Institute of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Orthopedics, Heping Hospital Attached to Changzhi Medical College, Changzhi, China.
Bone. 2022 Oct;163:116508. doi: 10.1016/j.bone.2022.116508. Epub 2022 Jul 28.
Diagnosis of rare skeletal diseases is based primarily on clinical phenotype and radiographic analysis. Genetic etiology of these heterogeneous diseases remains largely unknown. Here, we report the identification of two genomic mutations using exome sequencing from patients with multiple epiphyseal dysplasia (MED) of an unusual family in autosomal dominant and X-linked inheritance. A dominant mutation (c.2224G > A; p.Gly687Ser) in the known causal COL2A1 gene was identified in three patients with MED, deformed femoral heads and vertebral dysplasia. Furthermore, a hemizygous mutation (c.2830G > A; p.Ala944Thr) in the USP9X gene was identified in the fourth patient with short stature, MED, deformed femoral head, thoracic and lumbar platyspondyly, right ankle condyle dysplasia, and subchondral sclerosis. This is the first identification of an X-linked candidate causative gene in a patient with MED, suggesting a new clinical entity. Our findings shed a new light on the role of USP9X in MED-associated disorders.
罕见骨骼疾病的诊断主要基于临床表型和影像学分析。这些异质性疾病的遗传病因在很大程度上尚不清楚。在这里，我们报告了通过外显子组测序从常染色体显性遗传和 X 连锁遗传的不常见家族中的多发性骨骺发育不良（MED）患者中鉴定出的两个基因组突变。在三个具有 MED、变形股骨头和椎体发育不良的患者中鉴定出已知致病 COL2A1 基因中的显性突变（c.2224G>A;p.Gly687Ser）。此外，在第四位身材矮小、MED、变形股骨头、胸腰椎扁平椎、右踝关节软骨发育不良和软骨下硬化的患者中鉴定出 USP9X 基因的半合子突变（c.2830G>A;p.Ala944Thr）。这是在 MED 患者中首次鉴定出 X 连锁候选致病基因，提示一种新的临床实体。我们的发现为 USP9X 在与 MED 相关疾病中的作用提供了新的认识。
