Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma

Familial paragangliomas (PGL) are slow-growing, highly vascular, generally benign neoplasms, usually of the head and neck, that arise from neural cres t cells. This rare autosomal dominant disorder is highly penetrant and infl uenced by genomic imprinting through paternal transmission, Timely detectio n of these tumors may afford the affected individual the opportunity to avo id the potential serious morbidity associated with surgical removal and the mortality that may accompany local and distant metastases. Linkage to two distinct chromosomal loci, 11q13.1 and 11q23, has been previously reported. Recently, germline mutations in SDHD, a mitochondrial complex II gene on c hromosome 11q23, have been demonstrated, We evaluated members of seven fami lies with PGL, five previously studied and shown to have linkage to chromos ome 11q23, The entire coding region of the SDHD gene was sequenced and yiel ded four novel mutations and one mutation shared in three of our unrelated families, Novel mutations found included a truncating mutation in exon 2, a s well as a missense mutation, a deletion, and an insertion in exon 4, Thre e of our families had a common mutation in exon 3 (P81L) that has been repo rted and thought to be a founder mutation, A restriction enzyme assay was d eveloped for initial screening of this mutation. Molecular analysis is now available and recommended for presymptomatic diagnosis in those at-risk ind ividuals and for confirmatory diagnosis in those having PGL. (C) 2001 Wiley -Liss, Inc.