title: Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Frederic R
authors.initials: FR
authors.lastname: Acke
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Vanakker
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Steyaert
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Leeneer
authors.affiliation: Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.affiliation: Department of Otorhinolaryngology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Dhooge
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.affiliation: Department of Otorhinolaryngology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Els M R
authors.initials: EM
authors.lastname: De Leenheer
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Electronic address: Paul.Coucke@ugent.be.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
mesh_terms: D001168:Arthritis; D003095:Collagen Diseases / Q000235:genetics; D024161:Collagen Type XI / Q000235:genetics*; D003240:Connective Tissue Diseases; D004252:DNA Mutational Analysis; D059472:Exome; D056726:Genetic Association Studies; D006319:Hearing Loss, Sensorineural; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D010375:Pedigree; D012163:Retinal Detachment
chemical_list: C574182:COL11A1 protein, human; C499319:COL11A2 protein, human; D024161:Collagen Type XI
keywords: COL11A1; COL11A2; Exome sequencing; Next-generation sequencing; Stickler syndrome; Targeted NGS