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Array-CGH diagnosis in ovarian failure: identification of new molecular actors for ovarian physiology.

ABSTRACT: Ovarian failure (OF) is considered premature if it occurs before the age of 40. This study investigates the genetic aetiology underlying OF in women under the age of 40 years.We conducted an experimental prospective study performing all genome microarrays in 60 patients younger than 40 years presenting an OF revealed by a decrease of circulating Anti-Müllerian Hormone (AMH) and leading to an oocyte donation program.We identified nine significant copy number variations (CNVs) including candidate genes potentially implicated in reproductive function. These genes are principally involved in cell division and chromosome segregation (SYCE1, CLASP1, CENP-A, CDC16), in ciliary development and/or function (RSPH1, KIF24), are linked with known gonadal genes or expressed in female genital tract (CSMD1, SEMA6D, KIAA1324).Our data strengthen the idea that microarrays should be used in combination with karyotype for aetiological assessment of patients with OF. This analysis may have a therapeutic impact as the identification of new molecular actors for gonadal development or ovarian physiology is useful for the prediction of an ovarian reserve decline and makes possible preventive fertility preservation.

SUBMITTER: Jaillard S

PROVIDER: S-EPMC5048446 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Array-CGH diagnosis in ovarian failure: identification of new molecular actors for ovarian physiology.

Jaillard Sylvie S Akloul Linda L Beaumont Marion M Hamdi-Roze Houda H Dubourg Christele C Odent Sylvie S Duros Solène S Dejucq-Rainsford Nathalie N Belaud-Rotureau Marc-Antoine MA Ravel Célia C

Journal of ovarian research 20161003 1

<h4>Background</h4>Ovarian failure (OF) is considered premature if it occurs before the age of 40. This study investigates the genetic aetiology underlying OF in women under the age of 40 years.<h4>Methods</h4>We conducted an experimental prospective study performing all genome microarrays in 60 patients younger than 40 years presenting an OF revealed by a decrease of circulating Anti-Müllerian Hormone (AMH) and leading to an oocyte donation program.<h4>Results</h4>We identified nine significant ...[more]

PMID: 27716277

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Project description:STUDY QUESTION:Can high resolution array-CGH analysis on a cohort of women showing a primary ovarian insufficiency (POI) phenotype in young age identify copy number variants (CNVs) with a deleterious effect on ovarian function? SUMMARY ANSWER:This approach has proved effective to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms. WHAT IS KNOWN ALREADY:POI describes the progression toward the cessation of ovarian function before the age of 40 years. Genetic causes are highly heterogeneous and despite several genes being associated with ovarian failure, most of genetic basis of POI still needs to be elucidated. STUDY DESIGN, SIZE, DURATION:The current study included 67 46,XX patients with early onset POI (<19 years) and 134 control females recruited between 2012 and 2016 at the Medical Cytogenetics and Molecular Genetics Lab, IRCCS Istituto Auxologico Italiano. PARTICIPANTS/MATERIALS, SETTING, METHODS:High resolution array-CGH analysis was carried out on POI patients' DNA. Results of patients and female controls were analyzed to search for rare CNVs. All variants were validated and subjected to a gene content analysis and disease gene prioritization based on the present literature to find out new ovary candidate genes. Case-control study with statistical analysis was carried out to validate our approach and evaluate any ovary CNVs/gene enrichment. Characterization of particular CNVs with molecular and functional studies was performed to assess their pathogenic involvement in POI. MAIN RESULTS AND THE ROLE OF CHANCE:We identified 37 ovary-related CNVs involving 44 genes with a role in ovary in 32 patients. All except one of the selected CNVs were not observed in the control group. Possible involvement of the CNVs in POI pathogenesis was further corroborated by a case-control analysis that showed a significant enrichment of ovary-related CNVs/genes in patients (P = 0.0132; P = 0.0126). Disease gene prioritization identified both previously reported POI genes (e.g. BMP15, DIAPH2, CPEB1, BNC1) and new candidates supported by transcript and functional studies, such as TP63 with a role in oocyte genomic integrity and VLDLR which is involved in steroidogenesis. LARGE SCALE DATA:ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/); accession numbers SCV000787656 to SCV000787743. LIMITATIONS, REASONS FOR CAUTION:This is a descriptive analysis for almost all of the CNVs identified. Inheritance studies of CNVs in some non-familial sporadic cases was not performed as the parents' DNA samples were not available. Addionally, RT-qPCR analyses were carried out in few cases as RNA samples were not always available and the genes were not expressed in blood. WIDER IMPLICATIONS OF THE FINDINGS:Our array-CGH screening turned out to be efficient in identifying different CNVs possibly implicated in disease onset, thus supporting the extremely wide genetic heterogeneity of POI. Since almost 50% of cases are negative rare ovary-related CNVs, array-CGH together with next generation sequencing might represent the most suitable approach to obtain a comprehensive genetic characterization of POI patients. STUDY FUNDING/COMPETING INTEREST(S):Supported by Italian Ministry of Health grants 'Ricerca Corrente' (08C203_2012) and 'Ricerca Finalizzata' (GR-2011-02351636, BIOEFFECT) to IRCCS Istituto Auxologico Italiano.

Dataset Information

Array-CGH diagnosis in ovarian failure: identification of new molecular actors for ovarian physiology.

Publications

Array-CGH diagnosis in ovarian failure: identification of new molecular actors for ovarian physiology.

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