A systematic review and standardized clinical validity assessment of genes involved in female reproductive failure

Abstract

Genetic testing is becoming increasingly required at almost every stage of failed female reproduction/infertility. Nonetheless, clinical evidence for the majority of identified gene–disease relationships is ill-defined, thus leading to difficult gene variant interpretation and poor translation of existing knowledge into clinics. We aimed to identify the genes that have ever been implicated in monogenic female reproductive failure in humans and to classify the identified gene–disease relationship pairs using a standardized clinical validity assessment. A PubMed search following PRISMA guidelines was conducted on 20 September 2021 aiming to identify studies pertaining to genetic causes of phenotypes of female reproductive failure. The clinical validity of identified gene–disease pairs was assessed using standardized criteria, counting whether sufficient genetic and experimental evidence has been accumulated to consider a single gene ‘characterized’ for a single Mendelian disease. In total, 1256 articles were selected for the data extraction; 183 unique gene–disease pairs were classified spanning the following phenotypes: hypogonadotropic hypogonadism, ovarian dysgenesis, premature ovarian failure/insufficiency, ovarian hyperstimulation syndrome, empty follicle syndrome, oocyte maturation defect, fertilization failure, early embryonic arrest, recurrent hydatidiform mole, adrenal disfunction and Mullerian aplasia. Twenty-four gene–disease pairs showed definitive evidence, 36 – strong, 19 – moderate, 81 – limited and 23 – showed no evidence. Here, we provide comprehensive, systematic and timely information on the genetic causes of female infertility. Our classification of genetic causes of female reproductive failure will facilitate the composition of up-to-date guidelines on genetic testing in female reproduction, the development of diagnostic gene panels and the advancement of reproductive decision-making.

The genetic background of female reproductive disorders: a systematic review

“…FOXL2 (12), FMR1 (10), NOBOX (10), GDF9 (10), FIGLA (9), BMP15 (8), NR5A1 (8), PGRMC1 (8), ESR1 (8), FSHR (7), MCM9 (7), POF1B (6), NOG (6), STAG3 (6), FOXO3 (5), WT1 (5), AIRE (5), GALT (5), ATM (5), HSD17B4 (5), POLG (5), BMPR1 (5), MSH5 (5), SYCE1 (5), MCM8 (5), AR (5), DMC1 (5), PTHB1 (5), SOHLH1 (4), INHA (4), GNAS (4), PMM2 (4), HARS2 (4), LARS2 (4), NANOS3 (4), HFM1 (4), LHX8 www.co-obgyn.com largest international GWAS for PCOS provided 14 robust loci [12]. Recently, mendelian randomization studies have been conducted based on the GWAS findings aiming to investigate the causal relationship between PCOS and other diseases and confirmed the causal effect of BMI on PCOS development [13 & ].…”

“…Despite the rapid advances of genetics in the field of reproduction, still most GDRs remain unclear for numerous reasons [8 ▪▪ ]. Firstly, inheritance patterns are not always fully understood, which highlights the existing gap in understanding the molecular and genetic pathophysiology of impaired female reproductive function.…”

“…Limited only genes have been used in clinical practice to evaluate for female infertility, including FMRI for fragile X mental retardation I gene and CYP21A2 for 21-hydroxylase enzyme [5,6]. Recently, an increasing number of studies have suggested GDR, highlighting gene variants that could be utilized in reproductive medicine [7,8 ▪▪ ,9 ▪ ]. However, there is currently no agreed consensus on the suggested genetic testing for the work-up in subfertility.…”

Semaphorin 3A Increases in the Plasma of Women with Diminished Ovarian Reserve Who Respond Better to Controlled Ovarian Stimulation

“…Additionally, they reported a large deletion in SEMA3A associated with KS in a heterozygous state in two siblings and their clinically affected fathers [ 9 , 13 , 17 ]. Furthermore, SEMA3A has been linked to female reproductive failure due to an autosomal dominant mutation that causes hypogonadotropic hypogonadism (HH) [ 18 , 19 ].…”

The Role of MCM9 in the Etiology of Sertoli Cell-Only Syndrome and Premature Ovarian Insufficiency

“…Infertility affects around 15% of couples [1], and the causes can be complex and multifactorial. Major strides have been made in recent years to identify the contribution of genetic factors to both male and female causes of infertility [2,3]. In females, premature ovarian insufficiency [POI], characterized by a decreased ovarian follicular reserve in those aged <40 years, affects >1% of women [4,5].…”