Loss of RNA expression and allele-specific expression associated with congenital heart disease

doi:10.1038/ncomms12824

. 2016 Sep 27:7:12824.

doi: 10.1038/ncomms12824.

Loss of RNA expression and allele-specific expression associated with congenital heart disease

David M McKean^{1

2}, Jason Homsy^{1

2

3}, Hiroko Wakimoto¹, Neil Patel⁴, Joshua Gorham¹, Steven R DePalma^{1

5}, James S Ware^{1

6

7}, Samir Zaidi⁸, Wenji Ma⁹, Nihir Patel⁴, Richard P Lifton^{8

10}, Wendy K Chung¹¹, Richard Kim¹², Yufeng Shen^{9

13}, Martina Brueckner⁸, Elizabeth Goldmuntz¹⁴, Andrew J Sharp^{4

15}, Christine E Seidman^{1

2

5}, Bruce D Gelb^{4

15

16}, J G Seidman¹

Affiliations

¹ Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
² Cardiovascular Division, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts 02115, USA.
³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁴ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
⁵ Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts 02115, USA.
⁶ 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.
⁷ National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK.
⁸ Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
⁹ Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA.
¹⁰ Howard Hughes Medical Institute, Yale University, Connecticut 06510, USA.
¹¹ Department of Pediatrics and Medicine, Columbia University Medical Center, New York, New York 10032, USA.
¹² Section of Cardiothoracic Surgery, University of Southern California Keck School of Medicine, Los Angeles, California 90089, USA.
¹³ Department of Biomedical Informatics, Columbia University Medical Center, New York, New York 10032, USA.
¹⁴ Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
¹⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹⁶ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

PMID: 27670201
PMCID: PMC5052634
DOI: 10.1038/ncomms12824

Loss of RNA expression and allele-specific expression associated with congenital heart disease

David M McKean et al. Nat Commun. 2016.

. 2016 Sep 27:7:12824.

doi: 10.1038/ncomms12824.

Authors

Affiliations

¹ Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
² Cardiovascular Division, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts 02115, USA.
³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁴ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
⁵ Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts 02115, USA.
⁶ 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.
⁷ National Heart and Lung Institute, Imperial College London, London SW3 6NP, UK.
⁸ Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
⁹ Department of Systems Biology, Columbia University Medical Center, New York, New York 10032, USA.
¹⁰ Howard Hughes Medical Institute, Yale University, Connecticut 06510, USA.
¹¹ Department of Pediatrics and Medicine, Columbia University Medical Center, New York, New York 10032, USA.
¹² Section of Cardiothoracic Surgery, University of Southern California Keck School of Medicine, Los Angeles, California 90089, USA.
¹³ Department of Biomedical Informatics, Columbia University Medical Center, New York, New York 10032, USA.
¹⁴ Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
¹⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹⁶ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

PMID: 27670201
PMCID: PMC5052634
DOI: 10.1038/ncomms12824

Abstract

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.

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Figures

**Figure 1. Identification of extreme ASE genes in subjects with CHD.**
Shown are both alleles of a gene that differ by the SNP haploblocks ‘CC' (blue) and ‘GT' (red), as identified by WES, WGS or SNP-array genotyping. RNAseq analysis (read counts at heterozygous positions) reveals the expression of both alleles (biallelic RNA expression) or the disproportionate expression of one allele over another (ASE). RNAseq expression analyses (comparing each sample to the average of all other samples within a tissue group) identify relative loss and gain of expression. Variant analysis, in conjunction with RNAseq analysis, can further identify LOF mutations in the expressed allele (*).

**Figure 2. Extreme ASE genes preferentially identified in WGS subjects.**
Shown in a are the number of genes with a minimum expression of 2 r.p.m. (grey bars), and the number of expressed genes that contain heterozygous SNPs (black bars) for CHD WGS (n=30 tissues) and CHD WES probands (n=142 tissues), GTEx donors (n=113 tissues) and mouse C57Bl6/Castaneus F1 hybrids (n=7 tissues). s.d. is indicated. b The distribution of extreme ASE events per subject by genotyping platform. Extreme ASE events were identified in >70% of WGS subjects (n=14). However, extreme ASE events were identified in only ∼20% of WES subjects (n=130) and ∼45% of GTEx donors (n=95).

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References

1. Gelb B. D. & Chung W. K. Complex genetics and the etiology of human congenital heart disease. Cold Spring Harb. Perspect. Med. 4, a013953 (2014). - PMC - PubMed
1. Fahed A. C., Gelb B. D., Seidman J. G. & Seidman C. E. Genetics of congenital heart disease: the glass half empty. Circ. Res. 112, 707–720 (2013). - PMC - PubMed
1. Glessner J. T. et al.. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Circ. Res. 115, 884–896 (2014). - PMC - PubMed
1. Zaidi S. et al.. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013). - PMC - PubMed
1. Adzhubei I. A. et al.. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010). - PMC - PubMed

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[1] Gelb B. D. & Chung W. K. Complex genetics and the etiology of human congenital heart disease. Cold Spring Harb. Perspect. Med. 4, a013953 (2014). - PMC - PubMed

[2] Gelb B. D. & Chung W. K. Complex genetics and the etiology of human congenital heart disease. Cold Spring Harb. Perspect. Med. 4, a013953 (2014). - PMC - PubMed

[3] Fahed A. C., Gelb B. D., Seidman J. G. & Seidman C. E. Genetics of congenital heart disease: the glass half empty. Circ. Res. 112, 707–720 (2013). - PMC - PubMed

[4] Fahed A. C., Gelb B. D., Seidman J. G. & Seidman C. E. Genetics of congenital heart disease: the glass half empty. Circ. Res. 112, 707–720 (2013). - PMC - PubMed

[5] Glessner J. T. et al.. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Circ. Res. 115, 884–896 (2014). - PMC - PubMed

[6] Glessner J. T. et al.. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Circ. Res. 115, 884–896 (2014). - PMC - PubMed

[7] Zaidi S. et al.. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013). - PMC - PubMed

[8] Zaidi S. et al.. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013). - PMC - PubMed

[9] Adzhubei I. A. et al.. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010). - PMC - PubMed

[10] Adzhubei I. A. et al.. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010). - PMC - PubMed

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Loss of RNA expression and allele-specific expression associated with congenital heart disease

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Loss of RNA expression and allele-specific expression associated with congenital heart disease

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