Yang Wenke, Wang Shuyue, Huo Xiaodong, Yang Ke, Guo Zhenglong, Li Yanjun, Ji Xinying, Hao Bingtao, Liao Shixiu
Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China.
National Health Commission Key Laboratory of Birth Defects Prevention, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Zhengzhou, China.
Heliyon. 2024 Sep 2;10(17):e37355. doi: 10.1016/j.heliyon.2024.e37355. eCollection 2024 Sep 15.
encodes a transmembrane scaffold protein, kinase D-interacting substrate of 220 kDa, that regulates neurotrophin signaling. Variants in have been linked to spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome or prenatal fatal cerebral ventriculomegaly and arthrogryposis (VENARG). This study aimed to investigate the genotype-phenotype correlation of pathogenic variants.
We performed whole-exome sequencing on a patient with SINO syndrome and epilepsy. Identified pathogenic variants were confirmed using Sanger sequencing and evaluated with tools. A comprehensive literature review was conducted to analyze the genetic and phenotypic data of both the newly diagnosed patient and previously reported cases with variants.
We identified novel compound heterozygous variants in , c.1556C > T (p.Thr519Met) and c.2374C > T (p.Arg792*), in the patient. Our analysis revealed that biallelic loss-of-function variants in are associated with VENARG or autosomal recessive SINO (AR-SINO), whereas carboxy-terminal truncated variants that escape nonsense-mediated mRNA decay and lack amino acid residues 1507-1529 are linked to autosomal dominant SINO (AD-SINO). Patients with AR-SINO exhibit more severe clinical features compared to those with AD-SINO.
Our study expands the spectrum of variants associated with AR-SINO and provides a valuable genotype-phenotype correlation for pathogenic variants.
编码一种跨膜支架蛋白，即220 kDa的激酶D相互作用底物，其可调节神经营养因子信号传导。该基因的变异与痉挛性截瘫、智力残疾、眼球震颤和肥胖（SINO）综合征或产前致命性脑室扩大和关节挛缩（VENARG）有关。本研究旨在调查致病性该基因变异的基因型-表型相关性。
我们对一名患有SINO综合征和癫痫的患者进行了全外显子组测序。使用桑格测序法确认鉴定出的致病性变异，并使用相关工具进行评估。进行了全面的文献综述，以分析新诊断患者和先前报道的该基因变异病例的遗传和表型数据。
我们在该患者中鉴定出该基因的新型复合杂合变异，即c.1556C>T（p.Thr519Met）和c.2374C>T（p.Arg792*）。我们的分析表明，该基因的双等位基因功能丧失变异与VENARG或常染色体隐性SINO（AR-SINO）相关，而逃避无义介导的mRNA衰变且缺乏氨基酸残基1507-1529的羧基末端截短变异与常染色体显性SINO（AD-SINO）相关。与AD-SINO患者相比，AR-SINO患者表现出更严重的临床特征。
我们的研究扩展了与AR-SINO相关的该基因变异谱，并为致病性该基因变异提供了有价值的基因型-表型相关性。
