Frederic R Acke1, Fransiska Malfait2, Olivier M Vanakker2, Wouter Steyaert2, Kim De Leeneer2, Geert Mortier3, Ingeborg Dhooge4, Anne De Paepe2, Els M R De Leenheer4, Paul J Coucke5. 1. Department of Otorhinolaryngology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium; Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. 2. Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. 3. Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. 4. Department of Otorhinolaryngology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. 5. Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Electronic address: Paul.Coucke@ugent.be.
Abstract
INTRODUCTION: Stickler syndrome is caused by mutations in genes encoding type II and type XI collagens. About 85% of the pathogenic variants is found in COL2A1 (Stickler type 1), whereas a minority of mutations has been reported in COL11A1 (Stickler type 2) and COL11A2 (Stickler type 3). Beside the typical skeletal and orofacial manifestations, ocular anomalies are predominantly present in type 1 and type 2, while hearing loss is more pronounced in type 2 and type 3. METHODS: We performed COL11A1 mutation analysis for 40 type 2 Stickler patients and COL11A2 mutation analysis for five type 3 Stickler patients, previously all COL2A1 mutation-negative, using targeted next-generation sequencing (NGS) whereas whole-exome sequencing (WES) was performed in parallel for two patients. Three patients were analyzed for both genes due to unclear ocular findings. RESULTS: In total 14 COL11A1 and two COL11A2 mutations could be identified, seven of which are novel. Splice site alterations are the most frequent mutation type, followed by glycine substitutions. In addition, six variants of unknown significance (VUS) have been found. Identical mutations and variants were identified with both NGS techniques. CONCLUSION: We expand the mutation spectrum of COL11A1 and COL11A2 in Stickler syndrome patients and show that targeted NGS is an efficient and cost-effective molecular tool in the genetic diagnosis of Stickler syndrome, whereas the more standardized WES might be an alternative approach.
INTRODUCTION:Stickler syndrome is caused by mutations in genes encoding type II and type XI collagens. About 85% of the pathogenic variants is found in COL2A1 (Stickler type 1), whereas a minority of mutations has been reported in COL11A1 (Stickler type 2) and COL11A2 (Stickler type 3). Beside the typical skeletal and orofacial manifestations, ocular anomalies are predominantly present in type 1 and type 2, while hearing loss is more pronounced in type 2 and type 3. METHODS: We performed COL11A1 mutation analysis for 40 type 2 Stickler patients and COL11A2 mutation analysis for five type 3 Stickler patients, previously all COL2A1 mutation-negative, using targeted next-generation sequencing (NGS) whereas whole-exome sequencing (WES) was performed in parallel for two patients. Three patients were analyzed for both genes due to unclear ocular findings. RESULTS: In total 14 COL11A1 and two COL11A2 mutations could be identified, seven of which are novel. Splice site alterations are the most frequent mutation type, followed by glycine substitutions. In addition, six variants of unknown significance (VUS) have been found. Identical mutations and variants were identified with both NGS techniques. CONCLUSION: We expand the mutation spectrum of COL11A1 and COL11A2 in Stickler syndromepatients and show that targeted NGS is an efficient and cost-effective molecular tool in the genetic diagnosis of Stickler syndrome, whereas the more standardized WES might be an alternative approach.
Authors: Marina V Shulskaya; Anelya Kh Alieva; Ivan N Vlasov; Vladimir V Zyrin; Ekaterina Yu Fedotova; Natalia Yu Abramycheva; Tatiana S Usenko; Andrei F Yakimovsky; Anton K Emelyanov; Sofya N Pchelina; Sergei N Illarioshkin; Petr A Slominsky; Maria I Shadrina Journal: Front Aging Neurosci Date: 2018-05-15 Impact factor: 5.750