Department of Otolaryngology Head and Neck Surgery, General Hospital of Central Theater Command, Wuhan, China.
Institute of Rare Diseases, Sichuan University West China Hospital, Chengdu, China.
Mol Genet Genomic Med. 2022 May;10(5):e1933. doi: 10.1002/mgg3.1933. Epub 2022 Mar 25.
Analyze the clinical and genetic characteristics of a rare Chinese family with Multiple synostoses syndrome and identify the causative variant with the high-throughput sequencing approach.
The medical history investigation, physical examination, imaging examination, and audiological examination of the family members were performed. DNA samples were extracted from the family members. The candidate variant was identified by performing whole-exome sequencing of the proband, then verified by Sanger sequencing in the family.
The family named HBSY-018 from Hubei province had 18 subjects in three generations, and six subjects were diagnosed with conductive or mixed hearing loss. Meanwhile, characteristic features including short philtrum, hemicylindrical nose, and hypoplastic alae nasi were noticed among those patients. Symptoms of proximal interdigital joint adhesion and inflexibility were found. The family was diagnosed as Multiple synostoses syndrome type 1 (SYNS1).The inheritance pattern of this family was autosomal dominant. A novel mutation in the NOG gene c.533G>A was identified by performing whole-exome sequencing of the proband. The substitution of cysteine encoding 178th position with tyrosine (p.Cys178Tyr) was caused by this mutation, which was conserved across species. Co-segregation of disease phenotypes was demonstrated by the family verification.
The family diagnosed as SYNS1 was caused by the novel mutation (c.533G>A) of NOG. The combination of clinical diagnosis and molecular diagnosis had improved the understanding of this rare disease and provided a scientific basis for genetic counseling in the family.
分析一个罕见的中国多发性颅缝早闭综合征家系的临床和遗传特征，并采用高通量测序方法鉴定致病变异。
对家系成员进行病史调查、体格检查、影像学检查和听力学检查，提取家系成员的 DNA 样本。对先证者进行全外显子组测序，鉴定候选变异，然后在家系中进行 Sanger 测序验证。
来自湖北的 HBSY-018 家系共 18 人，三代人中有 6 人被诊断为传导性或混合性听力损失。同时，这些患者还存在短人中、半圆柱状鼻和鼻翼发育不全等特征性表现。近端指间关节黏连和活动度受限的症状也可见到。该家系被诊断为多发性颅缝早闭综合征 1 型（SYNS1）。该家系的遗传方式为常染色体显性遗传。通过对先证者进行全外显子组测序，发现了一个 NOV 基因 c.533G>A 的新突变。该突变导致第 178 位的半胱氨酸编码突变为酪氨酸（p.Cys178Tyr），该突变在物种间是保守的。通过家系验证，证实了疾病表型的共分离。
该家系诊断为 SYNS1，是由 NOV 基因的新突变（c.533G>A）引起的。临床诊断和分子诊断的结合提高了对这种罕见疾病的认识，并为家系中的遗传咨询提供了科学依据。
