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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. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Discussion Conclusion Androgen insensitivity syndrome (AIS) is a common condition among individuals with differences of sexual development (DSD) and results from germline allelic variants in the androgen receptor (AR) gene. Understanding the phenotypic consequences of AR allelic variants that disrupt the activation function 2 (AF2) region is essential to grasping its clinical significance.This study aims to provide insights into the phenotypic characteristics and clinical impact of AR mutations affecting the AF2 region in AIS patients. We achieve this by reviewing reported AR variants in the AF2 region among individuals with AIS, including identifying a new phenotype associated with the c.2138T>C variant (p.Leu713Pro) in the AR gene.We comprehensively reviewed AR variants within the AF2 region reported in AIS and applied molecular dynamics simulations to assess the impact of the p.Leu713Pro variant on protein dynamics.Our review of reported AR variants in the AF2 region revealed a spectrum of phenotypic outcomes in AIS patients. Molecular dynamics simulations indicated that the p.Leu713Pro variant significantly alters the local dynamics of the AR protein and disrupts the correlation and covariance between variables.The diverse phenotypic presentations observed among individuals with AR variants in the AF2 region highlight the complexity of AIS. The altered protein dynamics resulting from the p.Leu713Pro variant further emphasize the importance of the AF2 region in AR function.Our study provides valuable insights into AR mutations' phenotypic characteristics and clinical impact on the AF2 region in AIS. Moreover, the disruption of protein dynamics underscores the significance of the AF2 region in AR function and its role in the pathogenesis of AIS. [ABSTRACT FROM AUTHOR]