Male Infertility with Large-Headed Spermatozoa via the AURKC Gene

More than one million couples worldwide seek reproductive assistance each year (Chandra et al. 2005; Nyboe Andersen et al. 2009). In half the cases, male infertility is a major contributing factor. Common causes of male infertility include little or no sperm in the semen (i.e. azoospermia and oligozoospermia), low sperm motility (i.e. asthenozoospermia), and abnormal sperm morphology (i.e. teratozoospermia) (Cooke and Saunders 2002). Male infertility associated with large-headed, multiflagellar, polyploid spermatozoa is a classic teratozoospermia condition, characterized by a high percentage (30-100%) of bulky, irregular-shaped spermatozoa in the patient’s semen (German et al. 1981). In these patients, most spermatozoon heads have 2-4 times the normal DNA content and up to 6 distinct tails (Devillard et al. 2002). While intracytoplasmic sperm injection (ICSI) has been used to effectively treat patients exhibiting >30% large-headed spermatozoa, the pregnancy rate per transfer is low (~15%) and the risk of chromosomal abnormalities and perinatal death is higher than normal (Achard et al. 2007). As a result, the financial burdens and emotional stress of reproductive assistance is even greater for these patients.

In a cohort of 14 unrelated infertile men of African descent with a large-headed sperm phenotype, Dieterich and colleagues identified a homozygous cytosine (C) deletion in exon 3 (c.144delC) of the Aurora-C kinase (AURKC) gene, which encodes a conserved protein kinase responsible for chromosomal segregation during mitosis (Dieterich et al. 2007). In a subsequent study (Dieterich et al. 2009), the same group reported that of 32 patients with infertility and large-headed sperm, 31 were homozygous for the AURKC c.144delC variant while one patient was heterozygous for c.144delC and heterozygous for a novel AURKC missense variant p.Cys229Tyr. Women homozygous for c.144delC were healthy and had no problem conceiving naturally. Men heterozygous for a single AURKC variant were also unaffected. From these studies, it was estimated that, in North African populations, the allele frequency of c.144delC is ~2%, and the prevalence of AURKC-associated infertility is 1/10,000 men. Currently, the prevalence of AURKC-associated infertility in other ethnic groups is not known.

The sensitivity of this test is predicted to be nearly 100% for infertile men with a “typical” large-headed sperm phenotype (see Dieterich et al. Hum Mol Genet 18:1301-1309, 2009).

This test provides full coverage of all coding exons of the AURKC gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).