Differences in complexity of isolated brachydactyly type C cannot be attributed to locus heterogeneity alone

Hereditary isolated brachydactyly type C (OMIM 113100) mostly follows an au tosomal dominant pattern of inheritance with a marked variability in expres sion. This phenotype has been mapped to two different loci on chromosomes 1 2q24 and 20q11.2. The latter locus contains the cartilage-derived morphogen etic protein (CDMP) 1 gene, in which a null mutation has been found in pati ents with malformations restricted to the upper limbs, A more complex brach ydactyly type C phenotype has keen mapped to chromosome 12q24. Differences in complexity of these phenotypes have keen attributed to locus heterogenei ty, Clinical subclassification based on the degree of complexity of the phe notype has therefore been suggested. We present patients with a complex bra chydactyly type C phenotype in whom there is considerable intra- and interf amilial variability in expression. We show that clinical subclassification based on the complexity of the brachydactyly type C phenotype related to th e genetic defect is not feasible, We present evidence that differences in c omplexity are not only due to locus heterogeneity, but that genetic modifie rs and/or environmental factors must also play a role, (C) 2001 Wiley-Liss, Inc.