Repositioning the hereditary paraganglioma critical region on chromosome band 11q23

Hereditary paragangliomas (PGL, glomus tumors, MIM no.168000) are mostly be nign, slow-growing tumors of the head and neck region. The gene (or genes) affecting risk to PGL are subject to genomic imprinting: children of affect ed fathers exhibit an autosomal dominant pattern of disease inheritance, wh ereas children of affected mothers rarely if ever develop the disease throu gh maternal transmission. We previously confined the disease gene to an app roximately 6 Mb critical region on chromosome band 11q23 (PGL1). Based on h aplotype analysis of an extended Dutch pedigree, a 2 Mb sub-region between D11S938 and D11S1885 was proposed as the PGL1 critical interval. In this st udy, we excluded this interval by analysis of two new single tandem repeat polymorphisms (STRP) contained therein. Instead, we predicted a non-overlap ping, more proximal 2 Mb critical interval between D11S1637 and D11S897, an d evaluated this new region using nine STRP (D11S1986, five new, closely-li nked STRP, D11S1347, D11S3178, and D11S1987). Consistent with our predictio n, we observed substantial haplotype-sharing within the Dutch pedigree. We also analyzed four new American PGL families. A recombination event detecte d in one family further defined D11S1347 as the new telomeric border. We ob served significant haplotype-sharing within this new interval among three u nrelated American PGL families, strongly suggesting that they originated fr om a common ancestor. Thus, we confined PGL1 to an approximately 1.5 Mb reg ion between D11S1986 and D11S1347, and showed identity-by-descent sharing f or a group of American PGL families.