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Erich Roessler, M.D., Ph.D.

Associate Investigator, Medical Genetics Branch
Human Development Section

Scientific Summary

Dr. Roessler focuses on identifying human genetic mutations that contribute to birth defects and demonstrating how these mutations cause their pathophysiology. His research has impacted the field of the molecular genetics of forebrain development through the systematic genetic and environmental study of holoprosencephaly (HPE) susceptibility factors. HPE is the most common malformation of the human forebrain, and is often pathogenetically implicated in concurrent malformations of the face. Dr. Roessler has led the design, organization, implementation and interpretation of most of the Muenke lab's research investigations into HPE over the past decade and a half, especially with respect to the molecular aspects of HPE pathogenesis. The group has intensively investigated and reported dozens of developmental genes in the scientific literature . Dr. Roessler regularly offers his experience as a physician-scientist to bridge the expertise of basic researchers with active clinicians, collaborators and clinical trainees.

As a team leader, Dr. Roessler has helped to identify many of the genes implicated in HPE malformations, and understands the interconnections between environmental and genetic risk factors.  This fundamental understanding of disease mechanism helps during the process of genetic counseling, the articulation and development of novel research questions, and in establishing biological assays of gene function in model organisms, such as the zebrafish and mouse.

The zebrafish is an ideal organism to study many of the key steps of both laterality (body plan organization) and brain development (HPE and related malformations) by virtue of its optical transparency and rapid development (organogenesis within one day). Working with an extensive network of intramural cores and principal investigators, Dr. Roessler is developing and applying many of the essential strategies for individual gene and gene-network analysis. For example, in collaboration with the NIH zebrafish community and staff scientists in the Muenke lab, he has refined and developed a biosensor approach that allows for direct assessment of normalized biological activity of variant alleles.  This approach and its mathematical framework demonstrate the underlying strategy for human genome functional annotation. As technical challenges to revealing the secrets written in the human genome are revealed by advances in sequencing technology, scientists and clinicians are still left with immense challenges in interpretation of detected variations. In addition to conventional zebrafish manipulations, Dr. Roessler employs newer n-Counter Nanostring methods and targeted gene disruption using TALEN and CRISPER techniques. These strategies are superior to an individual variant or mutation counting method because they constrain the interpretation to actual experimental measurement.

By developing tools to analyze the biological effects of individual gene variants, in conjunction with members of the Muenke lab, Dr. Roessler has paved the way for meaningful genotype-phenotype characterization of changes in those genes most commonly associated with HPE spectrum disorders: SHH, SIX3, TGIF, ZIC2, CDON, BOC and GLI2.  Taken together, these mutational spectrum analyses and genotype-phenotype studies have established the basis for understanding HPE pathogenesis and the likely characteristics of future HPE genes.

A direct benefit of his sustained research and cumulative expertise is the collection of an unparalleled cohort of patients with HPE spectrum disorders. The HPE team has collected over 1,000 cases that now allow for sophisticated analyses using the latest in molecular techniques (e.g., array CGH, modifier screens on sub-cohorts of mutation carriers, whole-genome sequencing of selected pedigrees allowing for exploitation of Mendelian inheritance and comparative genotype-phenotype analysis).

Dr. Roessler has successfully competed for a proposal funded by the NHGRI Flagship committee and has collaborated extensively with the Genomics, Microscopy, Microarray, Zebrafish and Mouse Cores. His most recent work includes targeted capture of both coding and noncoding elements surrounding known HPE genes and potential candidate genes. Retrospective analysis of the molecular characteristics of well-established HPE genes across multiple diagnostic centers provides clear predictions for future HPE genes and their modifying factors. This approach will establish a clear framework for future whole genome analysis, as the initially prohibitive costs of medical sequencing continue to decline.

Dr. Roessler has contributed to dozens of molecular and clinical papers related to HPE and related disorders over the past several years. In addition, he has made substantial contributions to the experimental design and molecular approaches to the genetics of behavior (e.g., ADHD), craniofacial anomalies, and brain disorders distinct from HPE (e.g., schizencephaly), among others.

Human Development Section Members

Sung-Kook Hong, Staff Scientist
Ping Hu, Staff Biologist

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Posted: January 6, 2015