A missense mutation in IFT74, encoding for an essential component for intraflagellar transport of Tubulin, causes asthenozoospermia and male infertility without clinical signs of Bardet–Biedl syndrome

Cilia and flagella are formed around an evolutionary conserved microtubule-based axoneme required for fluid mucus clearance, tissue homeostasis, cell differentiation movement. The formation maintenance of cilia require bidirectional transit proteins along the axonemal microtubules, a process called intraflagellar transport (IFT). In humans, IFT defects contribute to large group systemic diseases, ciliopathies, which often display overlapping phenotypes. By performing exome sequencing cohort 167 non-syndromic infertile men displaying multiple morphological abnormalities sperm flagellum (MMAF) we identified two unrelated patients carrying homozygous missense variant adjacent splice donor consensus site IFT74 (c.256G > A;p.Gly86Ser). encodes core component machinery that is essential anterograde tubulin. We demonstrate this affects mRNA splicing induces production at least distinct mutant with abnormal subcellular localization flagellum. Importantly, while deficiency was previously implicated in cases Bardet–Biedl syndrome, pleiotropic ciliopathy variable expressivity, our data indicate mutation only results primary male infertility due MMAF, no other clinical features. Taken together, nature adds level complexity manifestations ciliary dysfunction, thus contributing expanding phenotypical spectrum ciliopathies.