Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma.
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.
McWhinney
Sarah R
SR
Clinical Cancer Genetics Program, Comprehensive Cancer Center, Department of Molecular Genetics, The Ohio State University 420 West 12th Avenue, Suite 690 TMRF, Columbus, Ohio 43210, USA.
Pilarski
Robert T
RT
Forrester
Shawnia R
SR
Schneider
Michael C
MC
Sarquis
M Marta
MM
Dias
Eduardo P
EP
Eng
Charis
C
D000328:Adult; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D010235:Paraganglioma / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013385:Succinate Dehydrogenase / Q000235:genetics*
D013385:Succinate Dehydrogenase