Loss of RNA expression and allele-specific expression associated with congenital heart disease.
Congenital heart disease (CHD), a prevalent birth defect occurring in 1% of newborns, likely results from aberrant expression of cardiac developmental genes. Mutations in a variety of cardiac transcription factors, developmental signalling molecules and molecules that modify chromatin cause at least 20% of disease, but most CHD remains unexplained. We employ RNAseq analyses to assess allele-specific expression (ASE) and biallelic loss-of-expression (LOE) in 172 tissue samples from 144 surgically repaired CHD subjects. Here we show that only 5% of known imprinted genes with paternal allele silencing are monoallelic versus 56% with paternal allele expression-this cardiac-specific phenomenon seems unrelated to CHD. Further, compared with control subjects, CHD subjects have a significant burden of both LOE genes and ASE events associated with altered gene expression. These studies identify FGFBP2, LBH, RBFOX2, SGSM1 and ZBTB16 as candidate CHD genes because of significantly altered transcriptional expression.
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Cardiovascular Division, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts 02115, USA.
David M
DM
McKean
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Cardiovascular Division, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts 02115, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Jason
J
Homsy
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hiroko
H
Wakimoto
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Neil
N
Patel
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Joshua
J
Gorham
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts 02115, USA.
Steven R
0000-0002-0381-5016
SR
DePalma
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|National Institute for Health Research Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College London, London SW3 6NP, UK.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK.
James S
0000-0002-6110-5880
JS
Ware
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Samir
S
Zaidi
Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA.
Wenji
W
Ma
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Nihir
N
Patel
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Howard Hughes Medical Institute, Yale University, Connecticut 06510, USA.
Richard P
RP
Lifton
Department of Pediatrics and Medicine, Columbia University Medical Center, New York, New York 10032, USA.
Wendy K
WK
Chung
Section of Cardiothoracic Surgery, University of Southern California Keck School of Medicine, Los Angeles, California 90089, USA.
Richard
R
Kim
Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA.|Department of Biomedical Informatics, Columbia University Medical Center, New York, New York 10032, USA.
Yufeng
Y
Shen
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Martina
M
Brueckner
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Elizabeth
E
Goldmuntz
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Andrew J
AJ
Sharp
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Cardiovascular Division, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts 02115, USA.|Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts 02115, USA.
Christine E
CE
Seidman
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Bruce D
0000-0001-8527-5027
BD
Gelb
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
J G
JG
Seidman
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001011:Aorta / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005333:Fetus; D015870:Gene Expression; D056726:Genetic Association Studies; D018392:Genomic Imprinting; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D012313:RNA / Q000378:metabolism*; D055815:Young Adult
D012313:RNA
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