Diversity in heritable disorders of connective tissue at a single center

Heritable disorders of connective tissue (HDCT) is a heterogeneous group of conditions caused by defects in genes responsible for extracellular matrix elements. Although next-generation sequencing (NGS) technology can be used to analyze many genes at a time, precisely diagnosing HDCT is still challenging because of the overlapping phenotypes and genotypes.

A 67-gene NGS targeted panel or whole-exome sequencing was employed for the diagnosis of HDCT over 4 years. Phenotypes and genotypes of patients were analyzed retrospectively.

Mutations in 16 genes were discovered in 34 patients with the suspicion of Ehlers-Danlos syndrome (n = 7), Marfan syndrome (n = 2), osteogenesis imperfecta (n = 3), skeletal dysplasia (n = 18), and others (n = 4). Eighteen patients were found to have mutations in collagen genes, three had SERPINF1 mutations, two had TRPV4 mutations, two had FBN1 mutations, two had COMP mutations, and mutations in seven other genes were found in one patient each. The eight patients with COL1A1 mutations had a wide variation in phenotype. Patients with COL3A1 and COL5A1 mutations presented with classic EDS, those with SERPINF1 mutations presented with typical OI type VI, those with TRPV4 mutations presented with severe spinal deformity, and those with COL2A1 mutations presented with syndromic or nonsyndromic bone dysplasia or only short stature.

A wide diversity in HDCT was observed. Therefore, knowledge about the phenotype-genotype correlation in HDCT is still crucial in the diagnosis of this group of diseases, and an improvement in the screening tool will be needed.