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Recurrent Rare Genomic Copy Number Variants and Bicuspid Aortic Valve Are Enriched in Early Onset Thoracic Aortic Aneurysms and Dissections.

Prakash S, Kuang SQ, GenTAC Registry InvestigatorsRegalado E, Guo D, Milewicz D - PLoS ONE (2016)

Bottom Line: The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts.We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD.Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.

ABSTRACT
Thoracic Aortic Aneurysms and Dissections (TAAD) are a major cause of death in the United States. The spectrum of TAAD ranges from genetic disorders, such as Marfan syndrome, to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to early onset TAAD (ETAAD). We conducted a genome-wide SNP array analysis of ETAAD patients of European descent who were enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Genotyping was performed on the Illumina Omni-Express platform, using PennCNV, Nexus and CNVPartition for CNV detection. ETAAD patients (n = 108, 100% European American, 28% female, average age 20 years, 55% with bicuspid aortic valves) were compared to 7013 dbGAP controls without a history of vascular disease using downsampled Omni 2.5 data. For comparison, 805 sporadic TAAD patients with late onset aortic disease (STAAD cohort) and 192 affected probands from families with at least two affected relatives (FTAAD cohort) from our institution were screened for additional CNVs at these loci with SNP arrays. We identified 47 recurrent CNV regions in the ETAAD, FTAAD and STAAD groups that were absent or extremely rare in controls. Nine rare CNVs that were either very large (>1 Mb) or shared by ETAAD and STAAD or FTAAD patients were also identified. Four rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (two duplications and two deletions) and 17q25.1 (three duplications). The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts. We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD. Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD.

No MeSH data available.


Related in: MedlinePlus

CNV Analysis Workflow.
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pone.0153543.g001: CNV Analysis Workflow.

Mentions: Samples were genotyped on HumanOmniExpress beadchips (Illumina, Inc., San Diego, CA) with appropriate quality standards for labeling, single base extension, hybridization, stringency and non-specific binding according to our previously published methods. Allele detection and genotype calling were performed in the GenomeStudio genotyping module (v 2011.1, Illumina, Inc.) using updated manifests in the hg19 genome build with 716,503 SNPs (manifest humanomniexpress-24v1-0_a, 15 samples) or 730,525 SNPs (manifest humanomniexpress-12v1_j, 93 samples). All SNPs in humanomniexpress-24 beadchips are also included in humanomniexpress-12 beadchips, which have an additional 14,022 SNPs that are not present in humanomniexpress-24. To equalize SNP densities between cases and controls, both the control Omni-2.5 panels (2,379,855 SNPs) and the Omni-Express panels were filtered to select only the subset of SNPs that overlap with OmniExpress arrays (704,517) prior to the analysis (Fig 1). Samples that did not cluster with HapMap CEU (Utah residents with ancestry from northern and western Europe) samples in multidimensional scaling analysis, replicate samples, unexpected duplicates or samples with mismatched gender, excess heterozygosity, excess homozygosity or more than 2% missing genotypes were excluded from further analysis. SNPs with call frequency < 0.98, cluster separation < 0.25 or heterozygote excess < -0.5 or >0.5 were also excluded.


Recurrent Rare Genomic Copy Number Variants and Bicuspid Aortic Valve Are Enriched in Early Onset Thoracic Aortic Aneurysms and Dissections.

Prakash S, Kuang SQ, GenTAC Registry InvestigatorsRegalado E, Guo D, Milewicz D - PLoS ONE (2016)

CNV Analysis Workflow.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836726&req=5

pone.0153543.g001: CNV Analysis Workflow.
Mentions: Samples were genotyped on HumanOmniExpress beadchips (Illumina, Inc., San Diego, CA) with appropriate quality standards for labeling, single base extension, hybridization, stringency and non-specific binding according to our previously published methods. Allele detection and genotype calling were performed in the GenomeStudio genotyping module (v 2011.1, Illumina, Inc.) using updated manifests in the hg19 genome build with 716,503 SNPs (manifest humanomniexpress-24v1-0_a, 15 samples) or 730,525 SNPs (manifest humanomniexpress-12v1_j, 93 samples). All SNPs in humanomniexpress-24 beadchips are also included in humanomniexpress-12 beadchips, which have an additional 14,022 SNPs that are not present in humanomniexpress-24. To equalize SNP densities between cases and controls, both the control Omni-2.5 panels (2,379,855 SNPs) and the Omni-Express panels were filtered to select only the subset of SNPs that overlap with OmniExpress arrays (704,517) prior to the analysis (Fig 1). Samples that did not cluster with HapMap CEU (Utah residents with ancestry from northern and western Europe) samples in multidimensional scaling analysis, replicate samples, unexpected duplicates or samples with mismatched gender, excess heterozygosity, excess homozygosity or more than 2% missing genotypes were excluded from further analysis. SNPs with call frequency < 0.98, cluster separation < 0.25 or heterozygote excess < -0.5 or >0.5 were also excluded.

Bottom Line: The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts.We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD.Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.

ABSTRACT
Thoracic Aortic Aneurysms and Dissections (TAAD) are a major cause of death in the United States. The spectrum of TAAD ranges from genetic disorders, such as Marfan syndrome, to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to early onset TAAD (ETAAD). We conducted a genome-wide SNP array analysis of ETAAD patients of European descent who were enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Genotyping was performed on the Illumina Omni-Express platform, using PennCNV, Nexus and CNVPartition for CNV detection. ETAAD patients (n = 108, 100% European American, 28% female, average age 20 years, 55% with bicuspid aortic valves) were compared to 7013 dbGAP controls without a history of vascular disease using downsampled Omni 2.5 data. For comparison, 805 sporadic TAAD patients with late onset aortic disease (STAAD cohort) and 192 affected probands from families with at least two affected relatives (FTAAD cohort) from our institution were screened for additional CNVs at these loci with SNP arrays. We identified 47 recurrent CNV regions in the ETAAD, FTAAD and STAAD groups that were absent or extremely rare in controls. Nine rare CNVs that were either very large (>1 Mb) or shared by ETAAD and STAAD or FTAAD patients were also identified. Four rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (two duplications and two deletions) and 17q25.1 (three duplications). The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts. We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD. Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD.

No MeSH data available.


Related in: MedlinePlus