In 3 infertile brothers from a consanguineous Algerian family with azoospermia (patients 406 and 412) or severe oligoasthenospermia (patient 401) (SPGF70; 619828), Yildirim et al. (2018) identified homozygosity for a c.679A-G transition (c.679A-G, NM_005390.1) in the PDHA2 gene, resulting in a met227-to-val (M227V) substitution at a highly conserved residue. Sanger sequencing confirmed the mutation and segregation with disease in the family; a heterozygous brother (409) showed mild necrozoospermia on semen analysis but was fertile. Female fertility appeared to be unaffected: a homozygous unmarried sister (408) had normal gonadotropic hormone levels. The mutation was present in the ExAC database at a low minor allele frequency (0.00009 in the Latino population and .00006 in the non-Finnish European population). Seven of 10 sibs in the family, including the 3 infertile brothers, also exhibited digital anomalies that were attributed to a linked mutation in the BMPR1B gene (see 603248).
In 2 unrelated infertile Tunisian men (P0253 and P0144) with azoospermia, Kherraf et al. (2022) identified homozygosity for the previously reported M227V substitution in the PDHA2 gene. Familial segregation was not reported; the variant was present in the gnomAD database at low minor allele frequency (.00006). The authors noted that although both men were homozygous for the same mutation, they exhibited different histologic subphenotypes and different outcomes on testicular sperm extraction (TESE), with one (P0253) showing hypospermatogenesis and a positive TESE, and the other (P0144) showing meiotic arrest and a negative TESE.
