Background Mutations in TRPV4, a gene that encodes a Ca2+ permeablenon-selective cation channel, have recently been found in a spectrum ofskeletal dysplasias that includes brachyolmia, spondylometaphysealdysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only atotal of seven missense mutations were detected, however. The fullspectrum of TRPV4 mutations and their phenotypes remained unclear.Objectives and methods To examine TRPV4 mutation spectrum andphenotype-genotype association, we searched for TRPV4 mutations byPCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands.Results TRPV4 mutations were found in all but one MD subject. In total,19 different heterozygous mutations were identified in 41 subjects; twowere recurrent and 17 were novel. In MD, a recurrent P799L mutation wasidentified in nine subjects, as well as 10 novel mutations includingF471del, the first deletion mutation of TRPV4. In SMDK, a recurrentR594H mutation was identified in 12 subjects and seven novel mutations.An association between the position of mutations and the diseasephenotype was also observed. Thus, P799 in exon 15 is a hot codon forMD mutations, as four different amino acid substitutions have beenobserved at this codon; while R594 in exon 11 is a hotspot for SMDKmutations.Conclusion The TRPV4 mutation spectrum in MD and SMDK, which showedgenotype-phenotype correlation and potential functional significance ofmutations that are non-randomly distributed over the gene, waspresented in this study. The results would help diagnostic laboratoriesestablish efficient screening strategies for genetic diagnosis of theTRPV4 dysplasia family diseases.