Corrine Kolka Welt

Background: Primary ovarian insufficiency (POI) is a heterogeneous disorder, with the relative frequency of known etiologies incompletely defined at a population level. Objectives: We used chart review and whole-genome sequencing (WGS) to determine known diagnoses, pathogenic variants, and common polygenic risk. Methods: Women with POI were identified using International Classification of Diseases codes. Established clinical etiologies were documented. A subset of 68 women without an identified cause underwent WGS. Rare pathogenic variants were identified using an electronic clinical decision support framework, and common genetic risk was quantified using a polygenic risk score (PGS) for age at natural menopause. Results: Of 899 women with POI, 289 carried a diagnosis of Turner syndrome (32.1%). Of the other 610 evaluable women, established clinical etiologies were identified in 8.1%, including FMR1 premutations (2.6%), chromosomal abnormalities (1.5%), and adrenal autoimmunity (1.8%). Among the 68 women with POI who underwent WGS, a likely causal genetic diagnosis was identified in 17.6% (12/68) of cases. Autosomal recessive variants were enriched among women with primary amenorrhea, whereas heterozygous or multiple rare variants in DNA damage repair pathways predominated in secondary amenorrhea. While overall mean PGS did not differ from controls, low PGS (<−0.5 standard deviation) compounded POI risk in a subset of women carrying rare variants. Conclusion: The population-level data supports rates of established POI etiologies and a gradation of genetic burden in which chromosomal abnormalities and recessive inheritance contribute to POI manifesting as primary amenorrhea, whereas heterozygous rare variants and common polygenic risk can predispose to secondary amenorrhea.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study ( n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Polycystic ovary syndrome (PCOS) is a complex, multi-system, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive-aged women. While insulin resistance (IR) is not a diagnostic feature, it is widespread in women with PCOS, and often more severe than in women of similar age and BMI. Conversely, women with rare Mendelian disorders of IR also present with features of PCOS. We hypothesize that PCOS is driven by underlying IR, which can be evaluated through a genetic approach. We curated and stratified 310 genes related to three mechanisms of IR using molecular and clinical criteria. We evaluated protein-altering genetic variation in 102 insulin signaling genes, 29 obesity genes, and 22 dyslipidemia genes from whole-exome sequencing data from 675 PCOS patients. 40 insulin signaling genes, 12 obesity genes, and 10 dyslipidemia genes were significantly enriched for protein-altering variation in PCOS cases compared to healthy population controls. Variants in these 62 significantly enriched genes affected 51% of PCOS cases in our study cohort. The 15 highest ranked genes were selected for follow-up: LMNA, LEPR, KCNJ11, BSCL2, ACACA, NTRK2, GCK, ABCC8, SLC2A2, POMC, MC4R, TBC1D4, INSR, NR0B2, and GCKR . 50% of variants identified in these 15 genes were pathogenic, 35% were likely pathogenic, and only 15% were variants of uncertain significance. These findings support IR as a central pathway in PCOS. Furthermore, this study demonstrates that a candidate pathway approach with sufficient pre-processing can successfully identify functionally relevant variants and genes underlying complex traits.

Background: Nonobstructive azoospermia (NOA) and primary ovarian insufficiency (POI) have common genetics that may also predispose patients to cancer risk. Objectives: We hypothesized that NOA or severe oligozoospermia and the risk of male cancers would be higher in families of women with POI. Methods: Women with POI were identified using International Classification of Disease codes in electronic medical records (1995-2021) from 2 major healthcare systems in Utah and reviewed for accuracy. Using genealogy information in the Utah Population Database, women with POI (n = 392) and their relatives were included if there were at least 3 generations of ancestors available. Men with NOA or severe oligozoospermia (≤5 million/mL) from the Subfertility Health and Assisted Reproduction and the Environment Study were identified in these families and risk was calculated in relatives compared to population rates. The relative risk of prostate and testicular cancer was examined using the Utah Cancer Registry. Results: There was an increased risk of NOA/severe oligozoospermia in relatives of women with POI among first- (relative risk 2.8 [95% confidence interval 1.1, 6.7]; P = .03), second- (3.1 [1.1, 6.7]; P = .02), and third-degree relatives (1.8 [1.1, 3.1]; P = .03). In these families with POI and NOA/oligozoospermia (n = 21), prostate cancer risk was higher in first- (3.5 [1.1, 8.1]; P = .016) and second-degree relatives (3.1 [1.9, 4.8]; P = .000008). Conclusion: The data demonstrate excess familial clustering of severe spermatogenic impairment compared to matched population rates, along with higher prostate cancer risk in relatives of women with POI. These findings support a common genetic contribution to POI, spermatogenic impairment, and prostate cancer.

We created the c.1286C>G stop-gain mutation found in a family with primary ovarian insufficiency (POI) at age 30 years. The Eif4enif1 C57/Bl6 transgenic mouse model contained a floxed exon 10-19 cassette with a conditional knock-in cassette containing the c.1286C>G stop-gain mutation in exon 10. The hybrid offspring of CMV-Cre mice with Eif4enif1WT/flx mice were designated Eif4enif1WT/Δ for simplicity. A subset of female heterozygotes (Eif4enif1WT/Δ) had no litters. In those with litters, the final litter was earlier (5.4 ± 2.6 vs 10.5 ± 0.7 months; P = .02). Heterozygous breeding pair (Eif4enif1WT/Δ × Eif4enif1WT/Δ) litter size was 60% of WT litter size (3.9 ± 2.0 vs 6.5 ± 3.0 pups/litter; P < .001). The genotypes were 35% Eif4enif1WT/flx and 65% Eif4enif1WT/Δ, with no homozygotes. Homozygote embryos did not develop beyond the 4- to 8-cell stage. The number of follicles in ovaries from Eif4enif1WT/Δ mice was lower starting at the primordial (499 ± 290 vs 1445 ± 381) and primary follicle stage (1069 ± 346 vs 1450 ± 193) on day 10 (P < .05). The preantral follicle number was lower starting on day 21 (213 ± 86 vs 522 ± 227; P < .01). Examination of ribosome protected mRNAs demonstrated altered mRNA expression. The Eif4enif1 stop-gain mice replicate the POI phenotype in women based on an earlier end to reproduction due to oocyte loss. The unique mouse model provides a platform to study regulation of protein translation across oocyte and embryo development in mammals.

STUDY QUESTION: Is there an increased risk of reproductive or colon cancer in women with Turner syndrome and their family members? SUMMARY ANSWER: Our data suggest that there is an increased risk for sigmoid colon cancer in women with Turner syndrome and an increased prostate cancer risk in second- and third-degree male relatives. WHAT IS KNOWN ALREADY: Turner syndrome has been associated with lower risk of breast cancer, but increased risk of gonadoblastoma and colon cancer in some, but not all studies. There is also evidence for a genetic predisposition to sex chromosome aneuploidy, which may indicate a predisposition to Turner syndrome and the associated cancer risk in family members. STUDY DESIGN, SIZE, DURATION: The study was a retrospective case–control study of women with Turner syndrome diagnosed from 1995 to 2021, their relatives, and population subjects from Utah. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with Turner syndrome were identified using International Classification of Disease (ICD) codes in electronic medical records from two major Utah healthcare systems and reviewed for accuracy. Women with Turner syndrome were linked to genealogy in the Utah Population Database. Cancer diagnoses (breast, ovarian, endometrial, colon, testicular, and prostate) were determined for women with Turner syndrome and their relatives using the Utah Cancer Registry. Live births to women with Turner syndrome were identified by linked birth certificates. The relative risk of cancer in women with Turner syndrome and in relatives was estimated by comparison to population rates matched by age, sex, and birthplace. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 289 women with Turner syndrome. Sigmoid colon cancer was increased in women with Turner syndrome (OR [95% CI] 24.2 [2.9, 87.4]; P = 0.0032). There were 233 women with Turner syndrome who had at least three generations of genealogical data. There was an increased risk of Turner syndrome in first- (OR [95% CI] 18.08 [2.19, 65.32]; P = 0.0057) and second-degree relatives (9.62 [1.17, 34.74]; P = 0.019), although numbers were very small. There was an increased risk of prostate cancer in second- (1.8 [1.4, 2.2]; P < 0.001) and third-degree relatives (1.3 [1.1, 1.5]; P < 0.001). There was no increased risk of colon cancer in relatives. LIMITATIONS, REASONS FOR CAUTION: Based on the small number of sigmoid colon cancer cases, it is possible that our data have overestimated the colon cancer risk. Limitations include the identification of Turner syndrome by a diagnosis code in one of the two major health systems in Utah. The population is largely northern European with 9.3% of the women self-identified as Hispanic and 2.4% as Native American or multiple races. The results may not be generalizable to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that women with Turner syndrome may need early screening for colon cancer. Additional studies are needed to identify risk factors for sex chromosome aneuploidy and cancer risk in women with Turner syndrome and their male relatives. STUDY FUNDING/COMPETING INTEREST(S): The work in this publication was supported by R56HD090159 and R01HD099487 (C.K.W.). We also acknowledge partial support for the Utah Population Database through grant P30 CA2014 from the National Cancer Institute. The Utah Cancer Registry is funded by the National Cancer Institute’s SEER Program, Contract No. HHSN261201800016I, the US Centers for Disease Control and Prevention’s National Program of Cancer Registries, Cooperative Agreement No. NU58DP007131, with additional support from the University of Utah and Huntsman Cancer Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.