Screening for Potential Genetic Factors that Cause Polycystic Ovary Syndrome in a Cohort of Palestinian Women رسالة ماجستير

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrinological disorder that affects women during their reproductive age. It is the leading cause of hyperandrogenism and anovulatory infertility in approximately 90% of cases. The complexity of PCOS is that it is highly heterogeneous, polygenic, and multifactorial, and it is accompanied by several comorbidities, including metabolic disorders, insulin resistance, type 2 diabetes mellitus, glucose intolerance, hypertension, and cardiovascular disorders. The prevalence of PCOS is constantly increasing, depending on ethnicity, and its etiology is believed to be rooted in environmental and genetic factors. However, its inheritance pattern is difficult to explain due to various relevant genes. Increasing PCOS cases are recorded among Palestinian females with a severe lack of genetic information. This study aimed to identify potentially pathogenic genetic variants associated with PCOS and to measure the frequency of the disease among Palestinian women who are attending IVF gynecological clinics for assisted reproductive techniques. Five women diagnosed with PCOS, according to Rotterdam Criteria, were recruited for the study. Whole-exome sequencing was conducted on five probands to identify relevant genetic variants linked to familial PCOS, followed by familial segregation analysis. In-silico-predicted tools were then employed to assess the potential deleterious effects of the identified variants. PCOS frequency was evaluated among a cohort of 200 patients from different regions of Palestine who attended IVF centers following specified diagnostic criteria. The data revealed from the five indicated families revealed 13 heterozygous variants in different genes, namely CYP21A2, LDLR, MCM6, IKBKB, STOX1, MC4R, IRS1, IRS2, PON1, and FBN1. In-silico analysis revealed four uncertain significance variants and seven pathogenic variants. The results suggested a possible association between LDLD (Arg595Trp), FBN1 (Gly1058Ser), PON1 (Met127Arg), STOX1 (Ile186Thr), MC4R (Glu308Lys), IRS1 (Ser564Asn, Arg1221Pro, Gly669Cys) and IRS2 (Ser66fs*27) polymorphisms and PCOS pathogenesis. Several studies reported the association of genetic factors with PCOS pathogenesis. However, these results are still controversial.