Small Indels in the Androgen Receptor Gene: Phenotype Implications and Mechanisms of Mutagenesis

Abstract

Context: Despite high abundance of small indels in human genomes, their precise roles and underlying mechanisms of mutagenesis in Mendelian disorders require further investigation.

Objective: To profile the distribution, functional implications, and mechanisms of small indels in the androgen receptor (AR) gene in individuals with androgen insensitivity syndrome (AIS).

Methods: We conducted a systematic review of previously reported indels within the coding region of the AR gene, including 3 novel indels. Distribution throughout the AR coding region was examined and compared with genomic population data. Additionally, we assessed their impact on the AIS phenotype and investigated potential mechanisms driving their occurrence.

Results: A total of 82 indels in AIS were included. Notably, all frameshift indels exhibited complete AIS. The distribution of indels across the AR gene showed a predominance in the N-terminal domain, most leading to frameshift mutations. Small deletions accounted for 59.7%. Most indels occurred in nonrepetitive sequences, with 15.8% situated within triplet regions. Gene burden analysis demonstrated significant enrichment of frameshift indels in AIS compared with controls (P < .00001), and deletions were overrepresented in AIS (P < .00001).

Conclusion: Our findings underscore a robust genotype-phenotype relationship regarding small indels in the AR gene in AIS, with a vast majority presenting complete AIS. Triplet regions and homopolymeric runs emerged as prone loci for small indels within the AR. Most were frameshift indels, with polymerase slippage potentially explaining half of AR indel occurrences. Complex frameshift indels exhibited association with palindromic runs. These discoveries advance understanding of the genetic basis of AIS and shed light on potential mechanisms underlying pathogenic small indel events.

Keywords: androgen insensitivity syndrome; androgen receptor; differences in sex development; disorders of sex development; human genetics; sex development.