Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns

Alexander H. Li, Neil A. Hanchard, Dieter Furthner, Susan Fernbach, Mahshid Azamian, Annarita Nicosia, Jill Rosenfeld, Donna Muzny, Lisa C.A. D'Alessandro, Shaine Morris, Shalini Jhangiani, Dhaval R. Parekh, Wayne J. Franklin, Mark Lewin, Jeffrey Towbin, Daniel J. Penny, Charles D. Fraser, James F. Martin, Christine Eng, James R. Lupski & 3 others Richard A. Gibbs, Eric Boerwinkle, John W. Belmont

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. Methods: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs. Results: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio=4.0, 95% confidence interval 2.5-6.5). Conclusions: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.

Original languageEnglish (US)
Article number95
JournalGenome medicine
Volume9
Issue number1
DOIs
StatePublished - Oct 31 2017

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Exome
Inheritance Patterns
Genetic Heterogeneity
Genes
Computational Biology
Genetic Association Studies
Rare Diseases

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns. / Li, Alexander H.; Hanchard, Neil A.; Furthner, Dieter; Fernbach, Susan; Azamian, Mahshid; Nicosia, Annarita; Rosenfeld, Jill; Muzny, Donna; D'Alessandro, Lisa C.A.; Morris, Shaine; Jhangiani, Shalini; Parekh, Dhaval R.; Franklin, Wayne J.; Lewin, Mark; Towbin, Jeffrey; Penny, Daniel J.; Fraser, Charles D.; Martin, James F.; Eng, Christine; Lupski, James R.; Gibbs, Richard A.; Boerwinkle, Eric; Belmont, John W.

In: Genome medicine, Vol. 9, No. 1, 95, 31.10.2017.

Research output: Contribution to journalArticle

Li, AH, Hanchard, NA, Furthner, D, Fernbach, S, Azamian, M, Nicosia, A, Rosenfeld, J, Muzny, D, D'Alessandro, LCA, Morris, S, Jhangiani, S, Parekh, DR, Franklin, WJ, Lewin, M, Towbin, J, Penny, DJ, Fraser, CD, Martin, JF, Eng, C, Lupski, JR, Gibbs, RA, Boerwinkle, E & Belmont, JW 2017, 'Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns', Genome medicine, vol. 9, no. 1, 95. https://doi.org/10.1186/s13073-017-0482-5
Li, Alexander H. ; Hanchard, Neil A. ; Furthner, Dieter ; Fernbach, Susan ; Azamian, Mahshid ; Nicosia, Annarita ; Rosenfeld, Jill ; Muzny, Donna ; D'Alessandro, Lisa C.A. ; Morris, Shaine ; Jhangiani, Shalini ; Parekh, Dhaval R. ; Franklin, Wayne J. ; Lewin, Mark ; Towbin, Jeffrey ; Penny, Daniel J. ; Fraser, Charles D. ; Martin, James F. ; Eng, Christine ; Lupski, James R. ; Gibbs, Richard A. ; Boerwinkle, Eric ; Belmont, John W. / Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns. In: Genome medicine. 2017 ; Vol. 9, No. 1.
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title = "Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns",
abstract = "Background: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. Methods: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs. Results: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio=4.0, 95{\%} confidence interval 2.5-6.5). Conclusions: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.",
author = "Li, {Alexander H.} and Hanchard, {Neil A.} and Dieter Furthner and Susan Fernbach and Mahshid Azamian and Annarita Nicosia and Jill Rosenfeld and Donna Muzny and D'Alessandro, {Lisa C.A.} and Shaine Morris and Shalini Jhangiani and Parekh, {Dhaval R.} and Franklin, {Wayne J.} and Mark Lewin and Jeffrey Towbin and Penny, {Daniel J.} and Fraser, {Charles D.} and Martin, {James F.} and Christine Eng and Lupski, {James R.} and Gibbs, {Richard A.} and Eric Boerwinkle and Belmont, {John W.}",
year = "2017",
month = "10",
day = "31",
doi = "10.1186/s13073-017-0482-5",
language = "English (US)",
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journal = "Genome Medicine",
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TY - JOUR

T1 - Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns

AU - Li, Alexander H.

AU - Hanchard, Neil A.

AU - Furthner, Dieter

AU - Fernbach, Susan

AU - Azamian, Mahshid

AU - Nicosia, Annarita

AU - Rosenfeld, Jill

AU - Muzny, Donna

AU - D'Alessandro, Lisa C.A.

AU - Morris, Shaine

AU - Jhangiani, Shalini

AU - Parekh, Dhaval R.

AU - Franklin, Wayne J.

AU - Lewin, Mark

AU - Towbin, Jeffrey

AU - Penny, Daniel J.

AU - Fraser, Charles D.

AU - Martin, James F.

AU - Eng, Christine

AU - Lupski, James R.

AU - Gibbs, Richard A.

AU - Boerwinkle, Eric

AU - Belmont, John W.

PY - 2017/10/31

Y1 - 2017/10/31

N2 - Background: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. Methods: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs. Results: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio=4.0, 95% confidence interval 2.5-6.5). Conclusions: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.

AB - Background: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. Methods: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs. Results: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio=4.0, 95% confidence interval 2.5-6.5). Conclusions: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.

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U2 - 10.1186/s13073-017-0482-5

DO - 10.1186/s13073-017-0482-5

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JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

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