Insights into TNXB-Related Classical-Like Ehlers-Danlos Syndrome: A Study of Polish Patients

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders with diverse clinical and genetic backgrounds. Classical-like EDS (clEDS, OMIM 606408) is an extremely rare autosomal recessive subtype caused by biallelic variants in TNXB. Fewer than 100 cases have been described worldwide. This study aimed to identify and characterise TNXB-related variants in two Polish patients with clinical features suggestive of clEDS.

Two male patients, aged 13 and 14 years, underwent comprehensive genetic testing, including next-generation sequencing (NGS) using a connective tissue gene panel, Multiplex Ligation-dependent Probe Amplification (MLPA), and Sanger sequencing. Family segregation analysis was performed to confirm compound heterozygosity.

NGS and confirmatory analyses identified compound heterozygous TNXB variants: c.[7222C>T];[8780T>C], p.[Pro2408Ser];[Ile2927Thr] in Patient 1, and c.[5947_5948delinsTT];[8300C>T], p.[Glu1983Leu];[Thr2767Ile] in Patient 2. Both variants were located in non-homologous TNXB exons, minimising the risk of misinterpretation due to pseudogene sequences. The clinical presentations of both patients were consistent with the major diagnostic criteria for classical-like EDS.

This report presents the first genetically confirmed Polish patients with a classical-like form of Ehlers-Danlos syndrome, expanding the known clinical and molecular spectrum of TNXB-related EDS. Our findings reinforce the notion that heterozygous TNXB variants, particularly frameshift alterations, may occasionally contribute to mild connective tissue manifestations in carriers, underscoring the complexity of genotype-phenotype correlations in this rare disorder.