Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases

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Tsuiko , O , Noukas , M , Zilina , O , Hensen , K , Tapanainen , J S , Magi , R , Kals , M , Kivistik , P A , Haller-Kikkatalo , K , Salumets , A & Kurg , A 2016 , ' Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases ' , Human Reproduction , vol. 31 , no. 8 , pp. 1913-1925 . https://doi.org/10.1093/humrep/dew142

Title: Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases
Author: Tsuiko, O.; Noukas, M.; Zilina, O.; Hensen, K.; Tapanainen, J. S.; Magi, R.; Kals, M.; Kivistik, P. A.; Haller-Kikkatalo, K.; Salumets, A.; Kurg, A.
Contributor: University of Helsinki, Clinicum
University of Helsinki, HUS Gynecology and Obstetrics
Date: 2016-08
Language: eng
Number of pages: 13
Belongs to series: Human Reproduction
ISSN: 0268-1161
URI: http://hdl.handle.net/10138/169138
Abstract: Can spontaneous premature ovarian failure (POF) patients derived from population-based biobanks reveal the association between copy number variations (CNVs) and POF? CNVs can hamper the functional capacity of ovaries by disrupting key genes and pathways essential for proper ovarian function. POF is defined as the cessation of ovarian function before the age of 40 years. POF is a major reason for female infertility, although its cause remains largely unknown. The current retrospective CNV study included 301 spontaneous POF patients and 3188 control individuals registered between 2003 and 2014 at Estonian Genome Center at the University of Tartu (EGCUT) biobank. DNA samples from 301 spontaneous POF patients were genotyped by Illumina HumanCoreExome (258 samples) and HumanOmniExpress (43 samples) BeadChip arrays. Genotype and phenotype information was drawn from the EGCUT for the 3188 control population samples, previously genotyped with HumanCNV370 and HumanOmniExpress BeadChip arrays. All identified CNVs were subjected to functional enrichment studies for highlighting the POF pathogenesis. Real-time quantitative PCR was used to validate a subset of CNVs. Whole-exome sequencing was performed on six patients carrying hemizygous deletions that encompass genes essential for meiosis or folliculogenesis. Eleven novel microdeletions and microduplications that encompass genes relevant to POF were identified. For example, FMN2 (1q43) and SGOL2 (2q33.1) are essential for meiotic progression, while TBP (6q27), SCARB1 (12q24.31), BNC1 (15q25) and ARFGAP3 (22q13.2) are involved in follicular growth and oocyte maturation. The importance of recently discovered hemizygous microdeletions of meiotic genes SYCE1 (10q26.3) and CPEB1 (15q25.2) in POF patients was also corroborated. This is a descriptive analysis and no functional studies were performed. Anamnestic data obtained from population-based biobank lacked clinical, biological (hormone levels) or ultrasonographical data, and spontaneous POF was predicted retrospectively by excluding known extraovarian causes for premature menopause. The present study, with high number of spontaneous POF cases, provides novel data on associations between the genomic aberrations and premature menopause of ovarian cause and demonstrates that population-based biobanks are powerful source of biological samples and clinical data to reveal novel genetic lesions associated with human reproductive health and disease, including POF. This study was supported by the Estonian Ministry of Education and Research (IUT20-43, IUT20-60, IUT34-16, SF0180027s10 and 9205), Enterprise Estonia (EU30020 and EU48695), Eureka's EUROSTARS programme (NOTED, EU41564), grants from European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, SARM, |EU324509) and Horizon 2020 innovation programme (WIDENLIFE, 692065), Academy of Finland and the Sigrid Juselius Foundation.
Subject: copy number variation
CNV
menopause
premature ovarian failure
POF
SNP genotyping
population-based biobank
HIDDEN-MARKOV MODEL
SNP GENOTYPING DATA
MENOPAUSAL TRANSITION
NATURAL MENOPAUSE
GRANULOSA-CELLS
GENOME
WOMEN
MUTATIONS
VARIANTS
MICE
3123 Gynaecology and paediatrics
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