FINE MAPPING OF AN IMPRINTED GENE FOR FAMILIAL NONCHROMAFFIN PARAGANGLIOMAS, ON CHROMOSOME 11Q23

Hereditary nonchromaffin paragangliomas (PGL; glomus tumors; MIM 16800 0) are mostly benign, slow-growing tumors of the head and neck region, inherited from carrier fathers in an autosomal dominant fashion subje ct to genomic imprinting. Genetic linkage analysis in two large, unrel ated Dutch families assigned PGL loci to two regions of chromosome 11, at 11q23 (PGL1) and 11q13.1 (PGL2). We ascertained a total of 11 Nort h American PGL families and confirmed maternal imprinting (inactivatio n). In three of six families, linkage analysis provided evidence of li nkage to the PGL1 locus at 11q23. Recombinants narrowed the critical r egion to an similar to 4.5-Mb interval flanked by markers D11S1647 and D11S622. Partial allelic loss of strictly maternal origin was detecte d in 5 of 19 tumors. The greatest degree of imbalance was detected at 11q23, distal to D11S1327 and proximal to CD3D. Age at onset of sympto ms was significantly different between fathers and children (Wilcoxon rank-sum test, P < .002). Affected children had an earlier age at onse t of symptoms in 39 of 57 father-child pairs (chi(2) = 7.74, P < .006) . However, a more conservative comparison of the number of pairs in wh ich a child had greater than or equal to 5 years earlier age at onset (n = 33) vis-a-vis that of complementary pairs (n = 24) revealed no si gnificant difference (chi(2) = 1.42, P > .2). Whether these data repre sent genetic anticipation or ascertainment bias can be addressed only by analysis of a larger number of father-child pairs.