Novel autosomal recessive SINO syndrome-associated KIDINS220 variants provide insight into the genotype-phenotype correlation
Wenke Yang,
Shuyue Wang,
Xiaodong Huo,
Ke Yang,
Zhenglong Guo,
Yanjun Li,
Xinying Ji,
Bingtao Hao,
Shixiu Liao
Affiliations
Wenke Yang
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; School of Basic Medical Sciences, Henan University, Kaifeng, China
Shuyue Wang
Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China; Central Hospital of Wuhan, Wuhan, China
Xiaodong Huo
Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China
Ke Yang
Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China
Zhenglong Guo
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
Yanjun Li
Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, China
Xinying Ji
School of Basic Medical Sciences, Henan University, Kaifeng, China; Corresponding author. School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China.
Bingtao Hao
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
Shixiu Liao
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; Corresponding author. Henan Provincial People's Hospital, People's Hospital of Henan University, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China.
Background: KIDINS220 encodes a transmembrane scaffold protein, kinase D-interacting substrate of 220 kDa, that regulates neurotrophin signaling. Variants in KIDINS220 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 KIDINS220 variants. Methods: We performed whole-exome sequencing on a patient with SINO syndrome and epilepsy. Identified pathogenic variants were confirmed using Sanger sequencing and evaluated with in silico 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 KIDINS220 variants. Results: We identified novel compound heterozygous variants in KIDINS220, c.1556C > T (p.Thr519Met) and c.2374C > T (p.Arg792*), in the patient. Our analysis revealed that biallelic loss-of-function variants in KIDINS220 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. Conclusions: Our study expands the spectrum of KIDINS220 variants associated with AR-SINO and provides a valuable genotype-phenotype correlation for pathogenic KIDINS220 variants.
