Human Molecular Genetics Advance Access originally published online on May 5, 2009
Human Molecular Genetics 2009 18(15):2768-2778; doi:10.1093/hmg/ddp212
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Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1
1 Faculté des Sciences Pharmaceutiques et Biologiques, UMR745 INSERM, Université Paris Descartes, Paris 75006, France 2 Service de Biochimie et de Génétique Moléculaire, Hôpital Beaujon, AP-HP, Clichy 92110, France 3 Service de Dermatologie, Hôpital Hôtel Dieu, Nantes 44093, France 4 Service de Dermatologie, CHU de Montpellier, Montpellier 34295, France 5 Service de Dermatologie, Desgenettes Hospital, Lyon 69003, France 6 CIC INSERM 006 7 Service de Dermatologie, Hôpital Henri Mondor, AP-HP, Université Paris 12, Créteil 94000, France 8 LIC EA4393, Hôpital Henri Mondor, Créteil 94000, France
* To whom correspondence should be addressed. Tel: +33 153739725; Fax: +33 144071754; Email: audrey.sabbagh{at}parisdescartes.fr
Received March 6, 2009; Accepted April 30, 2009
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder which displays considerable inter- and intra-familial variability in phenotypic expression. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 750 NF1 patients from 275 multiplex families collected through the NF-France Network. Twelve NF1-related clinical features, including five quantitative traits (number of café-au-lait spots of small size and of large size, and number of cutaneous, subcutaneous and plexiform neurofibromas) and seven binary ones, were scored. All clinical features studied, with the exception of neoplasms, showed significant familial aggregation after adjusting for age and sex. For most of them, patterns of familial correlations indicated a strong genetic component with no apparent influence of the constitutional NF1 mutation. Heritability estimates of the five quantitative traits ranged from 0.26 to 0.62. Moreover, we investigated for the first time the role of the normal NF1 allele in the variable expression of NF1 through a family-based association study. Nine tag SNPs in NF1 were genotyped in 1132 individuals from 313 NF1 families. No significant deviations of transmission of any of the NF1 variants to affected offspring was found for any of the 12 clinical features examined, based on single marker or haplotype analysis. Taken together, our results provided evidence that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease.