Pathogenic variants in medically actionable genes among women with Mayer-Rokitansky-Küster-Hauser syndrome

Introduction Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterised by the congenital absence of the uterus and vagina in 46,XX individuals, affecting approximately one in 5000 births. MRKH may be associated with renal, vertebral, skeletal and/or auditory anomalies. The study aim was to evaluate the prevalence of pathogenic and likely pathogenic (P/LP) variants in medically actionable genes (MAGs) in women with MRKH, compared with reference databases. This was deemed important since women with unexplained infertility had an increased risk of P/LP variants in MAGs.Methods Exome sequencing (ES) was performed on 145 women with MRKH. Variants were filtered to include only those in the 81 genes from the American College of Medical Genetics and Genomics (ACMG) SF V.3.2 list for secondary findings (ie, MAGs). Identified variants underwent confirmation by Sanger sequencing. The prevalence of variants in 59 genes (V.2.0) was compared with control data from the UK Biobank and Electronic Medical Records and Genomics (eMERGE) databases.Results Eighteen confirmed heterozygous P/LP variants in 16 of the 81 MAGs from ACMG SF V.3.2 were identified in 16/145 (11.0%) women with MRKH. When variants in 59 MAG (V.2.0) were compared with control databases, 14/145 (9.7%) had P/LP variants vs 2% in the UKB and 2.5% in eMERGE. Variant prevalence was ~sixfold higher than in the UK Biobank and ~fivefold higher than in the eMERGE database.Conclusions Women with MRKH demonstrate a high prevalence of P/LP variants in MAGs, suggesting a potential unidentified genomic component associated with the syndrome. This finding could affect genetic counselling and consideration for medical surveillance or intervention.