The population-level, multi-generational study found that close and distant relatives of women with primary ovarian failure had a higher risk of developing this condition compared to matched controls.
There may be a strong genetic component to primary ovarian failure (POF), according to the results of a multigenerational pedigree study of POI published in Fertility and sterility it is also the first population-based assessment of POI family reunification.
POI, like other conditions affecting fertility such as early menopause, is thought to be largely genetic. RMF1 (FMRP translational regulator 1) Premutations and autoimmune polyglandular syndromes are the most frequent known genetic causes. However, there is a lack of population-based studies to determine the true prevalence of familial IPOs beyond first-degree relatives.
“We hypothesized that POIs would exhibit excess family clustering of first- to third-degree relatives when studied at the population level and would indicate patterns of inheritance,” the authors wrote. The study examined trends in multigenerational pedigree data related to individuals with electronic medical records (EMRs) indicating a diagnosis of POI.
Women 40 years of age or younger with POI were identified by EMRs from the University of Utah Health Sciences Center and Intermountain Healthcare from 1995 to 2021. Nearly 85% of all residents of Utah are treated in these 2 health care systems. The Utah Population Database (UPDB), which links genealogical information with information from medical records and other sources of demographic data, was used to assess the family of POIs in the study. Eligible individuals had at least 3 generations of data in the system.
There were 1440 confirmed cases of POI in health care system databases, and 396 of these individuals had 3 generations of data available in the UPDB. These women had 2,132 first-degree relatives, 5,245 second-degree relatives, and 10,853 third-degree relatives. The risk of POI in the parents was compared to the risk in a control group matched by age, sex and place of birth.
Rates of POI were significantly higher in relatives of women with POI than in the general population. First-degree relatives of women with POI had a relative risk (RR) of 18.52 compared to the control group, second-degree relatives had an RR of 4.21, and third-degree relatives had an RR of 2 .67. Of the 396 cases initially identified, 6.3% had a loved one affected.
The researchers also used the Pedigree Familiarity Index (GIF) to test for excess relatedness to matched controls. The GIF measures the average relatedness per pair of all possible pairs of POI cases relative to the average relatedness of 1000 sets of matched controls. It is used in genealogical research and other family studies to assess the kinship of participants.
The GIF results in this study were significant, with POI cases showing a GIF of 5.24 overall and controls showing a GIF of 2.38. Notably, the distant GIF outcome that only includes third-degree relatives was not significantly different between controls and cases. The GIF statistic was mostly due to close relatives.
Additional relatives with POI were identified through the chart review, but were excluded from the family analyzes because they were found through a different methodology than the original group. However, they were added to an analysis of high-risk POI pedigrees.
Overall, 49 high-risk pedigrees were identified in the study. There were 12 families with affected mother and daughter, suggesting possible dominant or complex modes of inheritance, and 4 families with affected sister pairs, suggesting dominant or recessive inheritance. In the rest of the families, the closest relations were third-degree relatives, suggesting a dominant mode of inheritance with or without incomplete expressiveness or a complex mode of inheritance. In some families there is evidence of uniquely female expressiveness with the possibility of male carriers.
The results show excessive familiarity and family clustering of POIs compared to matched controls. First-degree relatives of women with POI were most at risk, but second- and third-degree relatives also had a higher RR than the general population. This study is the largest to date to assess the incidence of POIs in close and extended families of people with POIs.
“This finding supports the concept that ovarian aging has a strong genetic component with heterogeneous inheritance patterns and highlights the importance of understanding the heritability of ovarian aging and the risks of aberrant pathways,” the authors concluded.
Verrilli L, Johnstone E, Welt C, Allen-Brady K. Primary ovarian failure has a strong familial connection: results from a multigenerational pedigree study. Fertile Sterile. Published online October 22, 2022. doi:10.1016/j.fertnstert.2022.09.027
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