Genetic Disorders of Human Infertility

Abstract

Diagnostic identification of human genetic disorders causing male or female infertility is of paramount interest in each infertility clinic dealing with the term ‘idiopathic infertility’, which means ‘no reason found for observed infertility pathology’. In such cases, if there is a genetic disorder behind (in about 30%), there is usually a high risk of transfer of this genetic lesion to the offspring by the applied fertilisation protocol. Such genetic‐based infertility disorders can be unbalanced chromosome aberrations including aneuploidies and/or specific gene mutations, respectively. As comparative genomic hybridisation (CGH) and next‐generation sequencing (NGS) tools have now shown that the normal human genome can have a highly variable sequence composition, thus also in men and women with normal fertility, it has become a major challenge for the clinicians to then identify only those genome/gene mutations which may indeed cause the observed infertility pathology.

Key Concepts

  • Genetic disorders can cause about 30% male and female infertility.
  • Analysis of chromosome aberrations (aneuploidies) is mandatory before ART application in ‘idiopathic’ male and female infertility.
  • Artificial insemination protocols such as ICSI can increase genetic disorders causing infertility in offspring.
  • Genes causing male or female infertility can have pleiotropic somatic genetic disorders such as cystic fibrosis.
  • Genes on the Y chromosome causing male infertility (AZF genes) are inherited by ICSI to male offsprings with 100%.

Keywords: idiopathic male and female sterility; chromosome aberrations and aneuploidies; CFTR and CBAVD; azoospermia factors on Y chromosome; POI/POF syndrome; DSD females with 46,XY and tumour risk; CAIS and PAIS; mitochondrial lesions and infertility

Figure 1. Multiple genetic loci for the maintenance and progression of human folliculogenesis are located on the X chromosome. According to the OMIM database they are summarised under POF1 (OMIM: #311360) with FMR1 as the most prominent POF candidate gene (because most frequently mutated), POF2 (OMIM: #300511 and #300604) and POF4 (OMIM: #300247). Associated POF candidate genes, that is genes known to be expressed during human folliculogenesis, of which some were already found with mutations in women with POI/POF syndrome, are listed at the right. For further description see the text.
Figure 2. Schematic view of the CFTR exon structure with polymorphic (T)n tract at the intron 8 acceptor splice site (n = 5–9). In men with CBAVD, there is an increased frequency of the 5T variant causing most often (<90%) skipping of CFTR exon 9, which results in translation of the nonfunctional CFTR protein.
Figure 3. Schematic view of AZF gene content on the long arm of the human Y chromosome in Yq11. The pink coloured blocks mark the X–Y homologous sequence blocks. It includes also the AZFa deletion interval. Homologous blocks in the ampliconic repetitive sequence structure in distal Yq11 encompassing AZFb and AZFc deletion intervals are marked by the same colour code as designated by Kuroda‐Kawaguchi et al. . The 19 protein encoding Y genes mapped in Yq11 and expressed in the male germ line are distinguished by specific colours and represented by arrows with the corresponding 5′–3′ polarity (modified from Vogt et al., ).
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Vogt, Peter H(Dec 2017) Genetic Disorders of Human Infertility. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005520.pub2]