Genetics of human male infertility

Singapore Med J. 2009 Apr;50(4):336-47.


Infertility is defined as a failure to conceive in a couple trying to reproduce for a period of two years without conception. Approximately 15 percent of couples are infertile, and among these couples, male factor infertility accounts for approximately 50 percent of causes. Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In more than half of infertile men, the cause of their infertility is unknown (idiopathic) and could be congenital or acquired. Infertility in men can be diagnosed initially by semen analysis. Seminograms of infertile men may reveal many abnormal conditions, which include azoospermia, oligozoospermia, teratozoospermia, asthenozoospermia, necrospermia and pyospermia. The current estimate is that about 30 percent of men seeking help at the infertility clinic are found to have oligozoospermia or azoospermia of unknown aetiology. Therefore, there is a need to find the cause of infertility. The causes are known in less than half of these cases, out of which genetic or inherited disease and specific abnormalities in the Y chromosome are major factors. About 10-20 percent of males presenting without sperm in the ejaculate carry a deletion of the Y chromosome. This deleted region includes the Azoospermia Factor (AZF) locus, located in the Yq11, which is divided into four recurrently deleted non-overlapping subregions designated as AZFa, AZFb, AZFc and AZFd. Each of these regions may be associated with a particular testicular histology, and several candidate genes have been found within these regions. The Deleted in Azoospermia (DAZ) gene family is reported to be the most frequently deleted AZF candidate gene and is located in the AZFc region. Recently, a partial, novel Y chromosome 1.6-Mb deletion, designated "gr/gr" deletion, has been described specifically in infertile men with varying degrees of spermatogenic failure. The DAZ gene has an autosomal homologue, DAZL (DAZ-Like), on the short arm of the chromosome 3 (3p24) and it is possible that a defective autosomal DAZL may be responsible for the spermatogenic defect. The genetic complexity of the AZF locus on the long arm of the Y chromosome could be revealed only with the development of sequence tagged sites. Random attacks on the naked mitochondrial DNA (mtDNA) of sperm by reactive oxygen species or free radicals will inevitably cause oxidative damage or mutation to the mitochondrial genome with pathological consequences and lead to infertility in males. The key nuclear enzyme involved in the elongation and repair of mtDNA strands is DNA polymerase gamma, mapped to the long arm of chromosome 15 (15q25), and includes a CAG repeat region. Its mutation affects the adenosine triphosphate production. The introduction of molecular techniques has provided great insight into the genetics of infertility. Yet, our understanding of the genetic causes of male infertility remains limited.

Publication types

  • Review

MeSH terms

  • Azoospermia / diagnosis
  • Azoospermia / genetics
  • Chromosome Aberrations
  • Chromosome Deletion
  • Chromosomes, Human, Pair 15
  • Chromosomes, Human, Pair 3
  • Chromosomes, Human, Y / genetics
  • DNA Mutational Analysis
  • DNA Polymerase gamma
  • DNA Repair / genetics
  • DNA, Mitochondrial / genetics
  • DNA-Directed DNA Polymerase / genetics
  • Deleted in Azoospermia 1 Protein
  • Genetic Loci
  • Humans
  • Infertility, Male / diagnosis
  • Infertility, Male / genetics*
  • Male
  • Phenotype
  • RNA-Binding Proteins / genetics
  • Semen Analysis
  • Seminal Plasma Proteins / genetics
  • Spermatozoa / abnormalities


  • DAZ1 protein, human
  • DAZL protein, human
  • DNA, Mitochondrial
  • Deleted in Azoospermia 1 Protein
  • RNA-Binding Proteins
  • Seminal Plasma Proteins
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase