Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B

Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder chara cterized by hypoplasia/aplasia of distal phalanges and nails. Recently, het erozygous mutations of the orphan receptor tyrosine kinase (TK) ROR2, locat ed within a distinct segment directly after the TK domain, have been shown to be responsible for BDB. We report four novel mutations in ROR2 (two fram eshifts, one splice mutation, and one nonsense mutation) in five families w ith BDB. The mutations predict truncation of the protein within two distinc t regions immediately before and after the TK domain, resulting in a comple te or partial loss of the intracellular portion of the protein. Patients af fected with the distal mutations have a more severe phenotype than do those with the proximal mutation. Our analysis includes the first description of homozygous BDB in an individual with a 5-bp deletion proximal to the TK do main. His phenotype resembles an extreme form of brachydactyly, with extens ive hypoplasia of the phalanges and metacarpals/metatarsals and absence of nails. In addition, he has vertebral anomalies, brachymelia of the arms, an d a ventricular septal defect-features that are reminiscent of Robinow synd rome, which has also been shown to be caused by mutations in ROR2. The BDB phenotype, as well as the location and the nature of the BDB mutations, sug gests a specific mutational effect that cannot be explained by simple haplo insufficiency and that is distinct from that in Robinow syndrome.