Premature ovarian insufficiency - clinical orientations for genetic testing and genetic counselling

Abstract

Premature ovarian insufficiency (POI) is a heterogeneous disorder diagnosed in women before 40 years old and describes a wide range of impaired ovarian function, from diminished ovarian reserve to premature ovarian failure. Genetic etiology accounts for 20-25% of patients. The evidence that POI can be isolated (non-syndromic) or part of a pleiotropic genetic syndrome highlights its high heterogenous etiology. Chromosomal abnormalities as a cause of POI have a prevalence of 10-13%, being 45,X complement the most common cytogenetic cause of primary amenorrhea and mosaicism with a 45,X cell line more frequently associated with secondary amenorrhea. Other X chromosome aberrations include deletions, duplications, balanced and unbalanced X-autosome rearrangements involving the critical region for the POI phenotype (Xq13-Xq21 to Xq23-Xq27). The identification of two or more pathogenic variants in distinct genes argues in favor of a polygenic origin for POI. Hundreds of pathogenic variants (including mitochondrial) have been involved in POI etiology mainly with key roles in biological processes in the ovary, such as meiosis and DNA damage repair mechanisms, homologous recombination, follicular development, granulosa cell differentiation and proliferation, and ovulation. The most common single gene cause for premature ovarian insufficiency is the premutation for FMR1 gene (associated with fragile X syndrome) with alleles ranging from about 55 to about 200 CGG trinucleotide repeats. POI occurs in 20% of women with this premutation. As females with premutation or full mutation alleles are also at risk of having affected children, their genetic counselling should include the indication for prenatal diagnosis or preimplantation genetic testing after intracytoplasmic sperm injection and trophectoderm biopsy. In conclusion, in clinical practice high-resolution karyotype and FMR1 gene molecular study should be performed as first-tier tests in the assessment of POI. Additionally, array Comparative Genomic Hybridization (array-CGH) or specific next generation sequencing (NGS) panels should be considered to identify chromosomal deletions/duplications under karyotype resolution or other pathogenic variants in specific genes associated with POI. This is particularly important in patients with first or second-degree relatives also affected with POI, improving their reproductive and genetic counselling.