Hum Genet (1990) 85:12-14 9 Springer-Verlag1990 The achondroplasia gene is not linked to the locus for neurofibromatosis I on chromosome 17 S.-M. Pulst 1, J. M. Graham, Jr. 2, P. Fain 3, D. Barker 3, T. Pribyl 2, and J. R. Korenberg 2 1Division of Neurology and 2Division of Medical Genetics, Cedars-Sinai Medical Center, University of California, Los Angeles, CA 90048, USA 3 Department of Medical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA Received October 5, 1989 / Revised October 27, 1989 Summary. We have investigated genetic linkage of von Recklinghausen neurofibromatosis (NF1) and achondro- plasia (ACH) using chromosome-17 markers that are known to be linked to NF1. Physical proximity of the two loci was suggested by the report of a patient with mental retardation and the de novo occurrence of both NF1 and ACH. Since the chance of de novo occurrence of these two disorders in one individual is 1 in 600 mil- lion, this suggested a chromosomal deletion as a single unifying molecular event and also that the ACH and NF1 loci might be physically close. To test this, we per- formed linkage analysis on a three-generation family with ACH. We used seven DNA probes that are tightly linked to the NF1 locus, including DNA sequences that are known to flank the NF1 locus on the centromeric and telomeric side. We detected two recombinants between the ACH trait and markers flanking the NF1 locus. In one recombinant, the flanking markers themselves were nonrecombinant. Multi-point linkage analysis excluded the ACH locus from a region surrounding the NF1 locus that spans more than 15cM (lod score <-2). There- fore, analysis of this ACH pedigree suggests that the ACH locus is not linked to the NF1 locus on chromo- some 17. Introduction Achondroplasia (ACH) is the commonest type of short- limbed dwarfism and has clearly established autosomal dominant inheritance. Sporadic cases are the result of new mutations and occur at a rate of approximately 1.4 • 10 .5 to 1.8 • 10 .5 per gamete using modern diagnostic criteria to avoid inclusion of related disorders (Camera and Mastroiacovo 1982; Gardener 1977; Orioli et al. Offprint requests to." J.R. Korenberg, Room 2111, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA 1986). The nature of the genetic defect and the chromo- somal location of the ACH gene are not known. A chro- mosomal location of the ACH gene was recently sug- gested by the identification of a patient with de novo ACH, neurofibromatosis 1 (NF1) and a 47,XYY karyo- type (Wassman et al. 1988). Another patient with coinci- dent NF1 and ACH has apparently been identified in Vancouver, Canada (Edwards et al. 1988). Since the chance of de novo occurrence of NF1 and ACH in one individual is less than 1 in 600 million, this suggested a chromosomal deletion as a single unifying event and also that the ACH and NF1 loci might be physically and ge- netically close. Since the NF1 gene has recently been mapped to the proximal long arm of human chromosome 17 (Barker et al. 1987; Fain et al. 1987; Goldgar et al. 1989; Seizinger et al. 1987), the NF1 region on chromosome 17 is a can- didate location for the ACH gene. This genomic region has been relatively well characterized and multiple DNA VAW211 EW206 17H8 HHH202 VAW212 EW207 CRYB1 VAW215 EW204 NF1 p--- (CEN)-- 2cM--I-- lcM --[- 0-l-- 5cM --[- lcM -[-- q A Marker Recombination fraction 0.00 0.05 0.10 17H8 -INF -1.44 -0.89 CRYB1 -INF -0.30 -0.09 EW207 -INF -0.72 -0.44 EW204 -INF -0.72 -0.44 B Fig.1. A Genetic map of the NF1 region. B Pairwise analysis be- tween ACH and four chromosome-17 markers for three recombi- nation fractions