A novel compound heterozygous mutation in CFTR causing congenital bilateral absence of the vas deferens in a Chinese pedigree

Abstract Cystic fibrosis (CF) is an autosomal recessive disorder rarely found in Asian populations. Most males with CF are infertile because of obstructive azoospermia (OA) caused by congenital bilateral absence of the vas deferens (CBAVD). Compound heterozygous mutations of cystic fibrosis transmembrane conductance regulator (CFTR) are among the most common pathogenic factors in CBAVD. However, few genealogical analyses have been performed. In this study, whole-exome sequencing and co-segregation analysis were performed in a Chinese pedigree involving two siblings with CBAVD. Moreover, in vitro functional assays were used to analyze the pathogenicity of a novel CFTR mutation. We identified a novel compound heterozygous mutation of CFTR comprising the known disease-causing variant c.1210-11T > G (also known as IVS9‐5T) and c.2144delA;p.q715fs in two siblings with CBAVD. To verify the effects in vitro, we transfected vectors expressing wild-type and mutated CFTR into 293T cells. The results showed that the CFTR protein containing the frameshift mutation (c.2144delA) was 60 kD smaller. With testicular sperm aspiration/intracytoplasmic sperm injection-embryo transfer (TESA/ICSI-ET), both CBAVD patients fathered healthy offspring. Our study revealed that this novel compound heterozygous mutation is involved in CBAVD, expanding the known CFTR gene mutation spectrum of CBAVD patients and providing more evidence that compound heterozygous mutations can cause familial CBAVD.