Clinical Presentation and WES Analysis of a Large Iranian  Pedigree in Five Successive Generation Affected to Sever Multiple Synostosis 2 (SYNS2, Farhud Type)

Dariush D.  Farhud; Marjan  Zarif-Yeganeh; Hajar  Arian; Majid  Kashi; Tayebeh  Rezaee

doi:10.18502/ijph.v53i6.15912

Dariush D. Farhud School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
Marjan Zarif-Yeganeh Research Institute of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
Hajar Arian Research Institute of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
Majid Kashi Tabnak Radiology Center, Tehran, Iran
Tayebeh Rezaee Surgical Research Center, Department of Surgery, University of Connecticut Health Center, Farmington, CT, USA

DOI: https://doi.org/10.18502/ijph.v53i6.15912

Keywords: Multiple synostoses syndrome2; Iranian pedigree; Genetics

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.