Dataset Information

Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients.

ABSTRACT: Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.

SUBMITTER: Hoornaert KP

PROVIDER: S-EPMC2987380 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients.

Hoornaert Kristien P KP Vereecke Inge I Dewinter Chantal C Rosenberg Thomas T Beemer Frits A FA Leroy Jules G JG Bendix Laila L Björck Erik E Bonduelle Maryse M Boute Odile O Cormier-Daire Valerie V De Die-Smulders Christine C Dieux-Coeslier Anne A Dollfus Hélène H Elting Mariet M Green Andrew A Guerci Veronica I VI Hennekam Raoul C M RC Hilhorts-Hofstee Yvonne Y Holder Muriel M Hoyng Carel C Jones Kristi J KJ Josifova Dragana D Kaitila Ilkka I Kjaergaard Suzanne S Kroes Yolande H YH Lagerstedt Kristina K Lees Melissa M Lemerrer Martine M Magnani Cinzia C Marcelis Carlo C Martorell Loreto L Mathieu Michèle M McEntagart Meriel M Mendicino Angela A Morton Jenny J Orazio Gabrielli G Paquis Véronique V Reish Orit O Simola Kalle O J KO Smithson Sarah F SF Temple Karen I KI Van Aken Elisabeth E Van Bever Yolande Y van den Ende Jenneke J Van Hagen Johanna M JM Zelante Leopoldo L Zordania Riina R De Paepe Anne A Leroy Bart P BP De Buyzere Marc M Coucke Paul J PJ Mortier Geert R GR

European journal of human genetics : EJHG 20100224 8

Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect o ...[more]

PMID: 20179744

Similar Datasets

Project description:AimsTo compare the clinical and molecular genetic features of two phenotypically distinct subgroups of families with type 1 Stickler syndrome.BackgroundStickler syndrome (hereditary arthro-ophthalmopathy, McKusick Nos 108300 and 184840) is a dominantly inherited disorder of collagen connective tissue, resulting in an abnormal vitreous, myopia, and a variable degree of orofacial abnormality, deafness, and arthropathy. Stickler syndrome is the commonest inherited cause of rhegmatogenous retinal detachment in childhood with a risk of giant retinal tear (GRT) which is commonly bilateral and a frequent cause of blindness.MethodPedigrees were identified from the vitreoretinal service database and subclassified according to vitreoretinal phenotype. Ophthalmic, skeletal, auditory, and orofacial features were assessed. Linkage analysis was carried out with markers for the candidate genes COL2A1, COL11A1, and COL11A2. The COL2A1 gene was amplified as five overlapping PCR products. Direct sequencing of individual exons identified mutations.ResultsEight families exhibiting the type 1 vitreous phenotype were studied. Seven were consistent for linkage to COL2A1, with lod scores ranging from 2.1 to 0.3. In most instances linkage to COL11A1 and COL11A2 could be excluded. One family was analysed without prior linkage analysis. Three of the families exhibited a predominantly ocular phenotype with minimal or absent systemic involvement and were found to have mutations in exon 2 of COL2A1. Five other pedigrees with an identical ocular phenotype plus orofacial, auditory, and articular involvement had mutations in others regions of the COL2A1 gene. None of the pedigrees exhibited the characteristic lenticular, retinal pigment epithelial, or choroidal changes seen in Wagner syndrome.ConclusionsThese data confirm that type 1 Stickler syndrome is caused by mutations in the gene encoding type II collagen (COL2A1). In addition, data are submitted showing that mutations involving exon 2 of COL2A1 are characterised by a predominantly ocular variant of this disorder, consistent with the major form of type II procollagen in non-ocular tissues having exon 2 spliced out. Such patients are all at high risk of retinal detachment. This has important implications for counselling patients with regard to the development of systemic complications. It also emphasises the importance and reliability of the ophthalmic examination in the differential diagnosis of this predominantly ocular form of Stickler syndrome from Wagner's vitreoretinopathy.

Dataset Information

Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients.

Publications

Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets