Colman, Marlies

Guillemyn, Brecht

Laccone, Franco

Malfait, Fransiska

Nampoothiri, Sheela

Steichen - Gersdorf, Elisabeth

Symoens, Sofie

Syx, Delfien

Van Damme, Tim

English

Ghent University Academic Bibliography

Expanding the genotypic and phenotypic spectrum of the B3GAT3 linkeropathy1. Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.2. Department of Pediatrics, Medical University of Innsbruck, Austria 3. Institute of Medical Genetics, Vienna, Austria4. Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Kerala, IndiaMarlies.Colman@uGent.beOverview of the clinical features present in the different linkeropathiesXYLT1n=15XYLT2n=17B4GALT7*n=8B3GALT6n=27B3GAT3n=26Short stature 100% 53% 100% 100% 83%Skeletal dysplasia* 100% 94% 100% 100% 100% Joint hypermobility 40% NR 100% 88% 53%Bone fragility 7% 94% 62% 48% 67%Joint contractures NR NR 37% 59% 69%Facial dysmorphology* 100% 65% 87% 100% 100%Hyperextensible/lax skin NR NR 87% 68% 12%Cardiovascular involvement 7% 35% NR 16% 60% Intellectual disability 100% 35% 75% 20% 14% Ocular involvement NR 88% 62% NR 15% Hearing loss 7% 53% 25% NR 8% Table summarizing some of the clinical features in all reported patients of each linkeropathy.*With exclusion of the Larsen of Reunion Island syndrome cohort from Crathault et al.NR= Not ReportedColman Marlies1; Van Damme Tim1; Steichen-Gersdorf Elisabeth2; Laccone Franco3.; Nampoothiri Sheela4.; Syx Delfien1; Guillemyn Brecht1; Symoens Sofie1; Malfait Fransiska1Patient 1 with bulging of the thoracic cage, blue sclerae, cornealclouding, cutis laxa, long fingers, campylodactyly, spatulate distalphalanges and club feet. Radiography shows osteopenia, fracturesand joint contractures. He died at age of 2,5 months due to unknownreasons. The previously reported homozygous c.667G>A,p.(Gly223Ser) missense mutation was identified.Patient 2 with a short stature, genu valgum, a flat face andprominent eyes, long fingers, spatulate distal phalanges and pesplanus. Radiography shows radial head dislocation and a shortfemoral neck. An unreported homozygous c.416C>T, p.(Thr139Met)missense mutation was found.Defects in the enzymes responsible for the formation ofthe tetrasaccharide linker region between the proteoglycan coreprotein and the glycosaminoglycan side chains, lead to a spectrumof severe and overlapping autosomal recessive connective tissuedisorders, collectively coined ‘glycosaminoglycan linkeropathies’.We report the clinical findings of two novel patients with biallelicmutations in B3GAT3, encoding glucuronosyltransferase I (GlcAT-I),which catalyzes the addition of the ultimate saccharide to thelinker region.Loss-of-function mutations in B3GAT3 are associated with a complex connective tissue phenotype characterized by disproportionate short stature,skeletal dysplasia, facial dysmorphism, spatulate distal phalanges and - to a lesser extent - joint contractures, joint hypermobility with dislocations,cardiac defects and bone fragility. The more severe phenotypes seem to have mutations located in the substrate acceptor subdomain of the catalyticdomain while more mildly affected phenotypes seem to have mutations in the donor substrate binding subdomain.Patient 1 Patient 2Schematic representation of all reported mutations in the B3GAT3 geneand a representation of all missense mutations on an in silico model ofGlcAT-I in which the substrate donor is colored in dark grey and thesubstrate acceptor subdomain is colored light grey.1. c.245C>T; p.(Pro82Leu)2. c.416C>T; p.(Thr139Met)3. c.419C>T; p.(Pro140Leu)4. c.667G>A; p.(Gly223Ser)5. c.671T>A; p.(Leu224Gln)6. c.830G>A; p.(Arg277Gln)7. c.888+262T>G

Expanding the genotypic and phenotypic spectrum of the B3GAT3 linkeropathy

https://biblio.ugent.be/publication/8609155/file/8609157.pdf

Expanding the genotypic and phenotypic spectrum of the B3GAT3 linkeropathy

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Ghent University Academic Bibliography