Bookshelf

CAIS = complete androgen insensitivity syndrome; MAIS = mild androgen insensitivity syndrome; PAIS = partial androgen insensitivity syndrome

See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on variants detected in this gene.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

androgendb​.mcgill.ca; www​.hgmd.cf.ac.uk

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

AR pathogenic variant detection frequency in individuals with MAIS is more difficult to assess because of the assumption that MAIS diagnoses are often missed: (1) In the presence of deficient or defective androgen binding activity in genital skin fibroblasts in an XY individual with clinical findings of CAIS and PAIS, the likelihood of finding a pathogenic variant in the androgen binding domain of AR approached 40% [Weidemann et al 1996]. (2) In the presence of normal androgen binding in genital skin fibroblasts in an XY individual with clinical findings of PAIS, the likelihood of finding an AIS-causing AR variant is 10% or less, even when exon 1 is screened and/or sequenced in its entirety [Author, personal observation]. (3) Because the presence of an AR pathogenic variant, not abnormal androgen binding, is now the primary diagnostic criterion for AIS, defective androgen binding activity in an XY individual with clinical findings of CAIS, PAIS, or MAIS who does not have an AR pathogenic variant may be inappropriately precluded from the above diagnostic categories [Gottlieb et al 2012, Lek et al 2014, Mongan et al 2015]. Indeed, it has now been suggested that a new category of 46,XY disorder of sex development be established, in which no AR variant is found, although AR binding may be impaired [Lek et al 2014]. However, this would appear to be premature in light of the discovery of a number of cases of somatic mosaicism and intra-tissue genetic heterogeneity [Gottlieb et al 2012].

An informal survey of AIS databases in Canada, United States, and Great Britain showed that AR pathogenic variant detection frequency ranged from 65% to 95% in individuals with CAIS and from 40% to 45% in those with PAIS. The AIS database at the Lady Davis Institute for Medical Research (Montreal, Canada), which includes 138 individuals with CAIS or PAIS, reflects this variable detection rate [Gottlieb et al 2012]. Indeed, two additional reports have revealed a substantial percentage of individuals with putative PAIS in whom no AR variant has been found [Veiga-Junior et al 2012, Lek et al 2014].