Although genomic testing for many genetic disorders has become part of routine clinical care, this has not occurred in Australia for the management of female infertility, including premature ovarian insufficiency (POI). POI is a leading form of female infertility affecting up to 4% of women under the age of 40 and characterized by amenorrhea and elevated gonadotropins.
Genetic diagnosis for POI is challenging because 1) it is highly heterogeneous with over 100 causative genes affecting a wide variety of processes, 2) these known genes account for only a minority of patients and 3) most variants remain of uncertain significance until functional validation is performed.
We have studied a diverse cohort of over 200 girls/women with POI using whole exome sequencing, identifying cause in >20%. We have validated or discredited causation of genetic variants using various approaches such as multi-omic analysis of patient cells, modelling in Drosophila, zebrafish or mouse, and in-vitro functional assays. Our approach has led to multiple novel POI gene discoveries, such as TP63, TFAM, MRPL50, HROB, REC8, GGPS1 and more.
Importantly, we have shown that genomic sequencing can alter and improve patient management and outcomes. For example, we identified causative variants in NBN, EIF2B2 and LARS2 in three different patients presenting with apparently “isolated” POI. These genes are usually associated with syndromic POI in the context of cancer predisposition, neurodegeneration, and hearing loss respectively. In each case genomic sequencing identified syndromic POI before its full clinical manifestation. This enabled early intervention for associated co-morbidities, with the potential to improve patient outcomes.
Given the impact of genetic diagnoses on downstream patient care and outcomes, it is critical that variant curation is performed accurately with sufficient functional validation to be confident that variants reported as pathogenic are truly causal.