Background: The lethal group of short-rib polydactyly (SRP) includes type I (Saldino-Noonan; MIM 263530), type II (Majewski; MIM 263520), type III (Verma-Naumoff; MIM 263510), and type IV (Beemer-Langer; MIM 269860). Jeune and Ellis-van Creveld (EVC) dysplasias also used to be classified in the group of SRP. Recently, mutations in a gene encoding a protein involved in intraflagellar transport (IFT), IFT80, have been identified in 3/39 patients with Jeune dysplasia, but no extraskeletal manifestation.
Methods: Due to clinical and radiological similarities between Jeune dysplasia and the other lethal types of SRP we decided to investigate IFT80 in a cohort of foetuses with the lethal forms of SRP (Majewski, Verma-Naumoff, and Beemer-Langer) and cases antenatally diagnosed of Jeune dysplasia. Fifteen foetuses were ascertained to this study. We adopted a double molecular approach. For consanguineous families and for those with recurrent sibs we first performed a haplotype analysis around the gene locus and for the others we directly sequenced all the coding exons of IFT80.
Results: Using the haplotype approach for two families, we excluded the IFT80 region as a candidate for them. By direct sequencing of IFT80 in the other 13 cases we found a G-to-C transversion within exon 8 (G241R) in only one SRP case closely related to the type III phenotype.
Conclusions: Our findings demonstrate that mutations in IFT80 can also be responsible for a lethal form of SRP and provides the molecular basis for the Jeune-Verma-Naumoff dysplasia spectrum.
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