CFAP251 deletion and ICSI outcome in Tunisian infertile men with multiple morphological abnormalities of the sperm flagellum

Abstract

Multiple Morphological Abnormalities of the Sperm Flagella syndrome (MMAF) is a specific asthéno –tératozoospermia leading to male infertility and characterized by severe defects in the sperm's tail or flagellum. These abnormalities lead to greatly reduced or absent sperm motility, making it difficult for sperm to reach and fertilize an egg. MMAF is considered a genetic disorder, often inherited in an autosomal recessive manner. Significant advancements in high-throughput DNA sequencing have led to the identification of numerous genes linked to MMAF. While research is ongoing and the exact mechanisms are still being fully elucidated, over 40 genes have been associated with MMAF, accounting for about 60–70% of cases. Two infertile MMAF brothers undertaking ICSI were included. Whole exome sequencing was carried out for one of them. We identified a homozygous framshift variant c.[3007_3337del] in CFAP251 gene in the patient and in his affected brother. The deletion encompasses exons 20 and 21, transmitted from heterozygous parents. Consequently, 12.8% of the protein (147 amino acids) is predicted to be lost. The analysis of their ICSI attempts showed that no pregnancy was achieved for their couples. Our findings highlight the importance of whole exome sequencing in identifying genetic causes of MMAF and may provide valuable insights for clinical genetic counseling and assisted reproductive treatments for affected individuals.