The focus of my laboratory in recent years has been the development of a sequence-based approach to identify germline mutations in cancer genes. We have developed mutational analysis of the adenomatous polyposis coli (APC) gene for familial adenomatous polyposis (FAP) patients using denaturing high performance liquid chromatography (dHPLC) and sequence analysis, as well as a strategy to identify gross alterations. Similar approaches were utilized to identify germline mutations in mismatch repair genes, MLH1, MSH2, and MSH6 leading to hereditary non-polyposis colon cancer (HNPCC). We used microsatellite instability as a screening tool to identify HNPCC candidates in colorectal cancer patients.

One focus of our research has been defining the biological and functional significance of sequence variants in the dystrophin gene. While up to 30% of Duchenne and Becker muscular dystrophy patients carry non-deletion / duplication-type mutations, identification of novel variants presents interesting challenges in interpretation at the biological and clinical level. Our research addresses these challenges through predictive analysis tools and biological testing. The ultimate goal of our effort is to create an algorithm that will be clinically useful for interpretation of novel sequence variants.

New directions include clinical research collaborative projects focusing on mutational analysis of Rett syndrome patients (MeCP2 gene), Fanconi anemia patients (FANC genes), and rare disorders.

Wu G, Wu W, Hegde M, Fawkner M, Chong B, Love DR, Su L-K, Lynch P, Snow K, Richards CS. Detection of sequence variations in the Adenomatous Polyposis Coli (APC) gene using denaturing high-performance liquid chromatography.  GeneticTesting 5(4):281-290, 2002.

Hegde M, Lewis RA, Richards CS.  Diagnostic testing for X-linked ocular albinism (X-OA1) with a hierarchical mutation screening protocol. Genetic Testing 6(1):7-14, 2002.

Hegde M, Blazo M, Odenbaugh D, Richards C. Assay validation for identification of HNPCC-causing mutations in mismatch repair genes MLH1, MSH2, and MSH6. J Mol Diag. 2005 Oct;7(4):525-34.

Hegde M, Blazo M, Chong B, Chin LHE, Ward PA, Chintagumpala MM, Kim JY, Ayala G, Plon SE, Richards CS. A homozygous mutation in MSH6 causes Turcot Syndrome.  Clin Cancer Res. 2005 Jul 1;11(13):4689-93.

Richards CS and Hegde MR.  Familial Adenomatous Polyposis. In:Encyclopedia of Genomics, Proteomics and Bioinformatics. M. Dunn, L. Jorde, P. Little, S. Subramaniam, eds., B. Korf (section editor), John Wiley & Sons, UK (2005 in press).

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