Brachydactyly type B: Linkage to chromosome 9q22 and evidence for genetic heterogeneity

Brachydactyly type B (BDB), an autosomal dominant disorder, is the most sev ere of the brachydactylies and is characterized by hypoplasia or absence of the terminal portions of the index to little fingers, usually with absence of the nails. The thumbs may be of normal length but are often flattened a nd occasionally are bifid. The feet are similarly but less severely affecte d. We have per formed a genomewide linkage analysis of three families with BDB, two English and one Portugese. The two English families show linkage t o the same region on chromosome 9 (combined multipoint maximum LOD score 8. 69 with marker D9S257). The 16-cM disease interval is defined by recombinat ions with markers D9S1680 and D9S1786. These two families share an identica l disease haplotype over 18 markers, inclusive of D9S278-D9S280. This provi des strong evidence that the English families have the same ancestral mutat ion, which reduces the disease interval to <12.7 cM between markers D9S257 and D9S1851 in chromosome band 9q22. In the Portuguese family, we excluded linkage to this region, a result indicating that BDB is genetically heterog eneous. Reflecting this, there were atypical clinical features in this fami ly, with shortening of the thumbs and absence or hypoplasia of the nails of the thumb and hallux. These results enable a refined classification of BDB and identify a novel locus for digit morphogenesis in 9q22.