Clinical Presentation and WES Analysis of a Large Iranian Pedigree in Five Successive Generation Affected to Sever...

Bone Morphogenetic Proteins and the related Growth and Differentiation Factors (GDFs) are much conserved signaling proteins. GDF5 is pivotal for skeletal development. Several skeletal dysplasia and malformation syndromes are known as a result of mutations in GDF5. Multiple Synostosis Syndrome2 (SYNS2) is characterized by tarsal-carpal coalition, humeroradial synostosis, brachydactyly, and proximal symphalangism. In this study, we analyzed a large Iranian pedigree affected with a new type of SYNS2 (Farhud Type) in five successive generations.

In this family-based study (1982-2022), Genetic linkage analysis of the pedigree (58affected, 62healthy) excluded the locus on chromosome 17q21-q22 in our previous study. Thus, we focused on 20q11.22 locus and GDF5 gene. Genetic investigations were performed on 16 patients with SYNS2 and 40 healthy individuals.

Whole-exome-sequencing results identified a heterozygote missense mutation in exon2 of GDF5 (NG_008076.1:g.9239G>A, NM_000557.2:c.1424G>A, S475N, rs121909347). This mutation was found in all patients but not in the unaffected individuals. This missense mutation is notable because S475 is strictly conserved among different species, and it is located in a highly conserved and active mature domain of GDF5 (phyloP100way=7.64). The corresponding defect in GDF5 may have unknown interaction with normal active 3^rd and 4^th structure of the product. Further bioinformatics study (amino acid multiple alignments) showed that the S475 is a much-conserved residue in many different species.

These results introduce a new role of GDF5 in pathogenesis of a SYNS2 (Farhud Type), considered in genetic counseling, prenatal diagnosis, and as a potential target for molecular therapy, if possible.