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. Ehlers-Danlos syndrome, Classical-like, 1 (clEDS, MIM #606408) is one of the rarest subtypes caused by biallelic pathogenic variants in TNXB gene (MIM *600985). TNXB haploinsufficiency has been associated with Ehlers-Danlos Syndrome, Hypermobility Type; (hmEDS, MIM %130020) which is assumed to be most common EDS subtype in several reports but there is still insufficient evidence to clarify the underlying molecular mechanism. 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 (WES) 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 with clEDS and hEDS phenotypes due to a TNXB variant. 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.