Identification of a Missense Mutation in LRP4 Gene in a Palestinian Family with Cenani-Lenz Syndactyly

Abstract

Cenani-Lenz syndactyly is an autosomal-recessive congenital anomaly affecting mainly distal limb development. It is characterized by fusion and disorganization of metacarpal and phalangeal bones, radioulnar synostosis, and severe syndactyly of hands and feet. Here, we report the first case of Cenani-Lenz syndactyly among the Palestinian population. In our study, next-generation sequencing was performed on samples obtained from a large consanguineous family. Causative variant in NGS data was selected through standard bioinformatics tools. Candidate variant was Sanger sequenced in all available family members. Sequence analysis identified the homozygous missense mutation c.3049T>C (p.Cys1017Arg) in exon 22 of the LRP4 gene among four affected individuals, and perfectly segregated with the phenotype in the rest of the family. The gene LRP4 belongs to the low-density lipoprotein (LDL) receptor-related protein (LRP) family, which members are essential for various developmental processes. LRP4 gene is important for the control and modification of Wnt signaling, a pathway that has an important role in limb development. The identified variant is located in the extracellular EGF-like domain of LRP4 and is highly conserved across various species. We propose that this missense mutation will abolish the inhibitory effect of LRP4 and thus will lead to over activation of the Wntsignaling cascade. This variant is predicted to be “pathogenic” by SIFT, Polyphen-2 and Mutation taster software, but functional analyses are still required to further support the causality. Our study will contribute to the understanding of the pathogenesis underlying Cenani-Lenz syndactyly, improving clinical and molecular diagnosis; thus, making genetic counseling and preimplantation genetic diagnosis (PGD) easier in future.