Preliminary Study On The Clinical And Genetic Causes Of Congenital Bilateral Absence Of Vas Deferens

Part 1:Analysis of the clinical features of 566 patients with congenital bilateral absence of the vas deferensObjective:To summarize the clinical characters in patients diagnosed with congenital bilateral absence of the vas deferens(CB AVD)in the Chinese population.Materials and Methods:This retrospective investigation was conducted from Jan 2005 to Jan 2016 at Peking Union Medical College Hospital in China,involving 566 patients with CBAVD.The patients’ history,reproductive outcomes,and clinical characteristics were studied.All analyses were performed by SPSS 18.0 software.Results:The average age of the enrolled 566 men was 30.6 years(ranged from20 to 53 years old)and the mean infertility duration was 4.9 years(ranged from 3 months to 23 years).Most patients had bilaterally normal-sized testes(84.28%,477/566),normal epididymis(lift side:527/566 and right side:530/566).Occurrence of varicocele was 9.4%(53/566).Average sperm volume and pH were 0.88 mL and 6.35,respectively.Mean reproductive hormonal levels(FSH,LH,PRL,E2 and T)were normal.Percent of absence of seminal vesicle or hypoplastic seminal vesicles was 70.5%(141/200).367 patients underwent percutaneous epididymal sperm aspiration(PESA)and 91.6%(336/367)of these acquired sperm samples qualified for intracytoplasmic sperm injection(ICSI)therapy.We identified that 425 ICSI cycles were performed,leading to 265 live births.The clinical pregnancy and live birth rates per ICSI cycle were 54.3%(231/425)and 48.0%(204/425),respectively.All of the offspring were healthy,based on an assessment of well-being and recordings of the telephone follow-up after they were born.Conclusions:Our findings confirmed that CBAVD patients have normal-sized testes and epididymis,lower sperm volume and pH level,normal reproductive hormonal levels,absent or hypoplastic seminal vesicles and may accompany with varicocele.PESA together with ICSI procedures are helpful for treating infertile men with CBAVD.Part 2:Identification of the new causal genes of congenital bilateral absence of the vas deferens by whole exome sequencingObjective:To identify new causal genes of congenital bilateral absence of the vas deferens(CB AVD)in the Chinese population by using whole exome sequencing.Materials and Methods:The clinical data of 18 patients diagnosed with CBAVD were enrolled at Peking Union Medical College Hospital between Apr 2016 and Oct 2016.We exome-sequenced all the patients and subsequently confirmed the mutations by Sanger sequencing.Results:In the present study,we identified 12 CFTR rare mutations.We exome-sequenced 9 unrelated CBAVD patients and found two missense variants(c.G1709A;p.C570Y and c.A2968G;p.K990E)in two patients,respectively.Both variants were predicted to be deleterious in silico and highly conserved.The p.C570Y variant was located in the GPS domain which is functionally necessary for autoproteolysis,while the p.K990E variant was in the N-terminal fragment that may regulate the activity of adhesion-GPCR.Conclusions:Whole exome sequencing is an effective technology to identify new causal genes of CBAVD.To the best of our knowledge,they are the first two ADGRG2 variant identified in Chinese CBAVD patients,which further validated the disease-causing role of ADGRG2 in the congenital defect.