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Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE131323 | GEO | 2019/05/31

REPOSITORIES: GEO

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Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier [mouse]

Project description:Complex genetic inheritance is thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human congenital heart defect, left ventricular non-compaction (LVNC), can be caused by a combination of rare, inherited heterozygous missense single nucleotide variants. Whole exome sequencing of a nuclear family revealed novel single nucleotide variants of MYH7 and MKL2 in an asymptomatic father while the offspring with severe childhood-onset LVNC harbored an additional missense variant in the cardiac transcription factor, NKX2-5, inherited from an unaffected mother. Mice bred to compound heterozygosity for the orthologous missense variants in Myh7 and Mkl2 had mild cardiac pathology; the additional inheritance of the Nkx2-5 variant yielded a more severe LVNC-like phenotype in triple compound heterozygotes. RNA sequencing identified genes associated with endothelial and myocardial development that were dysregulated in hearts from triple heterozygote mice and human induced pluripotent stem cell–derived cardiomyocytes harboring the three variants, with evidence for NKX2-5’s contribution as a modifier on the molecular level. These studies demonstrate that the deployment of efficient gene editing tools can provide experimental evidence for complex inheritance of human disease.

2019-05-31 | GSE111394 | GEO

Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier [human]

2019-05-31 | GSE131322 | GEO

Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier

Project description:Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier

| PRJNA543244 | ENA

Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier [human]

Project description:Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier [human]

| PRJNA543252 | ENA

Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier [mouse]

Project description:Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier [mouse]

| PRJNA436906 | ENA

Oligogenic inheritance of a human heart disease involving a genetic modifier.

Project description:Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant's contribution as a genetic modifier.

| S-EPMC6557373 | biostudies-literature

Integrated multiomic characterization of congenital heart disease

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-22 | GSE203275 | GEO

Environmentally induced epigenetic transgenerational inheritance of ovarian disease

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-07-17 | E-GEOD-59278 | biostudies-arrayexpress

Identification of NKX2-5 transcriptional targets in the mouse embryonic heart

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-09-02 | E-GEOD-44576 | biostudies-arrayexpress

Investigation of somatic NKX2-5 mutations in congenital heart disease.

Project description:BackgroundReports of somatic mutations found in hearts with cardiac septal defects have suggested that these mutations are aetiologic in pathologic cardiac development. However, the hearts in these reports had been fixed in formalin for over 22 years. Because of the profound implication of this finding, we attempted to replicate it using fresh frozen tissue obtained in the current era from 28 patients with septal defects who underwent cardiac surgery and who were enrolled in our congenital heart disease tissue bank.MethodsOur cohort included patients with atrial septal defects (ASD, n = 13), ventricular septal defects (VSD, n = 5), and atrioventricular canal defects (AVCD, n = 10). Cardiac tissue samples were collected both from diseased tissue located immediately adjacent to the defect and from anatomically normal tissue located at a site remote from the defect (right atrial appendage). Tissue samples were immediately frozen in liquid nitrogen and stored at -80 degrees C. Genomic DNA was isolated and amplified using the same methodology described in the previously published reports. 42 pathologic cardiac tissue samples were sequenced.ResultsOne non-synonymous germline sequence variant was identified in one patient. Two synonymous germline sequence variants were identified in two separate patients. A common single nucleotide polymorphism (SNP) was identified in 16 patients. Based on the incidence of somatic mutations described in the previously published reports, our study was adequately powered to replicate the previous studies. No evidence of somatic mutations was found in this study.ConclusionSomatic mutations in NKX2-5 do not represent an important aetiologic pathway in pathologic cardiac development in patients with cardiac septal defects.

| S-EPMC2628540 | biostudies-literature

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