The following is a summary of “Small Indels in the Androgen Receptor Gene: Phenotype Implications and Mechanisms of Mutagenesis,” published in the January 2024 issue of Endocrinology by Ramos, et al.

Small indels in human genomes are abundant, but their precise roles and mechanisms in Mendelian disorders need further investigation. For a study, researchers sought to profile the distribution, functional implications, and mechanisms of small indels in the androgen receptor (AR) gene among individuals with androgen insensitivity syndrome (AIS).

A systematic review of previously reported indels within the AR gene’s coding region was conducted, including three novel indels. The distribution across the AR gene was examined and compared with genomic population data. The impact on the AIS phenotype was assessed, and potential mechanisms driving their occurrence were investigated.

A total of 82 indels in AIS were analyzed. All frameshift indels resulted in complete AIS. Indels were predominantly located in the N-terminal domain, mostly causing frameshift mutations. Small deletions accounted for 59.7% of the indels, with most occurring in nonrepetitive sequences and 15.8% in triplet regions. Gene burden analysis revealed significant enrichment of frameshift indels in AIS compared to controls (P < .00001), with deletions overrepresented in AIS (P < .00001).

The study underscored a robust genotype-phenotype relationship in AIS regarding small indels in the AR gene, primarily resulting in complete AIS. Triplet regions and homopolymeric runs were identified as prone loci for small indels within the AR gene. Most indels were frameshift, with polymerase slippage potentially explaining half of AR indel occurrences. Complex frameshift indels showed an association with palindromic runs. The findings enhanced understanding of the genetic basis of AIS and shed light on potential mechanisms underlying pathogenic small indel events.

Reference: academic.oup.com/jcem/article-abstract/109/1/68/7241776