A preliminary approach for designing an Iranian population based genetic panel for early diagnosis of susceptibility to premature ovarian insufficiency

Background and Aim: Premature ovarian insufficiency (POI) is declining ovarian function in a young woman, resulting in an earlier than average menopause. By postponing of marriage and delaying childbearing due to changing in the life style, women with POI, besides clinical symptoms, are high risk for infertility. POI is associated with some genetic variations including single nucleotide variants (SNVs). We aimed to highlight clinically important SNVs that are potentially correlated with POI in Iran due to their existence in Iranian apparently normal population.Methods: To find pathogenic SNVs in the genes associated with POI, according to consensus of two leading European societies, The European Society of Human Reproduction and Embryology (ESHRE) and The European Society of Human Genetics (ESHG), we investigated the reported SNVs for these genes in ClinVar as a valid database for classification of the genetic variations considering their clinical importance. Next, we checked the ClinVar SNVs in Iranome, an exome sequencing-based database for frequency of SNVs in Iranian normal population; SNVs that have not been reported in Iranome database are either intronic or had not been found in the studied Iranian population. Then, we shortlisted SNVs that had been reported in both ClinVar and Iranome excluding benign and likely benign SNVs.Results: Twenty seven genes were investigated according to their selection in the aforementioned consensus of ESHRE and ESHG. Of the reported variations for these genes in ClinVar, ۲۰۳۲ variants were SNVs. After excluding benign and likely benign SNVs, ۷۵ that were shared in ClinVar and Iranome entered to the final shortlist. According to the latest interpretation in ClinVar, of these ۷۵ SNVs, ۳۱ were with uncertain significance, ۴۰ had conflicting interpretation of pathogenicity and only ۴ SNVs had been classified as pathogenic. These ۷۵ SNVs are going to be prioritized for wet lab studies.Conclusion: By this in-silico approach, we excluded ۹۶.۳% of the SNVs, those were either clinically unimportant or unreported in Iranian normal population, from costly time consuming wet lab evaluation. It would be the preliminary basis for designing a genetic panel for early diagnosis of POI before clinical symptoms.

Keywords:

Premature ovarian insufficiency (POI) , single nucleotide variants (SNVs) , Iran , ClinVar , Iranome