ArticleGenome medicine2020
EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.
Article in Genome medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 32 citations in OpenAlex.
- Clinical relevance of mosaic variants detected by exome sequencing.The Journal of allergy and clinical immunology · 2026Article
- Accurate detection of somatic single-nucleotide variants from bulk RNA-seq data using RNA-MosaicHunter.Nucleic acids research · 2026Article
- Single-Cell Genomics and Somatic Variation in Circulating and Cardiac Resident Cells.Circulation research · 2026Review
- Expanding the Genome in a Bottle Truth Set: Detection and Validation of Novel Low-frequency Variants Using High-accuracy NanoSeq.bioRxiv : the preprint server for biology · 2025Article
- Comprehensive benchmarking of somatic single-nucleotide variant and indel detection at ultra-low allele fractions using short- and long-read data.bioRxiv : the preprint server for biology · 2025Article
- Current and future diagnostics of congenital heart disease (CHD).Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Candidate genes related to spiritual mediumship: a whole-exome sequencing analysis of highly gifted mediums.Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) · 2025Article
- A validated heart-specific model for splice-disrupting variants in childhood heart disease.Genome medicine · 2024Article
- CLEMENT: genomic decomposition and reconstruction of non-tumor subclones.Nucleic acids research · 2024Article
- In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease.International journal of molecular sciences · 2024Review
- Insights into the genetic architecture of congenital heart disease from animal modeling.Zoological research · 2023Review
- Artificial intelligence-based approaches for the detection and prioritization of genomic mutations in congenital surgical diseases.Frontiers in pediatrics · 2023Review
- Molecular genetic mechanisms of congenital heart disease.Current opinion in genetics & development · 2022Review
- Article
- Clonal hematopoiesis: Mutation-specific adaptation to environmental change.Cell stem cell · 2022Review
- A novelExperimental and therapeutic medicine · 2022Article
- Somatic Mutations in Cardiovascular Disease.Circulation research · 2022Review
- Genomic frontiers in congenital heart disease.Nature reviews. Cardiology · 2022Review
- SOX7 loss-of-function variation as a cause of familial congenital heart disease.American journal of translational research · 2022Article
- Review
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Authors and funding
24 authors at 12 institutions in 1 country.
Funding
Abstract
backgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.
methodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.
resultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.
conclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.
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