Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Identification of Copy Number Variants in Patients with Hypoplastic Left Heart Syndrome and Other Congenital Heart Defects

ABSTRACT: Hypoplastic left heart syndrome (HLHS) is a heterogeneous, lethal combination of congenital malformations that result in a heart unable to sustain systemic circulation. The genetic determinants of this disorder are largely unknown. Evidence of copy number variants (CNVs) contributing to the genetic etiology of HLHS and other congenital heart defects (CHDs) has been mounting. However, the functional effects of such CNVs have not been examined, particularly in cases where the variant of interest is found in only a single patient. Initially whole-genome SNP microarrays were employed to detect CNVs in two patient cohorts (N = 70 total) predominantly diagnosed with some form of nonsyndromic HLHS. We discovered 16 rare variants adjacent to or overlapping 20 genes associated with cardiovascular or premature lethality phenotypes in mouse knockout models. Fifteen of the 16 variants were identified in separate patients, suggestive of a private mutation model of disease. We evaluated the impact of selected variants on the expression of nine of these genes through quantitative PCR on cDNA derived from patient heart tissue. Four genes displayed significantly altered expression in patients with an overlapping or proximal CNV verses patients without such CNVs. Thus, rare and private genomic imbalances perturb transcription of genes affecting cardiogenesis in a subset of nonsyndromic HLHS patients. Some of these genes influence extracellular matrix structure, cardiac neural crest development, and coronary vascularization. A total of 70 samples from CHD patients, mostly with nonsyndromic HLHS, yielded SNP genotypes and probe intensity ratios of sufficient quality for CNV identification. Two classes of CNV detection algorithms (HMM and CBS) were employed. After identification, concordant entries were subjected to selection criteria based on rarity and gene content, which produced putative candidate genes for follow-up experiments.

ORGANISM(S): Homo sapiens

SUBMITTER: Mark Geraci

PROVIDER: E-GEOD-66032 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome.

Glidewell Steven C SC Miyamoto Shelley D SD Grossfeld Paul D PD Clouthier David E DE Coldren Christopher D CD Stearman Robert S RS Geraci Mark W MW

Clinical and translational science 20151104 6

<h4>Background</h4>Hypoplastic left heart syndrome (HLHS) is a heterogeneous, lethal combination of congenital malformations characterized by severe underdevelopment of left heart structures, resulting in a univentricular circulation. The genetic determinants of this disorder are largely unknown. Evidence of copy number variants (CNVs) contributing to the genetic etiology of HLHS and other congenital heart defects has been mounting. However, the functional effects of such CNVs have not been exam ...[more]

PMID: 26534787

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Project description:Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a mother to her child. The chromothripsis in the mothers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across 3-5 chromosomes. Two mothers did not show any phenotypic malformations, although 3-13 protein coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy number changes in two children. This resulted in gene dosage changes, which are likely responsible for their severe congenital phenotypes. In contrast, one child with severe congenital disease, carried all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy individuals strongly affects reproduction and is expected to substantially increase the risk of spontaneous abortions and severe congenital disease. We analyzed one patient-parent-mother's parents quintet (case 1) and a patient-siblings-parent quintet (case 2) with Illumina beadchip arrays and one patient-parent trio (case 3) to test for (de novo) copy number variants and to analyze the parental origin of the complex rearrangements in these patients. Here, we analyzed one patient-parent-mother's parents quintet to test for (de novo) copy number variants and to analyze the parental origin of the complex rearrangements in these patients.

Project description:Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a female carrier to her child. The chromothripsis in the carriers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across 3-5 chromosomes. Two carriers did not show any phenotypic malformations, although 3-13 protein coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy number changes in two children. This resulted in gene dosage changes, which are likely responsible for their severe congenital phenotypes. In contrast, one patient with severe congenital disease, carried all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy carriers strongly affects reproduction and is expected to substantially increase the risk of spontaneous abortions and severe congenital disease. We analyzed one patient-parent-mother's parents quintet (case 1) and a patient-siblings-parent quintet (case 2) with Illumina beadchip arrays and one patient-parent trio (case 3) to test for (de novo) copy number variants and to analyze the parental origin of the complex rearrangements in these patients. For case 2, the mother and patient's SNP array data was previously submitted [GSE37906]. aCGH data for case 3 is submitted seperately.

Project description:A database of apparently benign copy number variants (bCNVs) detected by a Spectral Genomics Inc./PerkinElmer BAC array platform has been maintained through the University of Utah Comparative Genomic Hybridization laboratory since 2005. The target population for this database represents 1275 patients with abnormal phenotypes, primarily children referred for developmental delay and mental retardation. These bCNVs are independent of any identified copy number abnormality detected. The most common 35 bCNVs observed and their frequencies are reported here, and a subset of ten of the patients studied was evaluated on a new oligonucleotide CNV array set designed by Agilent Technologies. There was a 76% concordance of calls detected by both array platforms in the same patients; the discordant regions may be due to differences in reference DNAs, or false positive/negative results on either array. The higher resolution of the Agilent oligonucleotide array compared to the BAC array allowed for further characterization to determine precise breakpoints of the observed CNVs, in addition to documenting additional CNVs of smaller sizes. As expected, observed CNVs and their frequencies were generally consistent with those of other previously published and available databases, including the Database of Genomic Variants (http://projects.tcag.ca/variation/). The availability of these data should assist other clinical laboratories in the evaluation of CNVs of unknown clinical significance. The Cytogenetics Laboratory at the University of Utah has been using aCGH to evaluate DNA derived from blood of patients with developmental delay, mental retardation and “syndromic” or dysmorphic phenotypes since 2005. From this database, we were able to determine which clones represented sequences which were frequently deleted or duplicated in our patient population. We identified our most common CNV regions and then selected DNAs from ten patients who exhibited copy number changes of those common regions for further study with the Agilent CNV microarray set. Normal male or female DNA from Promega was used as a sex-mismatched control. In addition to the ten clinical specimens, two self-self experiments for two patient samples were analyzed to estimate a false positive rate and to fine tune the parameters used for data analysis. A replicate hybridization was performed on one patient to determine reproducibility.

Dataset Information

Identification of Copy Number Variants in Patients with Hypoplastic Left Heart Syndrome and Other Congenital Heart Defects

Publications

Transcriptional Impact of Rare and Private Copy Number Variants in Hypoplastic Left Heart Syndrome.

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