Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes

Abstract

The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

“…Our results partly support the still controversial impression that bone quality might be impaired in cEDS [74][75][76][77][78], although undoubtfully less significant compared to other EDS subtypes (e.g. spondylodysplastic, arthrochalasia, kyphoscoliotic, and classical-like type 2 EDS) [9,43,44,48,49,52,59,65,68] or skeletal dysplasia [39], and suggests a potential involvement of skeletal fragility in determining a poorer quality of life (QoL) in adult patients. Our findings emphasize a milder phenotype and disease course in cEDS compared to hEDS [50,69] and other EDS subtypes (e.g.…”

“…This case highpoints that while molecular diagnosis in patients with a full-blown phenotype is mainly confirmatory, in those with an incomplete presentation it turns out to be fundamental, since these individuals might not be diagnosed or even be misdiagnosed. Indeed, considering the clinical overlap not only between the different EDS subtypes but also with other HCTDs [1,9,28,30,32,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], differential diagnosis is not always forthright. Differential diagnosis includes the molecularly unsolved hEDS that shares with cEDS gJHM and more than a few (muco) cutaneous signs; however, hEDS patients usually show a lower degree of scarring and skin hyperextensibility and much more striking gJHM complications [1,7,28,29,50].…”

Expanding the PURA syndrome phenotype: A child with the recurrent PURA p.(Phe233del) pathogenic variant showing similarities with cutis laxa

“…Summary results of WES are reported in Table S1. After application of a standardized in-house pipeline (Ritelli et al, 2019), and considering only variants previously associated with a disease phenotype, five candidate genes were identified (Table S2). Among these, WES did not disclose any pathogenic variant in all CL-related genes, which resulted fully covered as they were also analyzed separately to confirm the absence of any variant of unknown significance, but revealed the known NM_005859.4 (PURA):c.697_699del variant (rs786204835), which causes the deletion of a highly conserved amino acid residue [NP_005850.1(PURA):p. (Phe233del)] within the PUR-III domain of the protein ( Figure 1B).…”

Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

“…Biallelic B3GAT3 mutations are known to cause a skeletal dysplasia phenotype, JDSCD, characterised by shortened and bowed long bones, spine curvatures, and foot deformities. Other common features include facial dysmorphism, joint dislocation, congenital cardiac defects, joint contractures and bone fragility 16 18 19 22 26–31. Lethality before the age of 1 year has also been reported 29 30.…”