Genetic Analysis of Multiple Osteochondromatosis in a Cohort of Argentinean Patients

ASTEGGIANO CG. ; CAINO S; CUBILLA M.; ROMINA A; PAPAZOGLU M.; OBREGÓN MG.; LAPUNZINA P.; FANO V.; HEATH E. K

Cuidad de Mexico

Congreso; 5th Latin American Congress of Glycobiology and 2nd. Meeting of the Glycoscience in Thematic Network; 2019

Sociedad Latinoamericana de Glicobiologia

Introduction: Mutations in two tumors suppressor genes, EXT1 and EXT2, have been identified in multiple osteochondromatosis disease (MO), an autosomal dominant O-glycosylation disorder (EXT1/EXT2-CDG). The EXT1 (8q24.11,MIM 133700) and EXT2 (11p12,MIM #133701) genes, encode glycosyltransferases involved in heparan sulfate elongation in chondrocytes. The risk of malignant chondrosarcoma is 2%-5%. Aim: To enhance the power in genetic testing and to improve to our knowledge of the molecular bases of OM in Argentina. Methods: A longitudinal study including 35 unrelated MO patients (20% (n: 7) families) with history of OM). Clinical phenotyping from all 55 patients (35 index and 20 family affected members) were obtained. EXT1 and EXT2 were analyzed using a skeletal dysplasia panel (SkeletelSeqV5, n=368 genes, SeqCap EZ (Roche Nimblegen) and run on a NextSeq (Illumina) and MLPA. Bioinformatic analysis was performed. Results: The index patients had an average age: 13.56 (2.21-55.3 years-old); male 63.6% and 36.4% female. Main clinical features were: chronic pain and fatigue 74.5% (41/55); spinal tumors 10.9% (6/55); 18.1% short stature (10/55); limb length discrepancy 27.9% (12/43) and intellectual disability 10.9% (6/55). Clinical severity was classified as class I 34%, as class II 23% and as class III 43%. The life quality (PEDsQL 4.0) evaluated in children 7-18years-old, was 72.6% (DE 14.21) and adults (SF36) 32.86% (DE 9.77). A total of 20 different pathogenic variants in 35 probands, 13 (65%) in EXT1 and 7 (35%) in EXT2 were identified 13 (47%) frameshifts, 9 (31%) nonsense, 2 (6%) splicing and 5 (17%) missense. No EXT1 or EXT2 mutation in 5 (12%) patients whilst one patient presented FLNB variant (Larsen syndrome, MIM150250). Three patients with pathogenic variants showed mental disability (low CI), normal EEG, brain TAC and karyotype. Discussion: mutations were identified in 29/35 (83%) patients with OM. Interestingly, in our cohort (80%) were sporadic, in comparison to data where 90% have an affected parent. Phenotype cannot be predicted based on mutation type or gene. Recent studies (Inubushi et al, 2019) showed data supporting Palovarotene (a retinoic acid receptor) is a potential therapeutic agent for MO. In this sense, the genetic advances in this field will be necessary to include patients into future biologically based therapeutics. CONICET, FONCyT, UCC.