A novel pathogenic deletion in ISPD causes Walker-Warburg syndrome in a Chinese family

• Published in: Genes & genomics Vol. 45; no. 3; pp. 359 - 365
• Main Authors: Shi, Yuting, Fu, Yimei, Tao, Zhouteng, Yong, Wenjing, Peng, Huirong, Jian, Wenyang, Chen, Gang, Guo, Manhui, Zhao, Yanhua, Yao, Ruojin, Guo, Dewei
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.03.2023; Springer; Springer Nature B.V; 한국유전학회
• Subjects: Animal Genetics and Genomics; Biomedical and Life Sciences; C-Terminus; Chromosomes; Congenital defects; Cord blood; Cytoplasm; DNA microarrays; Dysplasia; East Asian People; Electrostatic properties; Exons; Female; Fetus; Fetuses; Force and energy; Gene deletion; Genetic analysis; Genetic aspects; Genetic disorders; Homozygote; Human Genetics; Humans; Hydrocephalus; Hydrocephalus - genetics; Karyotypes; Life Sciences; Localization; Male; Microbial Genetics and Genomics; Muscular dystrophy; Mutants; Mutation; Plant Genetics and Genomics; Pregnancy; Prenatal Diagnosis; Research Article; Sequence Deletion; Umbilical cord; Walker-Warburg Syndrome - diagnosis; Walker-Warburg Syndrome - genetics; Walker-Warburg Syndrome - pathology; 생물학; Congenital hydrocephalus; Mutation; Exome sequencing; Walker-Warburg syndrome; ISPD
• ISSN: 1976-9571; 2092-9293
• DOI: 10.1007/s13258-022-01296-z

Background Walker-Warburg syndrome (WWS) is a genetically heterogeneous disease that often presents with complex brain and eye malformations and congenital muscular dystrophy. Mutations of the ISPD gene have been identified as one of the most frequent causes of WWS. Objective The current study aimed to identify the cause of severe congenital hydrocephalus and brain dysplasia in our subject. Methods Genomic DNA was extracted from the fetus's umbilical cord blood and peripheral venous blood of the parents. The genetic analysis included whole-exome sequencing and qPCR. Additionally, in silico analysis and cellular experiments were performed. Results We identified a novel homozygous deletion of exons 7 to 9 in the ISPD gene of the fetus with WWS. In silico analysis revealed a defective domain structure in the C-terminus domain of the ISPD. Analysis of the electrostatic potential energy showed the formation of a new binding pocket formation on the surface of the mutant ISPD gene (ISPD-del ex7-9). Cellular study of the mutant ISPD revealed a significant change in its cellular localization, with the ISPD-del ex7-9 protein translocating from the cytoplasm to the nucleus compared to wild-type ISPD , which is mostly present in the cytoplasm. Conclusion The present study expands the mutational spectrum of WWS caused by ISPD mutations. Importantly, our work suggests that whole-exome sequencing could be considered as a diagnostic option for fetuses with congenital hydrocephalus and brain malformations when karyotype or chromosomal microarray analysis fails to provide a definitive diagnosis.