Detailed Clinical Report of Four Individuals from a Nusayri Family with a Rare TNXB Variant: Classical-Like and Hypermobile Types of Ehlers-Danlos Syndrome.

INTRODUCTION

Ehlers-Danlos syndrome (EDS, MIM #606408) is a group of clinically and genetically heterogeneous connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. EDS, Classical-like, 1 (clEDS, MIM #606408) is one of the rarest subtypes caused by biallelic pathogenic variants in TNXB (MIM *600985). TNXB haploinsufficiency has been suggested to be associated with EDS, hypermobility type (hEDS; OMIM %130020), which is considered one of the most common EDS subtypes. However, the underlying molecular mechanisms of hEDS remain largely unknown, and heterozygosity for TNXB variants has been proposed as a potential contributing factor rather than a definitive cause.

METHODS

We report four siblings from a consanguineous Nusayri family with three siblings affected with clEDS and one sibling with hEDS phenotypes. Whole-exome sequencing and RT-PCR analysis from peripheral blood samples were performed in affected siblings and parents.

RESULTS

A homozygous pathogenic TNXB variant (c.3763dup) was identified in three siblings with clEDS. Oldest brother, who met the criteria for hEDS, was heterozygous for this rare variant similar to the parents who were asymptomatic. TNXB expression analysis was significantly lower in homozygous individuals compared to heterozygotes but no significant difference was observed between symptomatic and asymptomatic heterozygotes.

CONCLUSION

This is the first detailed clinical report of a Nusayri family in which a homozygous TNXB variant is associated with clEDS, and in which one heterozygous carrier presents with clinical features consistent with hEDS. Our findings contribute to the limited literature on clEDS, particularly in understudied populations. The clinical findings suggest the potential role of TNXB haploinsufficiency in hEDS; however, further research is needed to elucidate the variable expressivity and possible incomplete penetrance associated with hmEDS.