A novel role for genomic copy number variants in female infertility

Abstract

ObjectiveCopy number variants (CNVs) are genomic aberrations that alter the number of copies of genomic segments and therefore have the potential to alter dosage-sensitive genes and/or functional elements. Recent studies have shown that CNVs underlie various complex spectrum disorders and that the severity of the disorder is correlated with overall CNV burden. To investigate the role of CNVs in female infertility spectrum disorders, we have performed a survey examining CNVs in a cohort of patients with unexplained infertility.DesignRetrospective cohort of female patients with unexplained infertility.Materials and MethodsGenomic DNA extracted from blood samples was obtained from patients undergoing non-donor in-vitro fertilization (IVF) cycles at a large academic medical center. CNVs were detected using a custom NimbleGen Comparative Genomic Hybridization (CGH) Whole-Genome Tiling Array optimized for fertility-related loci. The resulting log2 ratios of the raw intensities were then normalized and segmented. The prevalence of CNVs among the infertile cohort was compared to the Children's Hospital of Philadelphia (CHOP) CNV database of healthy individuals.ResultsApproximately 30% of the >3000 CNVs detected were unique to the infertile patients (P<10-7, Binomial Test of Proportions). Moreover, CNVs specific to the infertile cohort appear to be overrepresented among regions of the genome predicted to play a role in mammalian fertility (P<10-16, t-test).ConclusionThe set of CNVs uniquely observed in our female unexplained infertility cohort represent putative genetic biomarkers that may predict a range of infertility conditions difficult to diagnose with existing clinical data. ObjectiveCopy number variants (CNVs) are genomic aberrations that alter the number of copies of genomic segments and therefore have the potential to alter dosage-sensitive genes and/or functional elements. Recent studies have shown that CNVs underlie various complex spectrum disorders and that the severity of the disorder is correlated with overall CNV burden. To investigate the role of CNVs in female infertility spectrum disorders, we have performed a survey examining CNVs in a cohort of patients with unexplained infertility. Copy number variants (CNVs) are genomic aberrations that alter the number of copies of genomic segments and therefore have the potential to alter dosage-sensitive genes and/or functional elements. Recent studies have shown that CNVs underlie various complex spectrum disorders and that the severity of the disorder is correlated with overall CNV burden. To investigate the role of CNVs in female infertility spectrum disorders, we have performed a survey examining CNVs in a cohort of patients with unexplained infertility. DesignRetrospective cohort of female patients with unexplained infertility. Retrospective cohort of female patients with unexplained infertility. Materials and MethodsGenomic DNA extracted from blood samples was obtained from patients undergoing non-donor in-vitro fertilization (IVF) cycles at a large academic medical center. CNVs were detected using a custom NimbleGen Comparative Genomic Hybridization (CGH) Whole-Genome Tiling Array optimized for fertility-related loci. The resulting log2 ratios of the raw intensities were then normalized and segmented. The prevalence of CNVs among the infertile cohort was compared to the Children's Hospital of Philadelphia (CHOP) CNV database of healthy individuals. Genomic DNA extracted from blood samples was obtained from patients undergoing non-donor in-vitro fertilization (IVF) cycles at a large academic medical center. CNVs were detected using a custom NimbleGen Comparative Genomic Hybridization (CGH) Whole-Genome Tiling Array optimized for fertility-related loci. The resulting log2 ratios of the raw intensities were then normalized and segmented. The prevalence of CNVs among the infertile cohort was compared to the Children's Hospital of Philadelphia (CHOP) CNV database of healthy individuals. ResultsApproximately 30% of the >3000 CNVs detected were unique to the infertile patients (P<10-7, Binomial Test of Proportions). Moreover, CNVs specific to the infertile cohort appear to be overrepresented among regions of the genome predicted to play a role in mammalian fertility (P<10-16, t-test). Approximately 30% of the >3000 CNVs detected were unique to the infertile patients (P<10-7, Binomial Test of Proportions). Moreover, CNVs specific to the infertile cohort appear to be overrepresented among regions of the genome predicted to play a role in mammalian fertility (P<10-16, t-test). ConclusionThe set of CNVs uniquely observed in our female unexplained infertility cohort represent putative genetic biomarkers that may predict a range of infertility conditions difficult to diagnose with existing clinical data. The set of CNVs uniquely observed in our female unexplained infertility cohort represent putative genetic biomarkers that may predict a range of infertility conditions difficult to diagnose with existing clinical data.