Spermatogenic Failure 28

A number sign (#) is used with this entry because of evidence that spermatogenic failure-28 (SPGF28) is caused by homozygous or compound heterozygous mutation in the FANCM gene (609644) on chromosome 14q21.

Description

Spermatogenic failure-28 is characterized by nonobstructive azoospermia, with a Sertoli cell-only phenotype observed in testicular tissue (Kasak et al., 2018).

For a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).

Clinical Features

Kasak et al. (2018) studied 2 Estonian brothers, aged 26 and 29 years, who had been diagnosed with idiopathic nonobstructive azoospermia. Both had nearly 50% reduced total testicular volume, with elevated serum follicle-stimulating hormone (FSH; see 136530) levels, and 1 brother had elevated luteinizing hormone (LH; see 152780). One brother had cryptorchidism at birth, with spontaneous descent of testicles in the first year of life, and both brothers and their father had grade 1 to 2 left-sided varicocele. Testicular histology in both brothers revealed Sertoli cell-only syndrome, with complete lack of sperm and extensive sclerosis and tubular atrophy. Extended examination of epididymis and vas deferens in 1 brother confirmed bilaterality and revealed no obvious defects. The authors found that the brothers had increased DNA interstrand crosslink (ICL) sensitivity in lymphocytes, averaging 3 to 27 times more chromosomal breaks per cell than their father.

Yin et al. (2019) reported 3 brothers from a Pakistani family with infertility, 2 of whom were diagnosed with mild and severe oligoasthenospermia, respectively, whereas the third brother was azoospermic. Testosterone and pituitary hormone levels were reported as normal.

Molecular Genetics

In 2 Estonian brothers with nonobstructive azoospermia and Sertoli cell-only syndrome, Kasak et al. (2018) performed whole-exome sequencing and identified compound heterozygosity for a 1-bp duplication (609644.0003) and a splice site mutation (609644.0004) in the FANCM gene. Their unaffected parents were each heterozygous for one of the mutations. Whole-exome sequencing in an unrelated 52-year-old Estonian man with azoospermia, small testes, and elevated LH and FSH with low testosterone levels revealed homozygosity for a nonsense mutation in FANCM (Q1701X; 609644.0005). Targeted screening of FANCM in 296 Portuguese men with nonobstructive azoospermia identified 1 man who was homozygous for another nonsense mutation (R1931X; 609644.0006). Noting that testicular histology was unavailable for the latter 2 patients, the authors stated that the association between loss-of-function variants in FANCM and Sertoli cell-only syndrome remained to be verified in future patients.

In 3 Pakistani brothers with infertility due to oligoasthenospermia or azoospermia, Yin et al. (2019) identified homozygosity for a 13-bp deletion in the FANCM gene (609644.0007). Their first-cousin parents were heterozygous for the deletion.

Animal Model

Yin et al. (2019) generated mice homozygous for a loss-of-function frameshift mutation nearly equivalent to the mutations they identified in patients with SPGF28. Adult homozygous mice were generally subfertile and produced significantly smaller litters compared with wildtype mice and mice heterozygous for the mutation. Homozygous males also exhibited a drastic reduction in their testis size and cauda epididymal sperm count. Sperm motility decreased significantly and the proportion of morphologically abnormal sperm increased dramatically. Comparison of the testicular histology between homozygous and heterozygous mice revealed that the testicular tubules from adult homozygous mice were predominantly degenerated with increased apoptosis of germ cells and a partial maturation arrest at the round spermatid stage. However, routine blood tests performed on the adult homozygous mice demonstrated that the mutation did not cause bone marrow failure or cancer/tumor in the mice.