David H. Ledbetter, Ph.D.
Robert W. Woodruff Professor of Human Genetics
Director, Division of Medical Genetics
dledbetter@genetics.emory.edu
404.727.3875
Office: 305 G
Lab: 315
Whitehead Biomedical Research Building
615 Michael St.
Atlanta, GA 30322

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Dr. Ledbetter received his Ph.D. from the University of Texas at Austin in 1981 and joined the faculty at Baylor College of Medicine in Houston, where he rose to the rank of Professor. Prior to joining the faculty at Emory in 2003, Dr. Ledbetter was the founding Chair of the Department of Human Genetics at the University of Chicago (1996-2003). Dr. Ledbetter is a diplomat of the American Board of Medical Genetics (Clinical Cytogenetics) and a Founding Fellow of the American College of Medical Genetics. He has served on the Board of Directors of the American Society of Human Genetics and the American College of Medical Genetics. Among his awards are the 12th Carter Lecturer and Medal Recipient from the British Clinical Genetics Society in 1995. His educational activities include serving as a co-organizer and lecturer for American College of Medical Genetics Review Course since 1990 (previously the Baylor Review Course) and serving on the faculty of the Short Course in Medical and Experimental Mammalian Genetics in Bar Harbor, Maine, since 1992.

Research Description:
Research in our laboratory focuses on the molecular characterization of human developmental disorders. Specifically, we are interested in the mechanisms and consequences of chromosomal abnormalities (gene dosage imbalance and genomic imprinting) that result in abnormal brain development, mental retardation and behavioral disorders such as autism.

Earlier research focused on the discovery of the chromosomal basis of mental retardation syndromes and development of technologies for accurate diagnosis. Dr. Ledbetter discovered the chromosome 15 deletion causing Prader-Willi syndrome (obesity and mental retardation) while a graduate student, and shortly thereafter described the deletion of chromosome 17 that causes Miller-Dieker lissencephaly (“smooth brain”), a neuronal migration disorder causing profound mental retardation. While these disorders were initially studied by high-resolution chromosome banding techniques, the Ledbetter lab developed the first fluorescence in situ hybridization (FISH) diagnostic tests for microdeletion syndromes, greatly improving the accuracy of laboratory diagnosis.

In the early 1990s, we hypothesized that cryptic imbalances at human chromosome ends, the telomeres, might be a significant cause of unexplained mental retardation. To test this hypothesis, we developed a complete set of human telomeric probes for clinical and basic research applications. Studies from numerous laboratories using this clone set indicate that 3-6% of all unexplained mental retardation is due to telomere imbalances.

More recently, we developed high-resolution maps and clones around all human centromeric regions, and applied these to investigate the mechanism of formation of small, supernumerary ring chromosomes in humans. We discovered that a common mechanism of small ring formation involves centromere misdivision, producing a small ring chromosome and a complementary deletion chromosome. This mechanism was originally described in 1938 by Barbara McClintoch in classic studies on ring chromosome behavior in maize.

The development of microarray technology for whole-genome analysis of copy number is revolutionizing cytogenetics in research and clinical diagnostic laboratories. We have developed a “molecular karyotype” on an oligonucleotide array platform which allows detection of deletions or duplications >500 kb in size anywhere in the genome, and >50 kb in selected critical regions (compared to 5 Mb resolution of chromosome banding). This technology is leading to the discovery of new microdeletion syndromes and can be systematically used to develop a Gene Dosage Map for the human genome.

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