John W Belmont, M.D., Ph.D.
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Positions
- Adjunct Professor
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Molecular and Human Genetics
Baylor College of Medicine
Houston, TX US
- Member
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Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States
Education
- BA from University Of Texas At Austin
- 01/1974 - Austin, TX United States
- PhD from Baylor College Of Medicine
- 01/1980 - Houston, TX United States
- MD from Baylor College Of Medicine
- 01/1981 - Houston, TX United States
- Residency at Children's Hospital National Medical Center
- 01/1981 - Washington, DC United States
- Pediatrics
- Residency at Baylor College Of Medicine Affiliate Hospitals
- 01/1983 - Houston, TX United States
- Pediatrics
- Clinical Fellowship at Baylor College Of Medicine
- 01/1984 - Houston, TX United States
- Medical Genetics
Certifications
- Clinical Biochemical Genetics
- American Board of Medical Genetics
- General Pediatrics
- American Board of Pediatrics
- Clinical Genetics
- American Board of Medical Genetics
Professional Interests
- Structural congenital heart defects including abnormalities in laterality and hypoplastic left heart syndrome
- Medical population genetics
- Genetics of human immune responses
- Functional studies of Zic3
Professional Statement
Cardiovascular Genetics: Significant congenital cardiovascular malformations (CVM) occur in about 8 per 1000 live births. We are interested in identifying genetic factors that cause CVM or contribute to the risk for their occurrence. One project focuses on the underlying basis for CHARGE Syndrome. CHARGE is a complex phenotype that involves the development of the eye, ear, cranial nerves, brain, genitourinary system, and heart. Recently a gene, CHD7, has been found to cause CHARGE in about 65 percent of patients. Using a large set of CHARGE cases we have characterized the mutational spectrum in CHD7. We are using microarray and nextgen sequencing technology to screen for new genetic loci involved in the CHARGE-like phenotype.In an extension of the CHARGE project we are screening a large number of children affected with a severe cardiovascular malformation plus at least one other major birth defect – so called syndromic CVM. This occurs in about 20-30% of children with heart defects. We are using high resolution array-based copy number analysis to identify both de novo and familial chromosomal aberrations that explain the multiple congenital anomalies in these children. Approximately 7% of such children have one of 40 known genomic disorders. In an analysis of more than 700 affected children we have evidence for at least 16 new genomic disorders and single gene defects.
Another class of disorders that we are studying is called heterotaxy. These conditions are caused by disturbance in the establishment of the left-right body axis. So far mutations in a few genes have been identified as causing human heterotaxy using this sample set—the first of which was ZIC3, an X-linked transcription factor. Current efforts focus on collaborations that have identified mutations in genes that encode monocilia structural proteins. We have also been studying a mouse knockout mutant in Zic3 as a model for human heterotaxy. Our goal is to place Zic3 into one or more the critical pathways that are required for left right patterning. These studies have revealed a direct role for Zic3 in the early pre-cardiac mesoderm but not in cardiac neural crest.
The lab is also studying the genetics of hypoplastic left heart, coarctation of the aorta, aortic stenosis, and bicuspid aortic valve. Together, these defects are called left ventricular outflow tract obstruction (LVOTO) defects. Linkage analysis has identified several promising loci. We are carrying out the first genome wide association study involving these heart defects. We have completed array-based high throughput genotyping and are now examining the association of common DNA polymorphisms with risk of these conditions.
Vaccine Response as a Complex Trait: In collaboration with the Influenza Research Center we have established a program to analyze host genetic effects on response to seasonal influenza vaccine. We have studied gene expression profiles in individuals undergoing vaccination and have used the gene expression values as traits for gene mapping (called expression quantitative trait loci or eQTL). These studies have demonstrated an early phase of response to the vaccine that is predictive of the magnitude of the protective antibody response. This study has also identified a new kind of gene X environment interaction in which the genetic effect on specific transcript abundance becomes stronger following vaccine exposure.
Websites
Selected Publications
- Franco LM, Bucasas KL, Wells JM, Niño D, Wang X, Zapata GE, Arden N, Renwick A, Yu P, Quarles JM, Bray MS, Couch RB, Belmont JW, Shaw CA "Integrative genomic analysis of the human immune response to influenza vaccination." Elife. 2013 Jul 16;2:e00299. Pubmed PMID: 23878721
- Lalani SR, Ware SM, Wang X, Zapata G, (...), Belmont JW "MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development.." Hum Mol Genet.. 2013 1;22(21):4339-48. Pubmed PMID: 23773997
- Jiang Z, Zhu L, Hu L, Slesnick TC, Pautler RG, Justice MJ, Belmont JW "Zic3 is required in the extra-cardiac perinodal region of the lateral plate mesoderm for left-right patterning and heart development." Hum Mol Genet. 2013 Mar 1;22(5):879-89. Pubmed PMID: 23184148
- Bucasas KL, Mian AI, Demmler-Harrison GJ, Caviness AC, Piedra PA, Franco LM, Shaw CA, Zhai Y, Wang X, Bray MS, Couch RB, Belmont JW "Global gene expression profiling in infants with acute respiratory syncytial virus broncholitis demonstrates systemic activation of interferon signaling networks." Pediatr Infect Dis J. 2013 Feb;32(2):e68-76. Pubmed PMID: 23190772
- Lalani SR, Shaw C, Wang X, Patel A, (...), Belmont JW "Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities." Eur J Hum Genet. 2013 Feb;21(2):173-81. Pubmed PMID: 22929023
- French VM, van de Laar IM, Wessels MW, Rohe C, Roos-Hesselink JW, Wang G, Frohn-Mulder IM, Severijnen LA, de Graaf BM, Schot R, Breedveld G, Mientjes E, van Tienhoven M, Jadot E, Jiang Z, Verkerk A, Swagemakers S, Venselaar H, Rahimi Z, Najmabadi H, Meije "NPHP4 Variants Are Associated With Pleiotropic Heart Malformations." Circ Res. 2012 Jun 8;110(12):1564-74. Pubmed PMID: 22550138
- Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA "Clan genomics and the complex architecture of human disease." Cell. 2011 Sep 30;147(1):32-43. Pubmed PMID: 21962505
- Lemaire SA, McDonald ML, Guo DC, Russell L, Miller CC, Johnson RJ, Bekheirnia MR, Franco LM, Nguyen M, Pyeritz RE, Bavaria JE, Devereux R, Maslen C, Holmes KW, Eagle K, Body SC, Seidman C, Seidman JG, Isselbacher EM, Bray M, Coselli JS, Estrera AL, Safi H "Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1." Nat Genet. 2011;43(10):996-1000. Pubmed PMID: 21909107
- Bucasas KL, Franco LM, Shaw CA, Bray MS, Wells JM, Niño D, Arden N, Quarles JM, Couch RB, Belmont JW "Early patterns of gene expression correlate with the humoral immune response to influenza vaccination in humans." J Infect Dis. 2011 Apr;203(7):921-9. Pubmed PMID: 21357945
- Kuang SQ, Guo DC, Prakash SK, McDonald ML, Johnson RJ, Wang M, Regalado ES, Russell L, Cao JM, Kwartler C, Fraivillig K, Coselli JS, Safi HJ, Estrera AL, Leal SM, Lemaire SA, Belmont JW, Milewicz DM "Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections." PLoS Genet. 2011 Jun;7(6):e1002118. Pubmed PMID: 21698135
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