SHOX region mutation in Leri-Weill dischondrosteosis (LWS)

Background:LWS, a dominantly inherited skeletal dysplasia with short stature, mesomelia, and Madelung deformity, is the consequenceof haploinsufficiency of the SHOX gene caused by deletions or point mutations. Heterozygous deletions downstream this gene, involvingthe gene enhancers, have been recently demonstrated to cause LWS.Objective and hypotheses:We report the results obtained in 59 patients presenting with LWS clinical findings, analyzed both for SHOXgene and its enhancers.Methods:All samples were examined for copy number alterations within the SHOX gene and the PAR1 region by MLPA and/or bymicrosatellite analysis. All patients negative for deletion were screened for point mutations by direct sequencing of all the coding exons and the intron/exon boundaries of the gene isoform A (exon 2-6a).Results:Point mutations were detected in 5/59 families (8,4%; 2 in exon 3, 2 in exon 4 and 1 in exon 6a). The majority of mutations aremissense mutations (4 missense and 1 frameshift mutations) occurring predominantly in the homeodomain region respect to the OAR domain. In 23/59 (39%) families large deletions were found. Two (5%) involved only the SHOX enhancers region and were detected in 2 girl previously negative for SHOX mutations; one (3,9%) is an intragenic deletion involving only the 3 terminal exons, undiagnosed before use of MLPA; the remaining deletions (51%) involved the entire gene. Mutations were globally found in 47% of the families, below what was expected (reported mutation rate 55-64%). Deletions occur more frequently than point mutations (39 % vs 8,4%).Conclusions:The examination of patients previously resulted negative for SHOX alterations permitted to find the enhancers regiondeletion in 2 unrelated patients. These data underlies the necessity of re-analyze for enhancer deletions all “old” samples with an intactcoding region. Despite the characterization of this new class of mutations involving the enhancers region, the mutation rate in LWDpatients is far from 100%, suggesting the idea that other regulative elements may be involved.