Array comparative genomic hybridization profiling analysis reveals deoxyribonucleic acid copy number variations associated with premature ovarian failure.
BACKGROUND
Premature ovarian failure (POF) is defined by amenorrhea of at least 4- to 6-month duration, occurring before 40 yr of age, with two FSH levels in the postmenopausal range. Its etiology remains unknown in more than 80% of cases. Standard karyotypes, having a resolution of 5-10 Mb, have identified critical chromosomal regions, mainly located on the long arm of the X chromosome. Array comparative genomic hybridization (a-CGH) analysis is able to detect submicroscopic chromosomal rearrangements with a higher genomic resolution. We searched for copy number variations (CNVs), using a-CGH analysis with a resolution of approximately 0.7 Mb, in a cohort of patients with POF.


METHODS
We prospectively included 99 women. Our study included a conventional karyotype and DNA microarrays comprising 4500 bacterial artificial chromosome clones spread on the entire genome.


RESULTS
Thirty-one CNVs have been observed, three on the X chromosome and 28 on autosomal chromosomes. Data have been compared to control populations obtained from the Database of Genomic Variants (http://projects.tcag.ca/variation). Eight statistically significantly different CNVs have been identified in chromosomal regions 1p21.1, 5p14.3, 5q13.2, 6p25.3, 14q32.33, 16p11.2, 17q12, and Xq28.


CONCLUSIONS
We report the first study of CNV analysis in a large cohort of Caucasian POF patients. In the eight statistically significant CNVs we report, we found five genes involved in reproduction, thus representing potential candidate genes in POF. The current study along with emerging information regarding CNVs, as well as data on their potential association with human diseases, emphasizes the importance of assessing CNVs in cohorts of POF women.
Aboura
Azzedine
A
Department of Endocrinology, Saint-Antoine Hospital, Centre de Référence des Maladies, Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris, ER9 University Pierre et Marie Curie, 75005 Paris, France.
Dupas
Claire
C
Tachdjian
Gérard
G
Portnoï
Marie-France
MF
Bourcigaux
Nathalie
N
Dewailly
Didier
D
Frydman
René
R
Fauser
Bart
B
Ronci-Chaix
Nathalie
N
Donadille
Bruno
B
Bouchard
Philippe
P
Christin-Maitre
Sophie
S
D000328:Adult; D022202:Chromosomes, Artificial, Bacterial; D041321:Chromosomes, Human, X; D055028:Comparative Genomic Hybridization / Q000379:methods*; D004247:DNA / Q000235:genetics* / Q000302:isolation & purification; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D020869:Gene Expression Profiling / Q000379:methods*; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D007621:Karyotyping; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017698:Postmenopause; D016649:Primary Ovarian Insufficiency / Q000097:blood / Q000235:genetics*; D011446:Prospective Studies; D014178:Translocation, Genetic
D005640:Follicle Stimulating Hormone; D004247:DNA