Jia Hongshuai, Ma Tiantian, Liu Ziqin, Ouyang Yuru, Hao Chunsheng
Department of Urology, Capital Institute of Pediatrics, Beijing, China.
Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Transl Pediatr. 2021 May;10(5):1377-1385. doi: 10.21037/tp-21-26.
Aarskog-Scott syndrome (AAS) is most commonly inherited as an X-linked recessive genetic disease caused by mutations. AAS patients are most frequently male, and the clinical manifestations of facial abnormalities, skeletal deformities, and abnormal genitalia comprise a characteristic triad of diagnostic features. The results on the clinical and molecular analysis of a family that reveals a novel gene frameshift mutation in an 11-year-old boy displaying bilateral cryptorchidism associated with hypogonadism are reported here. This patient exhibited a characteristic triad of diagnostic features of ASS, including short stature, facial abnormalities, joint laxity, and typical scrotal fold. Whole-exome sequencing revealed the novel hemizygous mutation c.500delA in exon 3 of the patient's gene, resulting after a frameshift in the Tyr167 residue, while his mother is heterozygous of the same variant. Further in silico studies were performed to identify the pathological consequence of this gene mutation. Thus, our study shows that frameshifts disrupting the RhoGEF gene domain of represent the most prevalent causal mutations underlying AAS and expand the phenotypic and mutational spectra of this disease. Improved understanding of the phenotypic and pathological heterogeneity accompanying mutation can greatly enhance the clinical prognostic capabilities in the future and aid genetic counseling for AAS patients.
阿斯克格-斯科特综合征（AAS）最常见的遗传方式是由突变引起的X连锁隐性遗传病。AAS患者以男性居多，其临床表现为面部异常、骨骼畸形和生殖器异常，构成了具有诊断特征的典型三联征。本文报道了一个家庭的临床和分子分析结果，该家庭中一名11岁男孩出现双侧隐睾并伴有性腺功能减退，发现了一种新的基因移码突变。该患者表现出AAS诊断特征的典型三联征，包括身材矮小、面部异常、关节松弛和典型的阴囊褶皱。全外显子测序显示患者基因外显子3中存在新的半合子突变c.500delA，导致第167位酪氨酸残基发生移码，而其母亲为同一变异的杂合子。进一步进行了计算机模拟研究以确定该基因突变的病理后果。因此，我们的研究表明，破坏RhoGEF基因结构域的移码突变是AAS最常见的致病突变，并扩展了该疾病的表型和突变谱。对伴随突变的表型和病理异质性的更好理解可以极大地提高未来的临床预后能力，并有助于为AAS患者提供遗传咨询。
