Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events

Neil A. Hanchard, Luis A. Umana, Lisa D'Alessandro, Mahshid Azamian, Mojisola Poopola, Shaine A. Morris, Susan Fernbach, Seema R. Lalani, Jeffrey Towbin, Gloria A. Zender, Sara Fitzgerald-Butt, Vidu Garg, Jessica Bowman, Gladys Zapata, Patricia Hernandez, Cammon B. Arrington, Dieter Furthner, Siddharth K. Prakash, Neil E. Bowles, Kim L. McBride & 1 others John W. Belmont

Research output: Contribution to journalArticle

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Abstract

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.

Original languageEnglish (US)
Pages (from-to)2176-2188
Number of pages13
JournalAmerican Journal of Medical Genetics, Part A
Volume173
Issue number8
DOIs
StatePublished - Aug 1 2017

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Heart Diseases
Genes
Uncertainty
Medical Records
Single Nucleotide Polymorphism
Morbidity
Phenotype
Mortality

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events. / Hanchard, Neil A.; Umana, Luis A.; D'Alessandro, Lisa; Azamian, Mahshid; Poopola, Mojisola; Morris, Shaine A.; Fernbach, Susan; Lalani, Seema R.; Towbin, Jeffrey; Zender, Gloria A.; Fitzgerald-Butt, Sara; Garg, Vidu; Bowman, Jessica; Zapata, Gladys; Hernandez, Patricia; Arrington, Cammon B.; Furthner, Dieter; Prakash, Siddharth K.; Bowles, Neil E.; McBride, Kim L.; Belmont, John W.

In: American Journal of Medical Genetics, Part A, Vol. 173, No. 8, 01.08.2017, p. 2176-2188.

Research output: Contribution to journalArticle

Hanchard, NA, Umana, LA, D'Alessandro, L, Azamian, M, Poopola, M, Morris, SA, Fernbach, S, Lalani, SR, Towbin, J, Zender, GA, Fitzgerald-Butt, S, Garg, V, Bowman, J, Zapata, G, Hernandez, P, Arrington, CB, Furthner, D, Prakash, SK, Bowles, NE, McBride, KL & Belmont, JW 2017, 'Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events', American Journal of Medical Genetics, Part A, vol. 173, no. 8, pp. 2176-2188. https://doi.org/10.1002/ajmg.a.38309
Hanchard, Neil A. ; Umana, Luis A. ; D'Alessandro, Lisa ; Azamian, Mahshid ; Poopola, Mojisola ; Morris, Shaine A. ; Fernbach, Susan ; Lalani, Seema R. ; Towbin, Jeffrey ; Zender, Gloria A. ; Fitzgerald-Butt, Sara ; Garg, Vidu ; Bowman, Jessica ; Zapata, Gladys ; Hernandez, Patricia ; Arrington, Cammon B. ; Furthner, Dieter ; Prakash, Siddharth K. ; Bowles, Neil E. ; McBride, Kim L. ; Belmont, John W. / Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events. In: American Journal of Medical Genetics, Part A. 2017 ; Vol. 173, No. 8. pp. 2176-2188.
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abstract = "Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3{\%}). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.",
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AU - Azamian, Mahshid

AU - Poopola, Mojisola

AU - Morris, Shaine A.

AU - Fernbach, Susan

AU - Lalani, Seema R.

AU - Towbin, Jeffrey

AU - Zender, Gloria A.

AU - Fitzgerald-Butt, Sara

AU - Garg, Vidu

AU - Bowman, Jessica

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AU - Arrington, Cammon B.

AU - Furthner, Dieter

AU - Prakash, Siddharth K.

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AU - McBride, Kim L.

AU - Belmont, John W.

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N2 - Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.

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