Primordial follicle pool depletion is the cause of primary ovarian insufficiency (POI) in most women. POI afflicts 1-2% of women, and genetics contributes as much as 70% to POI. Besides infertility, women with POI are at increased risk for osteoporosis, cardiovascular morbidity and mortality. Currently only karyotype and FMR1 pre-mutation testing are offered to women with POI. Fertility preservation is currently feasible for women at risk for losing ovarian function, yet there is a great need for robust and better biomarkers capable of predicting ovarian insufficiency. We are interested in identifying genetic biomarkers that associate with POI. The role of the X chromosome and candidate autosomal genes implicated from knockout animal models has been hypothesized for a long time in the etiology of human POI, yet there is little to show at the gene level. We constructed a novel high-resolution genomic array that interrogates the X chromosome and 134 candidate autosomal gene copy numbers. We show that this array can detect genomic imbalances as small as 500 base pairs, and is superior to commercial arrays. We hypothesize that pathologic genomic imbalances involving the X chromosome and candidate autosomal loci, will be present in more than 10% of women who suffer POI. Moreover, we will sequence the X-chromosome exomes, as well as the exomes of 134 candidate autosomal genes to define contribution of pathogenic mutations to POI. Our proposal will test the relevance of our targeted approach in identifying pathogenic mutations in women with POI, and will stimulate further research into the feasibility of such targeted approaches to predict ovarian failure. Proposed studies may identify novel pathways, and provide future directions for basic science investigations relevant to human POI.

Public Health Relevance

Ovarian insufficiency adversely affects women's reproductive potential, psychosocial well-being, bone mineralization, cardiovascular health and life span. X-chromosome plays an important role in ovarian development and failure. We propose to determine genetic etiology of human ovarian failure through analyzing X-chromosome and candidate autosomal genes of affected women. Identification of novel genetic markers for human ovarian insufficiency will in the future help identify women at risk for increased medical morbidity and mortality, offer them early intervention(s) to preserve their reproductive options, and help design therapies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Taymans, Susan
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Magee-Women's Research Institute and Foundation
United States
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Katari, Sunita; Aarabi, Mahmoud; Kintigh, Angela et al. (2018) Chromosomal instability in women with primary ovarian insufficiency. Hum Reprod 33:531-538
Ren, Yu; Diao, Feiyang; Katari, Sunita et al. (2018) Functional study of a novel missense single-nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency. Mol Genet Genomic Med 6:276-281
Desai, Swapna; Wood-Trageser, Michelle; Matic, Jelena et al. (2017) MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency. J Clin Endocrinol Metab 102:576-582
Yatsenko, S A; Bakos, H A; Vitullo, K et al. (2016) High-resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X-linked blue cone monochromacy. Clin Genet 89:82-7
Katari, S; Wood-Trageser, M A; Jiang, H et al. (2015) Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin With Premature Ovarian Failure. J Clin Endocrinol Metab 100:2154-7
AlAsiri, Saleh; Basit, Sulman; Wood-Trageser, Michelle A et al. (2015) Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest 125:258-62
Wood-Trageser, Michelle A; Gurbuz, Fatih; Yatsenko, Svetlana A et al. (2014) MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet 95:754-62