July 15, 2022

Genetic causes of male infertility

Infertility is defined as the failure of a couple to achieve a clinical pregnancy after 12 months of regular unprotected sexual intercourse. Approximately 1 in 6 couples face infertility problems worldwide. Male factor is responsible for about 50% of infertility cases and it affects 7% of men. Male infertility has a multifactorial etiology with genetic causes representing 10–15%. The most common include chromosomal abnormalities, microdeletions of Y chromosome and single-gene disorders. 

Chromosomal abnormalities 

The frequency of chromosomal abnormalities in infertile men is estimated to be between 2-19.6%, significantly higher compared to the general population (<1%). Chromosomal aberrations are detected in 2.1-6.6% of patients with severe oligozoospermia and in 10%‐20% of patients with azoospermia. Klinefelter syndrome is the most common numerical aberration (1-2/1000 newborn males), followed by 47,XYY syndrome and small supernumerary marker chromosomes. Chromosomal translocations (reciprocal and Robertsonian) and inversions are the most frequent balanced structural disorders. It must be noted that the carriers of a balanced rearrangement are phenotypically normal, but have an increased risk of producing abnormal gametes and consequently abnormal children. 

Microdeletions of Y chromosome 

Y chromosome microdeletions usually occur in the euchromatic part of the long arm of the Y chromosome (Yq11), including the AZF. The AZF region comprises of AZFa, AZFb, AZFc, AZFd subregions, which are composed of repetitive elementes and are responsible for spermatogenesis. Aberrations of the Yq chromosome are currently detected in approximately 15% of infertile males, specifically in 13% of azoospermic males and in 1-7% of severely oligozoospermic males.  

Single-gene disorders 

Various autosomal recessive and autosomal dominant single-gene disorders are involved in human infertility. Mutations in the CFTR gene (Cystic Fibrosis Transmembrane Conductance Regulator) cause 60–70% of congenital absence of the vas deferens (CAVD) cases, a rare condition found in only 1–2% of infertile men. Mutations in Androgen Receptor (AR) gene have been also identified in 2% of infertile men, causing either mild or partial androgen insensitivity syndrome.  

Although genetic factors have been shown to play an important role in male infertility, in 40% of cases the exact cause remains unidentified. The advent of high-throughput technologies like next-generation sequencing and genome-wide association studies have led to the identification of several novel promising candidate genes for male infertility. Understanding the genetic cause of male infertility is clinically important for better prognosis, treatment and assessment of the risk of transmitting of genetic defects through natural or assisted reproductive technique. 

Mavrou Ariadni, Professor of Medical Genetics 

Kouvidi Elisavet, Biologist – Cytogeneticist, MSc, PhD 

Tsimela Hara, Biologist, BSc 

Katsidi Christina, MSc 

Genesis Genoma Lab