Search for a gene disrupted in a patient with acrodysostosis and a t(4;6)(q12;p23). J.G. Dauwerse¹, B. de Vries², C.H. Wouters², D.J.M. Peters¹, M.H. Breuning¹. 1) Dept of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; 2) Clinical Genetics Center Rotterdam, Rotterdam, The Netherlands.

   The index patient is a mentally normal 31 year-old male with height 1.40m (-6SD), arm span 1.26m and normal head circumference (54.5 cm = 25th centile) with a flat face, depressed nasal bridge, broad nasal root and anteverted nostrils. He had extreme brachydactyly of both hands and, to a lesser degree, of the feet. The aorta was sclerotic with insufficiency of the aortic valves. X-ray investigation showed acrodysostosis with relatively short ulna suggesting either acrodysostosis (MIM 101800) or a mild form of acromesomelic dysplasia. Both non-consanguineous parents and 5 sibs had normal postures. A de-novo 46,XY,t(4;6)(q12;p23) was found.
In order to find the gene(s) disrupted by the t(4;6) we began by mapping the chromosome 4 breakpoint more precisely. FISH with YAC clones selected from the SHGC chromosome 4 YAC map was performed on metaphase slides of the patient. Out of 40 YACs tested, five YACs turned out to span the chromosome 4 breakpoint. Using Alu-PCR fragments from the smallest YAC (330Kb) two PAC clones were isolated, which FISH signals were split by the translocation. Using the PACs, cosmids could be isolated and a restriction map of the region was constructed; however, cosmids spanning the breakpoint could not be isolated. Using the same FISH mapping approach a YAC (1.5Mb) spanning the chromosome 6 translocation breakpoint has also been identified. Currently various techniques are applied to identify genes in the cloned chromosome 4 region. Within the cosmid contig mapping distal to the translocation breakpoint we could place the PDGFRA-KIT genecluster. A fragment close to the breakpoint, showing cross-species conservation is currently being evaluated.