EM-mosaic detects mosaic point mutations that contribute to congenital heart disease
Abstract Background The 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. Methods We developed a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-04-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13073-020-00738-1 |
| _version_ | 1831636395685314560 |
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| author | Alexander Hsieh Sarah U. Morton Jon A. L. Willcox Joshua M. Gorham Angela C. Tai Hongjian Qi Steven DePalma David McKean Emily Griffin Kathryn B. Manheimer Daniel Bernstein Richard W. Kim Jane W. Newburger George A. Porter Deepak Srivastava Martin Tristani-Firouzi Martina Brueckner Richard P. Lifton Elizabeth Goldmuntz Bruce D. Gelb Wendy K. Chung Christine E. Seidman J. G. Seidman Yufeng Shen |
| author_facet | Alexander Hsieh Sarah U. Morton Jon A. L. Willcox Joshua M. Gorham Angela C. Tai Hongjian Qi Steven DePalma David McKean Emily Griffin Kathryn B. Manheimer Daniel Bernstein Richard W. Kim Jane W. Newburger George A. Porter Deepak Srivastava Martin Tristani-Firouzi Martina Brueckner Richard P. Lifton Elizabeth Goldmuntz Bruce D. Gelb Wendy K. Chung Christine E. Seidman J. G. Seidman Yufeng Shen |
| author_sort | Alexander Hsieh |
| collection | DOAJ |
| description | Abstract Background The 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. Methods We 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. Results EM-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. Conclusions We 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. |
| first_indexed | 2024-12-19T06:32:17Z |
| format | Article |
| id | doaj.art-b7f196ef4fc94a1c9c9e2a38f2b299d7 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-19T06:32:17Z |
| publishDate | 2020-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-b7f196ef4fc94a1c9c9e2a38f2b299d72022-12-21T20:32:22ZengBMCGenome Medicine1756-994X2020-04-0112111810.1186/s13073-020-00738-1EM-mosaic detects mosaic point mutations that contribute to congenital heart diseaseAlexander Hsieh0Sarah U. Morton1Jon A. L. Willcox2Joshua M. Gorham3Angela C. Tai4Hongjian Qi5Steven DePalma6David McKean7Emily Griffin8Kathryn B. Manheimer9Daniel Bernstein10Richard W. Kim11Jane W. Newburger12George A. Porter13Deepak Srivastava14Martin Tristani-Firouzi15Martina Brueckner16Richard P. Lifton17Elizabeth Goldmuntz18Bruce D. Gelb19Wendy K. Chung20Christine E. Seidman21J. G. Seidman22Yufeng Shen23Columbia University Medical CenterBoston Children’s HospitalHarvard Medical SchoolHarvard Medical SchoolHarvard Medical SchoolColumbia University Medical CenterHarvard Medical SchoolHarvard Medical SchoolColumbia University Medical CenterIcahn School of Medicine at Mount SinaiStanford UniversityChildren’s Hospital Los AngelesBoston Children’s HospitalUniversity of Rochester Medical CenterGladstone Institutes and University of California San FranciscoUniversity of Utah School of MedicineYale University School of MedicineRockefeller UniversityChildren’s Hospital of PhiladelphiaIcahn School of Medicine at Mount SinaiColumbia University Medical CenterHarvard Medical SchoolHarvard Medical SchoolColumbia University Medical CenterAbstract Background The 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. Methods We 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. Results EM-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. Conclusions We 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.http://link.springer.com/article/10.1186/s13073-020-00738-1MosaicSomaticCongenital heart diseaseExome sequencing |
| spellingShingle | Alexander Hsieh Sarah U. Morton Jon A. L. Willcox Joshua M. Gorham Angela C. Tai Hongjian Qi Steven DePalma David McKean Emily Griffin Kathryn B. Manheimer Daniel Bernstein Richard W. Kim Jane W. Newburger George A. Porter Deepak Srivastava Martin Tristani-Firouzi Martina Brueckner Richard P. Lifton Elizabeth Goldmuntz Bruce D. Gelb Wendy K. Chung Christine E. Seidman J. G. Seidman Yufeng Shen EM-mosaic detects mosaic point mutations that contribute to congenital heart disease Genome Medicine Mosaic Somatic Congenital heart disease Exome sequencing |
| title | EM-mosaic detects mosaic point mutations that contribute to congenital heart disease |
| title_full | EM-mosaic detects mosaic point mutations that contribute to congenital heart disease |
| title_fullStr | EM-mosaic detects mosaic point mutations that contribute to congenital heart disease |
| title_full_unstemmed | EM-mosaic detects mosaic point mutations that contribute to congenital heart disease |
| title_short | EM-mosaic detects mosaic point mutations that contribute to congenital heart disease |
| title_sort | em mosaic detects mosaic point mutations that contribute to congenital heart disease |
| topic | Mosaic Somatic Congenital heart disease Exome sequencing |
| url | http://link.springer.com/article/10.1186/s13073-020-00738-1 |
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