RT Journal Article
SR Electronic
T1 Early post-zygotic mutations contribute to congenital heart disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 733105
DO 10.1101/733105
A1 Alexander Hsieh
A1 Sarah U. Morton
A1 Jon A.L. Willcox
A1 Joshua M. Gorham
A1 Angela C. Tai
A1 Hongjian Qi
A1 Steven DePalma
A1 David McKean
A1 Emily Griffin
A1 Kathryn B. Manheimer
A1 Daniel Bernstein
A1 Richard W. Kim
A1 Jane W. Newburger
A1 George A. Porter, Jr.
A1 Deepak Srivastava
A1 Martin Tristani-Firouzi
A1 Martina Brueckner
A1 Richard P. Lifton
A1 Elizabeth Goldmuntz
A1 Bruce D. Gelb
A1 Wendy K. Chung
A1 Christine E. Seidman
A1 J. G. Seidman
A1 Yufeng Shen
YR 2019
UL http://biorxiv.org/content/early/2019/08/13/733105.abstract
AB 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.Results We developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. 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 frequency of mosaic variants above 10% mosaicism was 0.13/person in blood and 0.14/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 expressed at higher allele fraction compared to benign variants. 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.ASDAutism Spectrum DisorderCHDCongenital Heart DiseasednSNVde novo SNVDmisDeleterious Missense mutationDPsiteTotal Read Depth at a variant siteDPsampleSample-wide Average Read DepthExACExome Aggregation ConsortiumFDRFalse Discovery RategnomADGenome Aggregation DatabaseHHEHigh Heart ExpressionLOFLoss-of-FunctionLRLikelihood RatioMAFMinor Allele FractionNTotal Read DepthNaltAlternate Allele Read DepthOROdds RatioPCGCPediatric Cardiac Genomics ConsortiumpLIProbability of Loss-of-Function IntolerancePV4P-value for strand bias, baseQ bias, mapQ bias and tail distance bias (SAMtools)SNVSingle Nucleotide VariantVAFVariant Allele FractionWESWhole Exome Sequencing