The Cullen Foundation Endowed Chair in Molecular Genetics
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX, US
Baylor College of Medicine
Program in Integrative and Molecular and Biomedical Sciences
Baylor College of Medicine
Program in Translational Biology & Molecular Medicine
Baylor College of Medicine
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas, United States


PhD from New York University
Post-Doctoral Fellowship at New York University
Residency at Baylor College Of Medicine Affiliate Hospitals
Clinical Fellowship at Baylor College of Medicine
Medical Genetics
Sabbatical from Wellcome Trust Sanger Institute
DSc from Watson School of Biological Sciences, Cold Spring Harbor Laboratory
BA from New York University
MD from New York University School Of Medicine


American College of Medical Genetics
Clinical Genetics
American Board of Medical Genetics
Clinical Molecular Genetics
American Board of Medical Genetics

Professional Interests

  • Molecular genetics of Charcot-Marie-Tooth disease and related inherited neuropathies
  • Molecular mechanisms for human DNA rearrangements
  • Genomic disorders
  • Copy number variation (CNV) and disease
  • Human Genome Analysis

Professional Statement

To what extent are de novo DNA rearrangements in the human genome responsible for sporadic human traits including birth defects? How many human Mendelian and complex traits are due to structural changes and/or gene copy number variation (CNV)? What are the molecular mechanisms for human genomic rearrangements? The answers to these questions will impact both prenatal and postnatal genetic diagnostics, as well as patient management and therapeutics. Moreover, the answers have profound implications for human evolution.

For six decades, the molecular basis of disease has been addressed in the context of how mutations effect the structure, function, or regulation of a gene or its protein product. However, we have been living in a genocentric world. During the last decade it has become apparent that many disease traits are best explained on the basis of genomic alterations. Furthermore, it has become abundantly clear that architectural features of the human genome can result in genomic instability and susceptibility to DNA rearrangements that cause disease traits – I have referred to such conditions as genomic disorders.

Twenty-five years ago, it became evident that genomic rearrangements and gene dosage effects, rather than the classical model of coding region DNA sequence alterations, could be responsible for a common, autosomal dominant, adult-onset neurodegenerative trait—Charcot-Marie-Tooth neuropathy type 1A (CMT1A). With the identification of the CMT1A duplication and its reciprocal deletion causing hereditary neuropathy with liability to pressure palsies (HNPP), the demonstration that PMP22 copy-number variation (CNV) could cause inherited disease in the absence of coding-sequence alterations, was initially hard to fathom. How could such subtle changes—three copies of the normal “wild-type” PMP22 gene rather than the usual two—underlie neurologic disease?

Nevertheless, it has become apparent during this last decade and a half that neurodegeneration can represent the outcome of subtle mutations acting over prolonged time periods in tissues that do not generally regenerate, regardless of the exact molecular mechanism. This concept has revealed itself through 1) conformational changes causing prion disease, 2) the inability to degrade accumulated toxic proteins in amyloidopathies, α-synucleinopathies, and polyglutamine expansion disorders, and 3) alteration in gene copy number and/or expression levels through mechanisms such as uniparental disomy (UPD), chromosomal aberrations (e.g., translocations), and submicroscopic genomic rearrangements including duplications, deletions, and inversions. Specific deletions and duplications have recently been shown to be associated with both autism and schizophrenia, as well as with obesity.

Currently, structural variation of the human genome is commanding a great deal of attention. In the postgenomic era, the availability of human genome sequence for genome-wide analysis has revealed higher-order architectural features (i.e., beyond primary sequence information) that may cause genomic instability and susceptibility to genomic rearrangements. Nevertheless, it is perhaps less generally appreciated that any two humans contain more base-pair differences due to structural variation of the genome than resulting from single-nucleotide polymorphisms (SNPs). De novo genomic rearrangements have been shown to cause both chromosomal and Mendelian disease, as well as sporadic traits, but our understanding of the extent to which genomic rearrangements, gene CNV, and/or gene dosage alterations are responsible for common and complex traits remains rudimentary.

Central to our understanding of human biology, evolution, and disease is an answer to the following questions: What is the frequency of de novo structural genomic changes in the human genome? What are the molecular mechanisms for genomic rearrangements? and What is the genomic code?

Selected Publications


American Neurological Institute
Institute of Medicine
American Society for Clinical Investigation
American Association for the Advancement of Science
Society for Pediatric Research
Genetics Society of America
American Society of Human Genetics
American Society for Microbiology
American Academy of Pediatrics
American Federation for Medical Research
Harris County Hospital Society
Texas Medical Association
American Medical Association