Whole exome sequencing reveals ABCD1 variant as a potential contributor to male infertility

Male infertility (MI) is a polygenic condition mainly induced by spermatogenic failure/arrest or systemic disease with a large clinical spectrum. Lately, genetic sequencing allowed the identification of several variants implicated in both aforesaid situations.

In this case study, we performed whole exome sequencing (WES) on the genomic DNA of a 37-year-old Moroccan man with Non-Obstructive Azoospermia. Results revealed two variants in genes highly expressed in testicular tissue. The first was a heterozygous frameshift variant in the AURKC gene, causing a premature stop codon at position 71 of the AURKC protein, critical for spermatogenesis. The second was a hemizygous missense variant in the ABCD1 gene, resulting in an H299R substitution in the ABCD1 protein, essential for transporting Very Long Chain Fatty Acids (VLCFAs) into peroxisomes. ABCD1 variants are linked to X-linked Adrenoleukodystrophy (X-ALD), a disease caused by VLCFAs accumulation in cells. The patient's family pedigree suggests X-linked transmission of MI, which may be a subclinical form of late-onset X-ALD in affected members, indicating that the ABCD1 variant likely affects spermatogenesis. This hypothesis is supported by literature linking X-ALD to MI, ABCD1's high expression in human testes, and the significant impact of the H299R substitution on ABCD1 transporter's molecular dynamics.

These insights highlight the role of genetic mutations in male infertility, demonstrating that spermatogenesis can be disrupted either directly by specific mutations or indirectly through broader genetic disorders, underscoring the importance of comprehensive genetic testing.