Introduction to androgenetics: terminology, approaches, and impactful studies across 60 years

Abstract

Across six decades, androgenetics has consistently concentrated on discovering genetic causes and enhancing the molecular diagnostics of male infertility, disorders of sex development, and their broader implications on health, such as cancer and other comorbidities. Despite vast clinical knowledge, the training of andrologists often lacks fundamental basics in medical genetics. This work, as part of the Special Issue of Andrology "Genetics in Andrology", provides the core terminology in medical genetics and technological advancements in genomics, required to understand the ever-progressing research in the field. It also gives an overview of study designs and approaches that have frequently led to discoveries in androgenetics. The rapid progress in the methodological toolbox in human genetics is illustrated by numerous examples of impactful androgenetic studies over 60 years, and their clinical implications.

Keywords: androgenetics; clinical implications; genotype‐phenotype correlations; gonadal development; infertility; male reproduction; medical genetics terminology; molecular diagnostics.

FIGURE 1

(A) Types of DNA sequence variants: an SNV affects a single nucleotide in a genome (Sanger sequencing trace of a heterozygous SNV is shown); an indel is a short insertion or deletion (~1–50 bp); CNV (copy number variant) refers to variable copy numbers of a specific genomic segment among individuals due to longer deletions or duplications. (B) Inheritance modes: for autosomal dominant conditions, only one defective allele is enough to cause a disease; for autosomal recessive diseases to manifest, both alleles have to be defective; for X-linked diseases, whereby the mother is a carrier, half of the sons are affected. (C) Penetrance refers to the proportion of genetic variant carriers exhibiting the linked phenotype; variable expressivity indicates that individuals with the same genetic variant present the phenotype to varying degree of severity; pleiotropy refers to the phenomenon whereby a single gene is linked to several phenotypes; and oligogenicity means that the phenotype results from the combined effect of variants in a small number of genes.