A novel homozygous loss-of-function mutation in CCDC39 causes multiple morphological abnormalities of the sperm flagella in a primary ciliary dyskinesia patient

Abstract Research question Male infertility is one of the important symptoms in patients with primary ciliary dyskinesia (PCD). PCD-related male infertility is often caused by asthenozoospermia with barely normal sperm morphology. Multiple morphological abnormalities of the sperm flagella (MMAF) is a major cause of asthenozoospermia characterized by various malformed morphologies of sperm flagella. To date, a limited number of genes have been suggested to be involved in the pathogenesis of both PCD and MMAF. The physiological effects and molecular mechanisms of these genes remain unclear. Design Whole-exome sequencing (WES) was performed to identify the pathogenic mutation associated with MMAF in a PCD patient. Peripheral venous blood and semen sample of the PCD patient were collected. Transmission electron microscopy, immunofluorescence staining, and western blotting were conducted to confirm the pathogenicity of the identified mutation. Results A novel homozygous mutation, c.983 T>C (p. Leu328Pro), in CCDC39 was identified in two PCD affected siblings of a consanguineous family, showing a typical PCD phenotype, while the proband was infertile, which is associated with characterized MMAF. Furthermore, transmission electron microscopy revealed the abnormal ultrastructure in the patient's sperm flagella. Moreover, immunofluorescence staining revealed that CCDC39 was almost undetectable in the sperm, which was further confirmed by western blotting. Additionally, the outcome of intracytoplasmic sperm injection (ICSI) of the patient with the CCDC39 mutation was favorable. Conclusion This study demonstrates that a novel loss-of-function mutation of CCDC39 is the genetic cause of PCD and MMAF and initial reported that ICSI treatment has a good outcome. Therefore, the novel variant in CCDC39 contributes to the genetic diagnosis, counseling, and treatment for male infertility with MMAF phenotype in PCD patients.