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Background The lethal short rib polydactyly syndromes (SRP type IeIV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance. Among them, SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae. NEK1 mutations have been recently identified in SRP type II. Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance. Methods The aim of this study was to screen DYNC2H1 and NEK1 in 13 SRP type II cases and seven SRP type IV cases. It was not possible to screen DYNC2H1 in two patients due to insufficient amount of DNA. Results The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases. Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases. The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group. Conclusion This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity. [ABSTRACT FROM AUTHOR]

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 dysplasias also used to be classified in the SRP group. Recently, mutations in a gene encoding a protein involved in intraflagellar transport, IFT80, have been identified in 3/39 patients with Jeune dysplasia but no extraskeletal manifestation. Methods Because of clinical and radiological similarities between Jeune dysplasia and the other lethal types of SRP, the authors decided to investigate IFT80 in a cohort of fetuses with the lethal forms of SRP (Majewski, Verma-Naumoff and Beemer-Langer) and antenatally diagnosed cases of Jeune dysplasia. Fifteen fetuses were identified. A double-molecular approach was adopted. For consanguineous families and for those with recurrent sibs, a haplotype analysis around the gene locus was first performed, and, for the others, all the coding exons of IFT80 were directly sequenced. Results Using the haplotype approach for two families, the authors excluded the IFT80 region as a candidate for them. Direct sequencing of IFT80 in the other 13 cases showed a G-to-C transversion in exon 8 (G241R) in only one SRP case closely related to the type III phenotype. Conclusions The findings show that mutations in IFT80 can also be responsible for a lethal form of SRP and provide the molecular basis for the Jeune-Verma-Naumoff dysplasia spectrum. [ABSTRACT FROM AUTHOR]