Genetic causes of macrozoospermia and proposal for an optimized genetic diagnosis strategy based on sperm parameters

Macrozoospermia,characterized by the presence of largeheaded spermatozoa usually carrying several flagella,is one of the most severe phenotypes of male infertility.As in most cases,the gametes are chromosomally abnormal and cannot be used for assisted reproductive technologies(ART)(Ray et al.,2017).In 2007,subjects from consanguineous families were shown to carry the same homozygous deleterious AURKC variant(NM_001015878.2:c.144delC,later renamed c.145delC,p.Leu49TrpfsTer23),establishing AURKC as the first and main gene associated with macrozoospermia(Dieterich et al.,2007).Using flow cytometry,all spermatozoa from patients homozygous for the c.145delC variant were shown to be tetraploid,highlighting a cytokinesis blockage of the first meiotic divisions thus confirming that ART cannot be successful for these patients(Dieterich et al.,2009).

Mutations of the aurora kinase C gene causing macrozoospermia are the most frequent genetic cause of male infertility in Algerian men

Klinefelter syndrome and Y-chromosomal microdeletion analyses were once the only two genetic tests offered to infertile men. Analyses of aurora kinase C （AURKCj and DPY19L2 are now recommended for patients presenting macrozoospermia and globozoospermia, respectively, two rare forms of teratozoospermia particularly frequent among North African men. We carried out genetic analyses on Algerian patients, to evaluate the prevalence of these syndromes in this population and to compare it with the expected frequency of Klinefelter syndrome and Y-microdeletions. We carried out a retrospective study on 599 consecutive patients consulting for couple infertility at the assisted reproduction unit of the Ibn Rochd Clinique, Constantine, Algeria. Abnormal sperm parameters were observed in 404 men. Fourteen and seven men had typical macrozoospermia and globozoospermia profiles, respectively. Molecular diagnosis was carried out for these patients, for the AURKC and DPY19L2 genes. Eleven men with macrozoospermia had a homozygous AURKC mutation （79%）, corresponding to 2.7% of all patients with abnormal spermograms. All the men with globozoospermia studied （n = 5）, corresponding to 1.2% of all infertile men, presented a homozygous DPY19L2deletion. By comparison, we would expect 1.6% of the patients in this cohort to have Klinefelter syndrome and 0.23% to have Y-microdeletion. Our findings thus indicate that AURKCmutations are more frequent than Klinefelter syndrome and constitute the leading genetic cause of infertility in North African men. Furthermore, we estimate that AURKCand DPY19L2 molecular defects are 10 and 5 times more frequent, respectively, than Y-microdeletions.