ESPE Abstracts

Indels are highly abundant in human genomes and have contributed massively to genome evolution. However, the role of indels and their underlined mechanisms of mutagenesis in Mendelian disorders still needs to be appreciated. To explore the contribution of indels in a monogenic disorder, we analyzed all indels already described in the AR gene, including three novel indels found in our cohort. We analyzed the indel distribution through the AR coding region, compared with genomic and exonic populational data, and analyzed their impact on the AIS phenotype and their likely mechanism of mutagenesis. We present 82 different indels in the AR gene reported in individuals with AIS. In most cases (n=78; 95.1%), the phenotype is complete AIS (CAIS). There are four AR indels reported in mild AIS. Most short indels in the AR gene among AIS are frameshift indels (n=64; 79%). Indels are distributed along the entire AR gene, with NTD domain predominance (n=45; 54.9%), followed by LTD domain (n=28; 34.1%). Most are small deletions (n=49; 59.7%), followed by small insertions (n=29; 35.3%) and complex frameshift indels (n=4; 4.8%). Most indels are short (<10 bp; n=81 = 98.8%), with an average of 2.4 nucleotides by indel. Most indels are at non-repetitive sequences with no changes in copy counting (n= 68; 82.9%). Thirteen indels were identified within tandem repeats (15.8%), whereas seven indels were at homopolymers run (8.5%). Trinucleotide regions (Poly-Q, Poly-G) are prone to indels, but indels also happen in other trinucleotide stretches (Poli-L, Poly-P). Regarding the change in copy counting, thirty-nine (47.5%) indels are CCC indels. All small indels reported in MAIS are located at tandem repeats, while all at non-repetitive sequences caused CAIS. 3.65% of AR indels are at a 6bp consensus sequence (TG A/G A/G G/T A/C). In summary, indels represent a significant portion of the variants identified in the AR gene in patients with AIS. Unlike the non-synonymous variants related to this gene, there is a genotype-phenotype correlation (indel - CAIS congruency). However, small NFS indels at small triplet runs can slightly compromise AR function leading to the mild phenotype. Homopolymer runs, and trinucleotide repeats are exonic regions at risk for indels. Slippage explains half of the cases of AR indels. These results increase the molecular understanding of the androgen receptor disruption and the underlined mechanisms of indel mutagenesis in exonic regions and their implication on phenotype.