Report of new variants in PPIL1 underlying type 14 pontocerebellar hypoplasia and their associated phenotypic manifestations in two fetuses

• Published in: American journal of medical genetics. Part A 2023-08, Vol.191 (8), p.2193-2197
• Main Authors: Zhang, Yuxin, Yan, Lulu, Xie, Min, Xue, Jiangyang, Yang, Xumian, Xue, Yongming, Tian, Liyun, Li, Haibo
• Format: Article
• Language: English
• Subjects: Bioinformatics; Dysplasia; Fetuses; heterozygous missense mutations; Hydrogen bonding; Hypoplasia; Missense mutation; Mutation; pontocerebellar hypoplasia; PPIL1; whole‐exome sequencing
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.63238

Mutations in the PPIL1 gene have been linked to type 14 pontocerebellar hypoplasia (PCH14); however, prenatal clinical characteristics of PCH14 caused by mutations in the PPIL1 gene have not been reported. This study reports the first prenatal case of PCH14 diagnosed by whole‐exome sequencing (WES). Two fetuses with severe microcephaly and cerebral dysplasia, along with their parents, underwent WES. The effects of the discovered PPIL1 variants on PPIL1 protein function were investigated using bioinformatics tools. WES revealed two compound heterozygous missense mutations in PPIL1, c.376C > G (p.His126Asp) and c.392G > T (p.Arg131Leu), inherited from the mother and father, respectively. The co‐segregation of PPIL1 mutations in this family was confirmed using Sanger sequencing, identifying two PCH14‐affected fetuses. Bioinformatics analysis revealed that these mutations could disrupt the formation of hydrogen bonds, altering the structural stability of the PPIL1 protein. This study is the first to define the clinical characteristics of PCH14 during pregnancy and reports a novel heterozygous missense variant, expanding the PCH14‐related mutational spectrum of PPIL1.