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Molecular and Human Genetics

Houston, Texas

Department of Molecular and Human Genetics
Department of Molecular and Human Genetics
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John W. Belmont, M.D., Ph.D.

John W. Belmont, M.D., Ph.D.

Professor of Molecular and Human Genetics

Other Positions

Professor, Departments of Pathology & Immunology and Pediatrics; Program in Developmental Biology; Stem Cells and Regenerative Medicine (STaR) Center; USDA/ARS Children's Nutrition Research Center


B.A., University of Texas at Austin, 1974
M.D., Ph.D., Baylor College of Medicine, 1981
Resident, Pediatrics, Children's National Medical Center, 1983
Resident, Pediatrics, Baylor College of Medicine, 1984
Fellow, Medical Genetics, Baylor College of Medicine, 1986

Board Certifications

American Board of Pediatrics
American Board of Medical Genetics: Clinical Genetics and Clinical Biochemical Genetics

Professional Organizations

Member, American Society of Human Genetics
Member, American College of Medical Genetics
Member, American Society for Clinical Investigation
Member, Society for Pediatric Research

Clinical Interests

Birth Defects, Cardiovascular Genetics with special interest in cardiovascular malformations and connective tissue disorders

Research Interests

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.

Zic3 deficient embryo

A whole mount in situ hybridization with the brachyury probe (mesoderm) depicts a disruption of the notochord in a Zic3 deficient embryo.

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.

Selected Publications

  1. 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 (2013). Integrative genomic analysis of the human immune response to influenza vaccination. Elife 2: e00299. PubMed PMID: 23878721
  2. Lalani SR, Ware SM, Wang X, Zapata G, Tian Q, Franco LM, Jiang Z, Bucasas K, Scott DA, Campeau PM, Hanchard N, Umaña L, Cast A, Patel A, Cheung SW, McBride KL, Bray M, Craig Chinault A, Boggs BA, Huang M, Baker MR, Hamilton S, Towbin J, Jefferies JL, Fernbach SD, Potocki L, Belmont JW (2013). MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development. Hum. Mol. Genet., in press. PubMed PMID: 23773997
  3. Jiang Z, Zhu L, Hu L, Slesnick TC, Pautler RG, Justice MJ, Belmont JW (2013). Zic3 is required in the extra-cardiac perinodal region of the lateral plate mesoderm for left-right patterning and heart development. Hum. Mol. Genet. 22(5): 879-89. PubMed PMID: 23184148
  4. 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 (2013). Global gene expression profiling in infants with acute respiratory syncytial virus broncholitis demonstrates systemic activation of interferon signaling networks. Pediatr. Infect. Dis. J. 32(2): e68-76. PubMed PMID: 23190772
  5. Lalani SR, Shaw C, Wang X, Patel A, Patterson LW, Kolodziejska K, Szafranski P, Ou Z, Tian Q, Kang SH, Jinnah A, Ali S, Malik A, Hixson P, Potocki L, Lupski JR, Stankiewicz P, Bacino CA, Dawson B, Beaudet AL, Boricha FM, Whittaker R, Li C, Ware SM, Cheung SW, Penny DJ, Jefferies JL, Belmont JW (2013). Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities. Eur. J. Hum. Genet. 21(2): 173-81. PubMed PMID: 22929023
  6. 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, Meijers-Heijboer H, de Graaff E, Helbing WA, Willemsen R, Devriendt K, Belmont JW, Oostra BA, Amack JD, Bertoli-Avella AM (2012). NPHP4 variants are associated with pleiotropic heart malformations. Circ. Res. 110(12): 1564-74. PubMed PMID: 22550138
  7. Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA (2011). Clan genomics and the complex architecture of human disease. Cell 147(1): 32-43. PubMed PMID: 21962505
  8. Lemaire SA, McDonald ML, Guo DC, Russell L, Miller CC 3rd, 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 HJ, Belmont JW, Leal SM, Milewicz DM (2011). Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat. Genet. 43(10):996-1000. PubMed PMID: 21909107
  9. Bucasas KL, Franco LM, Shaw CA, Bray MS, Wells JM, Niño D, Arden N, Quarles JM, Couch RB, Belmont JW (2011). Early patterns of gene expression correlate with the humoral immune response to influenza vaccination in humans. J. Infect. Dis. 203(7): 921-9. PubMed PMID: 21357945
  10. 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; GenTAC Investigators (2011). Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections. PLoS Genet. 7(6): e1002118. PubMed PMID: 21698135

Contact Information

John W. Belmont, M.D., Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, MS BCM225
Houston, TX, 77030, U.S.A.

Phone: 713-798-4634
Fax: 713-798-8142

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