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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, Department of Molecular and Human Genetics

Other Positions

Professor, Department of Pediatrics; Program in Developmental Biology; Stem Cells and Regenerative Medicine (STaR) Center
Director, Cardiovascular Genetics Clinic

Education

B.A., University of Texas, 1974
M.D., Ph.D., Baylor College of Medicine, 1981
Resident, Pediatrics, Children's Hospital, National Medical Center, Washington, D.C., 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: Biochemical Genetics

Professional Organizations

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

Clinical Interests

Inborn Errors of Metabolism, Cardiovascular Genetics

Research Interests

Cardiovascular Genetics: Severe congenital cardiovascular malformations occur in about six per 1000 live births. We are analyzing several clinical disorders that provide specific routes to gene identification. 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 technology to screen for deletion alleles that may point to additional genetic loci involved in CHARGE.

In another project we are screening a large number of children affected with a severe cardiovascular malformation and at least one other major birth defect. This occurs in about one-third 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. Our preliminary results indicate that we can identify both new genomic disorders and single gene defects that contribute to nonsyndromic heart defects.

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.

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 four genes have been identified as causing human heterotaxy using this sample set—ZIC3, ACVR2B, LEFTYA, and CFC1/cryptic. Current efforts focus on the NODAL-dependent signaling pathway that operates in the node and left lateral plate mesoderm. Future studies will extend this into the node-specific functional pathways and the establishment of the midline. 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 asymmetry. These studies have revealed an unexpected role for Zic3 in gastrulation.

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 will use array-based high throughput genotyping to examine the association of common DNA polymorphisms with risk of these conditions.

Genomic Profiles and Diagnostic Genotyping: We are interested in applying high throughput genotyping to disease diagnosis, disease risk screening, and pharmocogenetic testing. We have developed a panel of several thousand SNPs and mutations responsible for Mendelian diseases that will allow very inexpensive genotyping of clinically valid genetic variants. We expect these methods will ultimately be applied as a general screening procedure to enhance care for individual patients.

Selected Publications

  1. Roessler E, Ouspenskaia MV, Karkera JD, Vélez JI, Kantipong A, Lacbawan F, Bowers P, Belmont JW, Towbin JA, Goldmuntz E, Feldman B, Muenke M (2008). Reduced NODAL Signaling Strength via Mutation of Several Pathway Members Including FOXH1 Is Linked to Human Heart Defects and Holoprosencephaly. Am. J. Hum. Genet. 83(1): 18-29. [Pub Med]
  2. Ou Z, Berg JS, Yonath H, Enciso VB, Miller DT, Picker J, Lenzi T, Keegan CE, Sutton VR, Belmont J, Chinault AC, Lupski JR, Cheung SW, Roeder E, Patel A (2008). Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet. Med. 10(4): 267-77. [Pub Med]
  3. Shinawi M, Shao L, Jeng LJ, Shaw CA, Patel A, Bacino C, Sutton VR, Belmont J, Cheung SW (2008). Low-level mosaicism of trisomy 14: phenotypic and molecular characterization. Am. J. Med. Genet. A. 146A(11): 1395-405. [Pub Med]
  4. Seldin MF, Qi L, Scherbarth HR, Tian C, Ransom M, Silva G, Belmont JW, Gamron S, Allievi A, Palatnik SA, Saurit V, Paira S, Graf C, Guillerón C, Catoggio LJ, Prigione C, Berbotto GA, García MA, Perandones CE, Truedsson L, Abderrahim H, Battagliotti CG, Pons-Estel BA, Alarcon-Riquelme ME (2008). Amerindian ancestry in Argentina is associated with increased risk for systemic lupus erythematosus. Genes Immun. 9(4): 389-93. [Pub Med]
  5. Ben-Shachar S, Ou Z, Shaw CA, Belmont JW, Patel MS, Hummel M, Amato S, Tartaglia N, Berg J, Sutton VR, Lalani SR, Chinault AC, Cheung SW, Lupski JR, Patel A (2008). 22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome. Am. J. Hum. Genet. 82(1): 214-21. [Pub Med]
  6. Beaudet AL, Belmont JW (2008). Array-based DNA diagnostics: let the revolution begin. Annu. Rev. Med. 59: 113-29. [Pub Med]
  7. Sabeti PC, et al (2007). Genome-wide detection and characterization of positive selection in human populations. Nature 449(7164): 913-8. [Pub Med]
  8. International HapMap Consortium (2007). A second generation human haplotype map of over 3.1 million SNPs. Nature 449(7164): 851-61. [Pub Med]
  9. Karkera JD, Lee JS, Roessler E, Banerjee-Basu S, Ouspenskaia MV, Mez J, Goldmuntz E, Bowers P, Towbin J, Belmont JW, Baxevanis AD, Schier AF, Muenke M (2007). Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans. Am. J. Hum. Genet. 81(5): 987-94 [Pub Med]
  10. Lalani SR, Safiullah AM, Fernbach SD, Harutyunyan KG, Thaller C, Peterson LE, McPherson JD, Gibbs RA, White LD, Hefner M, Davenport SL, Graham JM, Bacino CA, Glass NL, Towbin JA, Craigen WJ, Neish SR, Lin AE, Belmont JW (2006). Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation. Am. J. Med. Genet. 78(2): 303-14. [Pub Med]
  11. McBride KL, Pignatelli R, Lewin M, Ho T, Fernbach S, Menesses A, Lam W, Leal SM, Kaplan N, Schliekelman P, Towbin JA, Belmont JW (2005). Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability. Am. J. Med. Genet. A. 134A(2): 180-6. [Pub Med.]
  12. Ware SM, Peng J, Zhu L, Fernbach S, Colicos S, Casey B, Towbin J, Belmont JW (2004). Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am. J. Med. Genet. 74(1): 93-105. [Pub Med]
  13. Purandare SM, Ware SM, Kwan KM, Gebbia M, Bassi MT, Deng JM, Vogel H, Behringer RR, Belmont JW, Casey B (2002). A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development 129(9): 2293-302. [Pub Med]
  14. Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M, Izykowski B, Phillips J, Doroshow R, Walot I, Hoft R, Neufeld EF (2001). Enzyme-replacement therapy in mucopolysaccharidosis I. N. Engl. J. Med. 344(3): 182-8. [Pub Med]
  15. Kosaki K, Bassi MT, Kosaki R, Lewin M, Belmont J, Schauer G, Casey B (1999). Characterization and mutation analysis of human LEFTY-A and LEFTY-B, homologues of murine genes implicated in left-right axis development. Am. J. Hum. Genet. 64(3): 712-21. [Pub Med]
  16. Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins N, Copeland NG, Bedell MA, Edelhoff S, Disteche CM, Simoneaux DK, Fanslow WC, Belmont JW, Spriggs MK (1993). CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259(5097): 990-3. [Pub Med]
  17. Belmont JW, Henkel-Tigges J, Chang SMW, Wager-Smith K, Kellems RE, Dick JE, Magli MC, Phillips RA, Bernstein A, Caskey CT (1986). Expression of human adenosine deaminase in murine hematopoietic progenitor cells following retroviral transfer. Nature 322(6077): 385-7. [Pub Med]

More Publications (PubMed)

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
E-mail:

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