A novel locus for brachydactyly type A1 on chromosome 5p 13.3-p 13.2. (Letters to JMG).

The brachydactylies are a group of inherited disorders characterised by shortened or malformed digits that are thought to be the result of abnormal growth of the phalanges and/or metacarpals. First classified by Bell into types A, B, C, D, and E, they were reclassified by Temtamy and McKusick (1) and Fitch. (2) Brachydactyly type A1 (BDA1, MIM 112500) is characterised by shortened or absent middle phalanges. Often the second and fifth digits, as well as the first proximal phalanx, are the most severely affected. In addition, all of the small tubular bones tend to be reduced in size and the metacarpals may be shortened, particularly the fifth metacarpal. Radial/ulnar clinodactyly, as well as malformed or absent epiphyses, have also been reported. (1, 2) Complex syndromes have been described in which BDA1 is one of a number of manifestations. (3)

Recently, genetic linkage for a BDA1 locus has been reported to map to 2q35-q36 in two unrelated Chinese families. (4) Subsequent sequence analysis identified mutations in the Indian Hedgehog gene (Ihh) in affected subjects. (5) There have been no other reports of linkage for BDA1, although identification of a balanced translocation between 5q11.2 and 17q23 in a girl with Klippel-Feil anomaly and BDA1 suggests that there may be a BDA1 locus on either chromosome 5 or 17. Mastrobattista et al (6) examined a number of candidate genes, including HoxD, Msx1, Msx2, FGF1, and FGF2, in two families with BDA1, but did not find evidence of linkage. Genes involved in two of the other types of brachydactyly have been described. Mutations in CDMP1, a member of the TGF-[beta] superfamily, have been found in a variant of autosomal dominant brachydactyly type C in which the middle phalanges of the second, third, and fifth fingers are shortened. (7) Mutations in this gene also cause Hunter-Thompson and Grebe acromesomelic dy splasias, two autosomal recessive conditions. (8) In addition, dominant mutations in ROR2, an orphan receptor tyrosine kinase, have been shown to cause brachydactyly type B. (9, 10)

We have recently described a three generation family with mild BDA1, (3) in which 13 affected subjects exhibited shortened middle and distal phalanges, proximal first phalanx, and fifth metacarpal. Consistently, the middle phalanges of affected members were below 2 SD of age matched norms. Most of the proximal first phalanges and fifth metacarpals of affected subjects were similarly 2 SD below the norms. Affected members also tended to be of short stature. The children who were studied had coned and prematurely fused epiphyses. Several members, such as the proband, had clinodactyly of one or more digits. A number of subjects also had a broad distal hallux and/or broad, slightly adducted forefoot. Since our initial report, we have ascertained an additional 15 family members including nine affected subjects. The phenotype of these additional family members is similar to those subjects in the family already described, and no additional clinical findings were associated with BDA1 in this family. We now report li nkage of BDA1 in this kindred to a novel locus on chromosome 5.

METHODS

The linkage study comprised 34 …