Dataset Information

Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

ABSTRACT: The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because of uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss-of-function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation.We analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of >5000 individuals from the National Heart, Lung, and Blood Institute's Exome Sequencing Project, as well as the rates of structural variation from the Database of Genomic Variants. Most variants were rare, with over half unique to 1 individual. Cardiomyopathy-associated genes exhibited a rate of nonsense variants, about 96.1% lower than other Mendelian disease genes. We tested the ability of in silico algorithms to distinguish between a set of variants in MYBPC3, MYH7, and TNNT2 with strong evidence for pathogenicity and variants from the Exome Sequencing Project data. Algorithms based on conservation at the nucleotide level (genomic evolutionary rate profiling, PhastCons) did not perform as well as amino acid-level prediction algorithms (Polyphen-2, SIFT). Variants with strong evidence for disease causality were found in the Exome Sequencing Project data at prevalence higher than expected.Genes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the single gene causality model.

SUBMITTER: Pan S

PROVIDER: S-EPMC3526690 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

Pan Stephen S Caleshu Colleen A CA Dunn Kyla E KE Foti Marcia J MJ Moran Maura K MK Soyinka Oretunlewa O Ashley Euan A EA

Circulation. Cardiovascular genetics 20121016 6

<h4>Background</h4>The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because of uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss-of-function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation.<h4>Methods and results</h4>We analyzed the rates of single nucleotide genetic var ...[more]

PMID: 23074333

Similar Datasets

Project description:A number of human genetic polymorphisms are prevalent in tropical populations and appear to offer protection against symptomatic and/or severe malaria. We compared the prevalence of four polymorphisms, the sickle hemoglobin mutation (β globin E6V), the α-thalassemia 3.7kb deletion, glucose-6-phosphate dehydrogenase deficiency caused by the common African variant (G6PD A-), and the CD36 T188G mutation in 1344 individuals residing in districts in eastern (Tororo), south-central (Jinja), and southwestern (Kanungu) Uganda. Genes of interest were amplified, amplicons subjected to mutation-specific restriction endonuclease digestion (for sickle hemoglobin, G6PD A-, and CD36 T188G), reaction products resolved by electrophoresis, and genotypes determined based on the sizes of reaction products. Mutant genotypes were common, with many more heterozygous than homozygous alleles identified. The prevalences (heterozygotes plus homozygotes) of sickle hemoglobin (28% Tororo, 25% Jinja, 7% Kanungu), α-thalassemia (53% Tororo, 45% Jinja, 18% Kanungu) and G6PD A- (29% Tororo, 18% Jinja, 8% Kanungu) were significantly greater in Tororo and Jinja compared to Kanungu (p<0.0001 for all three alleles); prevalences were also significantly greater in Tororo compared to Jinja for α-thalassemia (p=0.03) and G6PD A- (p<0.0001). For the CD36 T188G mutation, the prevalence was significantly greater in Tororo compared to Jinja or Kanungu (27% Tororo, 17% Jinja, 18% Kanungu; p=0.0004 and 0.0017, respectively). Considering ethnicity of study subjects, based on primary language spoken, the prevalence of mutant genotypes was lower in Bantu compared to non-Bantu language speakers, but in the Jinja cohort, the only study population with a marked diversity of language groups, prevalence did not differ between Bantu and non-Bantu speakers. These results indicate marked differences in human genetic features between populations in different regions of Uganda. These differences might be explained by both ethnic variation and by varied malaria risk in different regions of Uganda.

Dataset Information

Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

Publications

Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets