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Phenotypic heterogeneity of genomic disorders and rare copy-number variants.

ABSTRACT: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02).Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

SUBMITTER: Girirajan S

PROVIDER: S-EPMC3494411 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Phenotypic heterogeneity of genomic disorders and rare copy-number variants.

Girirajan Santhosh S Rosenfeld Jill A JA Coe Bradley P BP Parikh Sumit S Friedman Neil N Goldstein Amy A Filipink Robyn A RA McConnell Juliann S JS Angle Brad B Meschino Wendy S WS Nezarati Marjan M MM Asamoah Alexander A Jackson Kelly E KE Gowans Gordon C GC Martin Judith A JA Carmany Erin P EP Stockton David W DW Schnur Rhonda E RE Penney Lynette S LS Martin Donna M DM Raskin Salmo S Leppig Kathleen K Thiese Heidi H Smith Rosemarie R Aberg Erika E Niyazov Dmitriy M DM Escobar Luis F LF El-Khechen Dima D Johnson Kisha D KD Lebel Robert R RR Siefkas Kiana K Ball Susie S Shur Natasha N McGuire Marianne M Brasington Campbell K CK Spence J Edward JE Martin Laura S LS Clericuzio Carol C Ballif Blake C BC Shaffer Lisa G LG Eichler Evan E EE

The New England journal of medicine 20120912 14

<h4>Background</h4>Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.<h4>Methods</h4>We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.<h4>Results</h4>Among the affected children, 10.1% ca ...[more]

PMID: 22970919

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Project description:Endometriosis is a complex gynecological condition that affects 6-10% of women in their reproductive years and is defined by the presence of endometrial glands and stroma outside the uterus. Twin, family, and genome-wide association (GWA) studies have confirmed a genetic role, yet only a small part of the genetic risk can be explained by SNP variation. Copy number variants (CNVs) account for a greater portion of human genetic variation than SNPs and include more recent mutations of large effect. CNVs, likely to be prominent in conditions with decreased reproductive fitness, have not previously been examined as a genetic contributor to endometriosis. Here we employ a high-density genotyping microarray in a genome-wide survey of CNVs in a case-control population that includes 2,126 surgically confirmed endometriosis cases and 17,974 population controls of European ancestry. We apply stringent quality filters to reduce the false positive rate common to many CNV-detection algorithms from 77.7% to 7.3% without noticeable reduction in the true positive rate. We detected no differences in the CNV landscape between cases and controls on the global level which showed an average of 1.92 CNVs per individual with an average size of 142.3 kb. On the local level we identify 22 CNV-regions at the nominal significance threshold (P<0.05), which is greater than the 8.15 CNV-regions expected based on permutation analysis (P<0.001). Three CNV's passed a genome-wide P-value threshold of 9.3 × 10(-4); a deletion at SGCZ on 8p22 (P = 7.3 × 10(-4), OR = 8.5, Cl = 2.3-31.7), a deletion in MALRD1 on 10p12.31 (P = 5.6 × 10(-4), OR = 14.1, Cl = 2.7-90.9), and a deletion at 11q14.1 (P = 5.7 × 10(-4), OR = 33.8, Cl = 3.3-1651). Two SNPs within the 22 CNVRs show significant genotypic association with endometriosis after adjusting for multiple testing; rs758316 in DPP6 on 7q36.2 (P = 0.0045) and rs4837864 in ASTN2 on 9q33.1 (P = 0.0002). Together, the CNV-loci are detected in 6.9% of affected women compared to 2.1% in the general population.

Dataset Information

Phenotypic heterogeneity of genomic disorders and rare copy-number variants.

Publications

Phenotypic heterogeneity of genomic disorders and rare copy-number variants.

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