD 的 14 岁女孩在伊朗血统的近亲家庭中以常染色体隐性方式分离疾病。患者有严重的身材矮小、多发性硬化病变、夹层椎骨、锥形瓶畸形和松弛区。多灶性活动性骨病理提示多灶性骨炎症或多处较松的骨折。全外显子组测序和 Sanger 测序确认揭示了 LRRK1 基因中一个新的纯合子停止增益突变（c.G2785T，p.E929X）。这是伊朗人群中 LRRK1 基因的第一个突变，也是 OSMD 的基础，也是全球第三个病例。该突变位于 Roc 域的 C 端，与前两个 LRRK1 突变中受影响的域不同。此外，还讨论了与前两个病例不同的一组新的临床适应症。