Multiple morphological abnormalities of sperm flagellum (MMAF) is a rare cause of primary infertility. Genetic variants in cilia- and flagella-associated protein 43 (CFAP43) are associated with asthenoteratospermia and MMAF; however, the detailed pathogenic mechanisms are still to be completely elucidated. Here, we identified novel compound heterozygous mutations in CFAP43, c.1859_1860+8delinsGT, and c.3071A>G (p.N1024S), by whole-exome sequencing (WES). The proband had a typical MMAF phenotype; Sanger sequencing confirmed these mutations and showed that they cosegregated within the family. Further analysis of the patient’s sperm samples indicated that the CFAP43 mutations result in aberrant RNA splicing. Additionally, we observed disturbance and partial deletion of the mitochondrial sheath, along with a significant reduction in translocase of outer mitochondrial membrane 20 (TOM20) expression. This study suggests that infertility associated with CFAP43 loss of function may be linked to mitochondrial dysfunction. Finally, assisted reproductive technology using intracytoplasmic sperm injection (ICSI) resulted in a successful pregnancy and live birth. Our study expands the spectrum of pathogenic CFAP43 mutations and provides valuable insights for genetic counseling and personalized reproductive strategies in patients with MMAF.

Keywords: CFAP43; ICSI; infertility; MMAF; sperm flagella