Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency

Abstract

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported natural menopause under the age of 40. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes we ruled out even modest penetrance, with 99.9% (13,699/13,708) of all protein truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P=1.59*10 -6 ) and SOHLH2 (3.48 years earlier menopause, P=1.03*10 -4 ). Collectively our results suggest that for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that the majority of POI cases are likely oligogenic or polygenic in nature, which has major implications for future clinical genetic studies, and genetic counselling for families affected by POI.

Connecting the dots: the role of fatigue in female infertility

“…Premature Ovarian Insufficiency. Premature ovarian insufficiency (POI) develops the breakdown of ovarian function and menopause before the age of 40, affects about 1% of women, and is one of the main causes of female infertility [55]. A crosssectional study showed fatigue was a highly prevalent symptom closely associated with menopause in the recruited Chinese women with POI [56].…”

The molecular genetics of nELAVL in brain development and disease

“…Amongst seventy families that underwent extensive genetic analysis, two siblings were compound heterozygous for two missense variants in ELAVL2 . This is an intriguing link given the requirement for Elavl2 in oogenesis [ 45 , 48 ], but given the large amount of genetic heterogeneity, further families are likely needed to confirm this as a causative Mendelian gene for POI [ 59 ].…”

Genetic Variants in KNDy Pathway Lack Association with Premature Ovarian Insufficiency in Mexican Women: A Sequencing-Based Cohort Study

“…Genetic predisposition and chromosomal abnormalities, including fragile-X syndrome, Turner syndrome, and X structural abnormalities or X aneuploidy, are common causes of POI. The genetic cause of POI is often single-gene disorders, with pathological variations in about 100 genes documented in the academic literature [ 1 , 6 , 7 ]. These genes are implicated in various biological processes such as development (Wilms tumor, type 1 = WT1 ; nuclear receptor subfamily 5, group a, member 1 = NR5A1 ), meiosis (helicase for meiosis 1 = HFM1 ; mutS homolog 4 = MSH4 ; DNA meiotic recombinase 1 = DMC1 ; tubulin β 8 class VIII = TUBB8 ), follicle development (bone morphogenetic protein 15 = BMP15 ; newborn ovary homeobox = NOBOX ; specific bHLH transcription factor for folliculogenesis = FIGLA; forkhead box L2 = FOXL2 ), hormonal signaling ( FSH , FSH receptor = FSHR; luteinizing hormone subunit β = LH ; LH receptor = LHR ), metabolism (mitochondrial leucyl-tRNA synthetase 2, mitochondrial = LARS2), and immune regulation (autoimmune regulator = AIRE ) [ 1 ].…”