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Hum Reprod. 2017 Jul 1;32(7):1512-1520. doi: 10.1093/humrep/dex089.

New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing.

Author information

1
Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24N° 63C-69, CP 112111, Bogotá DC, Colombia.
2
Inserm 1185, Le Kremlin-Bicêtre 94276, Université Paris-Saclay, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France.
3
Fundación Instituto de Inmunología de Colombia (FIDIC), Carrera 50 N° 26-20, CP 111321, Bogotá DC, Colombia.
4
Universidad de Ciencias Aplicadas y Ambientales (UDCA), Calle 222 N° 55-37, CP 111166, Bogotá DC, Colombia.
5
Basic Sciences Department, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 N° 63C-69, CP 112111, Bogotá DC, Colombia.
6
Service d'Endocrinologie-Diabète-Nutrition, CHU de Reims-Hôpital Robert-Debré, 51092 Reims, France.
7
APHP, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicêtre 94275, France.

Abstract

STUDY QUESTION:

Is it possible to identify new mutations potentially associated with non-syndromic primary ovarian insufficiency (POI) via whole-exome sequencing (WES)?

SUMMARY ANSWER:

WES is an efficient tool to study genetic causes of POI as we have identified new mutations, some of which lead to protein destablization potentially contributing to the disease etiology.

WHAT IS KNOWN ALREADY:

POI is a frequently occurring complex pathology leading to infertility. Mutations in only few candidate genes, mainly identified by Sanger sequencing, have been definitively related to the pathogenesis of the disease.

STUDY DESIGN, SIZE, DURATION:

This is a retrospective cohort study performed on 69 women affected by POI.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

WES and an innovative bioinformatics analysis were used on non-synonymous sequence variants in a subset of 420 selected POI candidate genes. Mutations in BMPR1B and GREM1 were modeled by using fragment molecular orbital analysis.

MAIN RESULTS AND THE ROLE OF CHANCE:

Fifty-five coding variants in 49 genes potentially related to POI were identified in 33 out of 69 patients (48%). These genes participate in key biological processes in the ovary, such as meiosis, follicular development, granulosa cell differentiation/proliferation and ovulation. The presence of at least two mutations in distinct genes in 42% of the patients argued in favor of a polygenic nature of POI.

LIMITATIONS, REASONS FOR CAUTION:

It is possible that regulatory regions, not analyzed in the present study, carry further variants related to POI.

WIDER IMPLICATIONS OF THE FINDINGS:

WES and the in silico analyses presented here represent an efficient approach for mapping variants associated with POI etiology. Sequence variants presented here represents potential future genetic biomarkers.

STUDY FUNDING/COMPETING INTEREST(S):

This study was supported by the Universidad del Rosario and Colciencias (Grants CS/CIGGUR-ABN062-2016 and 672-2014). Colciencias supported Liliana Catherine Patiño´s work (Fellowship: 617, 2013). The authors declare no conflict of interest.

KEYWORDS:

female infertility; molecular etiology; polygenic disease; primary ovarian insufficiency; whole-exome sequencing

PMID:
28505269
DOI:
10.1093/humrep/dex089
[Indexed for MEDLINE]

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