Department of Otolaryngology-Head and Neck Surgery, Chinese PLA Institute of Otolaryngology, Chinese PLA General Hospital, Medical School of Chinese PLA, 28 Fuxing Road, Beijing, 100853, China.
Centre of Clinical Aerospace Medicine, School of Aerospace Medicine, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi'an, 710032, Shanxi Province, China.
BMC Med Genomics. 2021 Jun 28;14(1):170. doi: 10.1186/s12920-021-01020-y.
Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses, and flattened vertebral bodies. COL2A1 has been confirmed as the pathogenic gene. Hearing loss represents an infrequent manifestation for 25-30% of patients with SEDC. The characteristics of the hearing impairment were rarely documented.
Audiological, ophthalmic, imaging examinations were conducted on the family members. The whole exome sequencing (WES) was performed to detect the candidate gene, and the Sanger sequencing was used to confirm the causative variation.
COL2A1 c.1510G>A (p.G504S), a hot spot variation, was identified as the disease-causing mutation of the Chinese Li nationality family with SEDC. This variation was co-segregated with the SEDC phenotype in the family and was absent in the 1000 Genomes Project, ESP and ExAC. Clinically, several manifestations were first demonstrated in SEDC patients caused by p.G504S, including sensorineural hearing loss, auditory ossicles deformity, retinal detachment, sacrum cracked and elbow and wrist joints deformity. Other classical SEDC manifestations such as bones and joints pain, midfacial dysplasia, disproportionate short stature, spinal deformity, thoracocyllosis, coxa arthropathy, myopia and waddling gait were also showed in the family patients.
We first identified the mutation p.G504S in COL2A1 gene as the pathogenesis in a Chinese Li nationality family and reported the correlation between p.G504S and atypical clinical phenotypes including sensorineural hearing loss, auditory ossicles deformity, retinal detachment, sacrum cracked and elbow and wrist joints deformity. Our findings would extend the phenotypic spectrum of SEDC and deepen clinicians' understanding of genotype-phenotype correlation of the disease.
先天性脊椎骨骺发育不良（SEDC）是一种常染色体显性遗传性软骨发育不良，其特征为不成比例的身材矮小、骨骺异常和扁平椎体。COL2A1 已被确认为致病基因。听力损失是 SEDC 患者 25-30%的罕见表现。听力障碍的特征很少有文献记录。
对家系成员进行了听力、眼科、影像学检查。进行了全外显子组测序（WES）以检测候选基因，并使用 Sanger 测序证实了致病变异。
确定了 COL2A1 c.1510G>A（p.G504S），这是一个热点变异，是一个中国李姓 SEDC 家系的致病突变。该变异在家系中与 SEDC 表型共分离，且不存在于 1000 基因组计划、ESP 和 ExAC 中。临床上，首次在 p.G504S 所致 SEDC 患者中发现了一些表现，包括感音神经性听力损失、听小骨畸形、视网膜脱离、骶骨裂和肘腕关节畸形。该家系患者还表现出其他典型的 SEDC 表现，如骨骼关节疼痛、面中部发育不良、不成比例的身材矮小、脊柱畸形、胸廓畸形、髋关节病、近视和鸭步。
我们首次在一个中国李姓家系中确定了 COL2A1 基因中的突变 p.G504S 为发病机制，并报告了 p.G504S 与非典型临床表型之间的相关性，包括感音神经性听力损失、听小骨畸形、视网膜脱离、骶骨裂和肘腕关节畸形。我们的发现扩展了 SEDC 的表型谱，并加深了临床医生对该疾病基因型-表型相关性的认识。
