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Large Germline Deletions of Mitochondrial Complex II Subunits SDHB and SDHD in Hereditary Paraganglioma

Clinical Cancer Genetics Program (S.R.M., R.T.P., C.E.), Human Cancer Genetics Program (S.R.M., R.T.P., M.M.S., C.E.), Comprehensive Cancer Center, Department of Molecular Genetics (S.R.M., C.E.), and Division of Human Genetics (R.T.P., C.E.), Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210; Department of Pediatrics, Southern Illinois University School of Medicine (S.R.F., M.C.S.), Springfield, Illinois 62794; Departments of Medicine (M.M.S.) and Endocrinology (E.P.D.), Federal University of Minas Gerais, Belo Horizonte, Brazil; Department of Endocrinology (E.P.D.), Hospital Felício Rocho, Belo Horizonte, Brazil; and Cancer Research UK, Human Cancer Genetics Research Group (C.E.), University of Cambridge, Cambridge CB2 1XY, United Kingdom

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., The Ohio State University Human Cancer Genetics Program, 420 West 12th Avenue, Suite 690 TMRF, Columbus, Ohio 43210. E-mail: eng-1{at}medctr.osu.edu.

More than 30% of adrenal pheochromocytomas are hereditary. These neuroendocrine tumors are major components of three inherited cancer syndromes: multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and pheochromocytoma/paraganglioma syndrome (PC/PGL). Germline mutations in RET; VHL; and SDHB, SDHC, and SDHD are associated with multiple endocrine neoplasia type 2, VHL, and PC/PGL, respectively. The majority (>70%) of hereditary extraadrenal PCs [catecholamine-secreting paragangliomas (PGL)] are accounted for by germline intragenic mutations in SDHB, SDHC, or SDHD. Therefore, a subset of hereditary PGL is not accounted for. Here we report two unrelated hereditary PGL families, one with a germline whole-gene deletion of SDHD (family 4194), the other a partial deletion of SDHB (family BRZ01). Although they were initially designated mutation negative for all of the PC-associated genes after PCR-based analysis, we suspected that a large deletion or rearrangement might be present. Genotyping around the PC-associated genes demonstrated that both families were consistent with linkage with one of these genes. Using fine structure genotyping and semiquantitative duplex PCR analysis, we identified an approximately 96-kb deletion spanning SDHD in family 4194 and an approximately 1-kb deletion involving the 5' end of SDHB in family BRZ01. Thus, including SDHB and SDHD deletion analysis could increase gene-testing sensitivity for PGL patients, which would aid in genetic counseling and management of patients and families.

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