Hereditary connective tissue disorders: novel genotype-phenotype correlations, disease-genes and pathogenetic factors affecting disability

Hereditary soft connective tissue disorders (HCTDs)are a group of clinically variable and genetically heterogeneous conditions caused by constitutional abnormalities of the various components of the extracellular matrix (ECM). Although singularly rare, this community of syndromes are an emerging clinical phenomenon commonly encountered in different specialized settings, including but not limited to rheumatology, physical medicine, cardiology/heart surgery, and clinical genetics. EDS is probably the most common reason of referral in outpatient services dedicated to HCTDs. The 2017 international classification identifies 13 different clinical EDS forms due to mutations in no less than 19 genes. Nevertheless, probably no more than 20% of the patients who have a clinical diagnosis of EDS receive a molecular confirmation by the identification of the responsible mutation. On the other hand, EDS shares many features with the other HCTDs, and such a clinical similarity likely mirrors a common pathogenesis, at least, in specific cases. Therefore, it is expected that novel genes and novel genotype-phenotype correlations for known genes will be identified for EDS. Understanding the biological variability underpinning such a clinical variability is of utmost importance for seeking a tailored approach in the management of these patients. San Camillo-Forlanini Hospital (SCFH) is the Coordinator of the Regional (Lazio, Italy) reference centers for EDS and full member of the European Reference Network (ERN) for rare musculoskeletal diseases (ReCONNET). Since 2010, more than 800 patients who were referred to SCFH, received a diagnosis of EDS and were put under periodic medical follow-up. The aims of this PhD project were: 1) to highlight new genotype-phenotype correlations in HCTDs; 2) to identify novel disease genes for EDS-like phenotypes; 3) to explore disability determinants in a EDS patient cohort. In this context, for the years 2017-2019, the results of the current PhD project included (i) the discovery of the molecular cause of the exceptionally rare X-linked EDS variant, which resulted mutated in FLNA; (ii) the identification of TAB2 and MAP3K7, two genes encoding components of the non-canonic TGFβ-pathway, as responsible of phenotypes resembling EDS; (iii) characterization of musculoskeletal phenotype of hypermobile EDS, the most common EDS variant; (iv) characterization of the skin phenotype of classical EDS, the second most common EDS variant; (v) the exploration of the neurodevelopmental attributes of joint hypermobility in children with different forms of EDS and adults with hEDS in order to open the path for the identification of severity scoring in these disorders; (vi) the delineation of a severity scoring for adults with hypermobile EDS and HSD (hEDS/HSD); (vii) the clinical and molecular characterization of osteogenesis imperfecta/EDS overlap (OI/EDS); and (viii) the exploration of cellular effects of the mutations identified in TAB2 and MAP3K7. The related research activity resulted in 15 publications and SCFH was also represented in the International committee who published the current classification on EDS. The project has been nurtured by a multispecialistic team, aimed at exploring the biological and clinical variability of HCTDs with a true translational intent.