Early post-zygotic mutations contribute to congenital heart disease
biorxiv(2019)
摘要
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.
* ASD
: Autism Spectrum Disorder
CHD
: Congenital Heart Disease
dnSNV
: de novo SNV
Dmis
: Deleterious Missense mutation
DPsite
: Total Read Depth at a variant site
DPsample
: Sample-wide Average Read Depth
ExAC
: Exome Aggregation Consortium
FDR
: False Discovery Rate
gnomAD
: Genome Aggregation Database
HHE
: High Heart Expression
LOF
: Loss-of-Function
LR
: Likelihood Ratio
MAF
: Minor Allele Fraction
N
: Total Read Depth
Nalt
: Alternate Allele Read Depth
OR
: Odds Ratio
PCGC
: Pediatric Cardiac Genomics Consortium
pLI
: Probability of Loss-of-Function Intolerance
PV4
: P-value for strand bias, baseQ bias, mapQ bias and tail distance bias (SAMtools)
SNV
: Single Nucleotide Variant
VAF
: Variant Allele Fraction
WES
: Whole Exome Sequencing
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关键词
Mosaic,Somatic,Congenital Heart Disease,Exome Sequencing
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