The vast majority of reported (likely) pathogenic missense variants in the genes coding for the fibrillar collagens leads to the substitution of one of the obligatory glycine residues in the Gly-Xaa-Yaa repeat sequence of the triple helical domain. Their phenotypic consequences and deleterious effects have been well-documented. However, with increasing access to molecular diagnostic testing based on next-generation sequencing techniques, such as sequencing of multi-gene panels and wholeexome sequencing, non-glycine substitutions are more frequently identified in individuals suspected to have a heritable collagen disorder, but their pathogenic effect is often difficult to predict. Some specific non-glycine substitutions in the proa1(I)- (p.(Arg312Cys)) and proa1(III)- (glutamic acid to lysine at different positions) collagen chain have been identified in a number of individuals presenting a phenotype showing features of both classical and vascular Ehlers-Danlos syndrome. The number of reported individuals with these defects is currently very low, and several of these non-glycine substitutions had initially been categorised as variants of unknown significance (VUS), complicating early diagnosis, accurate counselling, management guidelines, and correct classification. This collaborative study reports on the phenotype of 22 and 7 individuals harbouring these rare variants in COL1A1 and COL3A1, respectively, expanding our knowledge on clinical presentation, phenotypic variability, and natural history, and informing on the risk for potentially life-threatening events, such as vascular, gastro-intestinal, and pregnancy-related complications.

Atypical variants in {COL}1A1 and {COL}3A1 associated with classical and vascular Ehlers-Danlos syndrome overlap phenotypes: expanding the clinical phenotype based on additional case reports / Colman, Marlies; Castori, Marco; Micale, Lucia; Ritelli, Marco; Colombi, Marina; Ghali, Neeti; Van Dijk, Fleur; Marsili, Luisa; Weeks, Adrienne; Vandersteen, Anthony; Rideout, Andrea; Legrand, Anne; Frank, Michael; Mirault, Tristan; Ferraris, Alessandro; DI GIOSAFFATTE, Niccolo'; Grammatico, Paola; Grunert, Juergen; Frank, Charissa; Symoens, Sofie; Syx, Delfien; Malfait, Fransiska. - In: CLINICAL AND EXPERIMENTAL RHEUMATOLOGY. - ISSN 1593-098X. - 40:5(2022), pp. S46-S62. [10.55563/clinexprheumatol/kzkq6y]

Atypical variants in {COL}1A1 and {COL}3A1 associated with classical and vascular Ehlers-Danlos syndrome overlap phenotypes: expanding the clinical phenotype based on additional case reports

Niccolo' Di Giosaffatte;Paola Grammatico;
2022

Abstract

The vast majority of reported (likely) pathogenic missense variants in the genes coding for the fibrillar collagens leads to the substitution of one of the obligatory glycine residues in the Gly-Xaa-Yaa repeat sequence of the triple helical domain. Their phenotypic consequences and deleterious effects have been well-documented. However, with increasing access to molecular diagnostic testing based on next-generation sequencing techniques, such as sequencing of multi-gene panels and wholeexome sequencing, non-glycine substitutions are more frequently identified in individuals suspected to have a heritable collagen disorder, but their pathogenic effect is often difficult to predict. Some specific non-glycine substitutions in the proa1(I)- (p.(Arg312Cys)) and proa1(III)- (glutamic acid to lysine at different positions) collagen chain have been identified in a number of individuals presenting a phenotype showing features of both classical and vascular Ehlers-Danlos syndrome. The number of reported individuals with these defects is currently very low, and several of these non-glycine substitutions had initially been categorised as variants of unknown significance (VUS), complicating early diagnosis, accurate counselling, management guidelines, and correct classification. This collaborative study reports on the phenotype of 22 and 7 individuals harbouring these rare variants in COL1A1 and COL3A1, respectively, expanding our knowledge on clinical presentation, phenotypic variability, and natural history, and informing on the risk for potentially life-threatening events, such as vascular, gastro-intestinal, and pregnancy-related complications.
2022
Ehlers-Danlos syndrome; vascular rupture; collagen; joint hypermobility; skin hyperextensibility; connective tissue
01 Pubblicazione su rivista::01a Articolo in rivista
Atypical variants in {COL}1A1 and {COL}3A1 associated with classical and vascular Ehlers-Danlos syndrome overlap phenotypes: expanding the clinical phenotype based on additional case reports / Colman, Marlies; Castori, Marco; Micale, Lucia; Ritelli, Marco; Colombi, Marina; Ghali, Neeti; Van Dijk, Fleur; Marsili, Luisa; Weeks, Adrienne; Vandersteen, Anthony; Rideout, Andrea; Legrand, Anne; Frank, Michael; Mirault, Tristan; Ferraris, Alessandro; DI GIOSAFFATTE, Niccolo'; Grammatico, Paola; Grunert, Juergen; Frank, Charissa; Symoens, Sofie; Syx, Delfien; Malfait, Fransiska. - In: CLINICAL AND EXPERIMENTAL RHEUMATOLOGY. - ISSN 1593-098X. - 40:5(2022), pp. S46-S62. [10.55563/clinexprheumatol/kzkq6y]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1671766
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