Leslie G. Biesecker works in the Genetic Disease Research Branch. The research in the lab centers on questions pertaining to developmental biology and birth defects. We are interested in pursuing novel mechanisms of normal mammalian development and disruptions of those processes that lead to birth defects. The work in the laboratory includes three main areas, single gene malformation disorders, medical genetics of Anabaptist sects, and novel techniques to identify chromosomal aberrations.

The main areas of research in the lab are investigations into Pallister-Hall Syndrome (PHS), McKusick-Kaufmann syndrome, Oral-Facial-Digital syndrome type VI, and Greig cephalopolysyndactyly syndrome. These disorders are single-gene human developmental anomaly syndromes that cause birth defects of variable severity. We are using classical positional cloning techniques to isolate the cause of these disorders, perform genotype-phenotype correlations, and clinical studies to determine the range of severity and overlap among these disorders. We have determined the molecular abnormality of Pallister-Hall syndrome, showing that it is allelic to Greig cephalopolysyndactyly syndrome and a form of simple polydactyly. Studies are under way to characterize the molecular mechanism that leads to the development of three distinct phenotypes from alterations in a single gene, GLI3.

The second area is the medical genetics of Anabaptist sects, predominantly Old Order Amish and Mennonite sects. Persons in these cultural isolates are susceptible to a number of autosomal recessive disorders due to founder effects and homozygosity. These disorders provide a tool to understand the pathophysiology of rare disorders including developmental anomalies, metabolic conditions, and adult onset diseases. These disorders are characterized in clinical field work and by positional cloning strategies. We have recently determined the molecular abnormality for glycogen storage disease type 6, or Hers disease of the Mennonites. The alteration of the gene leads to a subtle change in the gene that explains the mild nature of the disorder. Implementation of molecular diagnosis and carrier testing in this population is under development. We are currently performing positional cloning of two other phenotypes, McKusick-Kaufman syndrome (hydrometrocolpos-polydactyly) and Amish microcephaly.

Lastly, we are focusing on submicroscopic deletions as a mechanism of undefined anomaly syndromes, VACTERL association, and unexplained stillbirth. It is well known that small deletions and duplications can lead to malformation syndromes. It has long been suspected that sub-microscopic chromosomal aberrations cause a significant number of these syndromes. We have used the technique of microsatellite analysis to determine the parent of origin of each chromosome arm in affected children to determine the frequency of duplications and deletions. The study has shown that 1/3 to 1/2 of all duplications and deletions are missed by standard cytogenetics techniques. This work suggests that improved clinical cytogenetic techniques would lead to better diagnostic yield in the genetics clinic.