Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1)

The relationship of genetic factors to variable expressivity in neurofibromatosis 1 (NF1) is poorly understood. We examined familial aggregation of NF1 features among different classes of affected relatives. Clinical information was obtained from the National NF Foundation International Database on 904 affected individuals in 373 families with 2 or more members with NF1. We used multivariate probit regression to measure the associations between various classes of relatives for each of 10 clinical features of NF1, while simultaneously adjusting for covariates including related features, age, and gender. Two distinct patterns were observed when we compared associations between first- and second-degree relatives, sibs, and parent-child pairs: Lisch nodules and café-au-lait spots had greater associations between first-degree relatives than between second-degree relatives, while subcutaneous neurofibromas, plexiform neurofibromas, café-au-lait spots, and intertriginous freckling had greater associations between sibs than between parents and children. In addition, Lisch nodules, subcutaneous neurofibromas, and cutaneous neurofibromas had greater associations between affected fathers and children than between affected mothers and children. These familial patterns suggest that unlinked modifying genes and the normal NF1 allele may both be involved in the development of particular clinical features of NF1, but that the relative contributions vary for different features.