Whole Exome Sequencing with Comprehensive Gene Set Analysis Identified a Biparental-Origin Homozygous c.509G>A Mutation in PPIB Gene Clustered in Two Taiwanese Families Exhibiting Fetal Skeletal Dysplasia during Prenatal Ultrasound

Abstract

Skeletal dysplasia (SD) is a complex group of bone and cartilage disorders often detectable by fetal ultrasound, but the definitive diagnosis remains challenging because the phenotypes are highly variable and often overlap among different disorders. The molecular mechanisms underlying this condition are also diverse. Hundreds of genes are involved in the pathogenesis of SD, but most of them are yet to be elucidated, rendering genotyping almost infeasible except those most common such as fibroblast growth factor receptor 3 (FGFR3), collagen type I alpha 1 chain (COL1A1), collagen type I alpha 2 chain (COL1A2), diastrophic dysplasia sulfate transporter (DTDST), and SRY-box 9 (SOX9). Here, we report the use of trio-based whole exome sequencing (trio-WES) with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy. A biparental-origin homozygous c.509G>A(p.G170D) mutation in peptidylprolyl isomerase B (PPIB) gene was identified. The results support a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirm that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies (e.g., SD), especially in cases suggesting autosomal recessive inheritance. Moreover, the finding of an identical PPIB mutation in two non-consanguineous families highlights the possibility of the founder effect, which deserves future investigations in the Taiwanese population.

Hydrops in first trimester as unreported prenatal finding of dyssegmental dysplasia confirmed by exome sequencing

“…This report describes the prenatal findings of the rare disease of DDSH and shows that the application of WES to heterogeneous diseases, such as SD, enables the discovery of underlying genetic defects. Of note, the homozygous HSPG2 mutation detected may imply a founder effect in the Taiwanese population, which we noted previously in several monogenic diseases such as autosomal recessive renal tubular dysgenesis, osteogenesis imperfecta Type IX and aromatic L‐amino acid decarboxylase deficiency 6 .…”

Editorial: Emerging New Tests and Their Impact Upon the Practice of Reproductive Genetics

“…Notably, a few earlier reports from Taiwan had pointed out that the mutant allele c.857-619_1269 + 243delinsTTGCCTTGC of the AGT gene is very likely to be a founder variant in the Chinese population, which may aid in the prompter identification of the molecular pathology in that rapid trio-WEs case (Ma et al, 2019;Tseng et al, 2020). Such founder effect alleles are not uncommon in the Chinese population and had been reported previously at other inherited disorders such as the c.509G > A/p.G170D mutation of the PPIB gene causing the osteogenesis imperfecta IX in the Chinese population, and the way to estimate the mutation dating was also reported (Chang et al, 2020;Zhu et al).…”

A Founder Pathogenic Variant of PPIB Unique to Chinese Population Causes Osteogenesis Imperfecta IX

“…Shared haplotype was delineated by identifying the homozygous SNPs surrounding the pathogenic variant detected in the proband. We included data reported in patients from the Taiwan region ( Chang et al, 2020 ) as well as the SNP data of the 11 carriers found in the Chinese cohort. The founder effect was identified by taking individuals without the c.509G > A variant from the Chinese WES cohort as control.…”

“…Jiang et al reported the first Chinese OI-IX case with a compound heterozygous variant in PPIB ( Jiang et al, 2017 ). Chang et al reported two fetuses with a homozygous PPIB variant (c.509G > A/p.G170D) from the Taiwan region) ( Chang et al, 2020 ).…”