title: 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.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Gent, Belgium. [corrected]
authors.forename: Kristien P
authors.initials: KP
authors.lastname: Hoornaert
authors.forename: Inge
authors.initials: I
authors.lastname: Vereecke
authors.forename: Chantal
authors.initials: C
authors.lastname: Dewinter
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
authors.forename: Frits A
authors.initials: FA
authors.lastname: Beemer
authors.forename: Jules G
authors.initials: JG
authors.lastname: Leroy
authors.forename: Laila
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authors.lastname: Bendix
authors.forename: Erik
authors.initials: E
authors.lastname: Björck
authors.forename: Maryse
authors.initials: M
authors.lastname: Bonduelle
authors.forename: Odile
authors.initials: O
authors.lastname: Boute
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Christine
authors.initials: C
authors.lastname: De Die-Smulders
authors.forename: Anne
authors.initials: A
authors.lastname: Dieux-Coeslier
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Mariet
authors.initials: M
authors.lastname: Elting
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Guerci
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hilhorts-Hofstee
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder
authors.forename: Carel
authors.initials: C
authors.lastname: Hoyng
authors.forename: Kristi J
authors.initials: KJ
authors.lastname: Jones
authors.forename: Dragana
authors.initials: D
authors.lastname: Josifova
authors.forename: Ilkka
authors.initials: I
authors.lastname: Kaitila
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kjaergaard
authors.forename: Yolande H
authors.initials: YH
authors.lastname: Kroes
authors.forename: Kristina
authors.initials: K
authors.lastname: Lagerstedt
authors.forename: Melissa
authors.initials: M
authors.lastname: Lees
authors.forename: Martine
authors.initials: M
authors.lastname: Lemerrer
authors.forename: Cinzia
authors.initials: C
authors.lastname: Magnani
authors.forename: Carlo
authors.initials: C
authors.lastname: Marcelis
authors.forename: Loreto
authors.initials: L
authors.lastname: Martorell
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu
authors.forename: Meriel
authors.initials: M
authors.lastname: McEntagart
authors.forename: Angela
authors.initials: A
authors.lastname: Mendicino
authors.forename: Jenny
authors.initials: J
authors.lastname: Morton
authors.forename: Gabrielli
authors.initials: G
authors.lastname: Orazio
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis
authors.forename: Orit
authors.initials: O
authors.lastname: Reish
authors.forename: Kalle O J
authors.initials: KO
authors.lastname: Simola
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Smithson
authors.forename: Karen I
authors.initials: KI
authors.lastname: Temple
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Van Aken
authors.forename: Yolande
authors.initials: Y
authors.lastname: Van Bever
authors.forename: Jenneke
authors.initials: J
authors.lastname: van den Ende
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Van Hagen
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Zelante
authors.forename: Riina
authors.initials: R
authors.lastname: Zordania
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.forename: Marc
authors.initials: M
authors.lastname: De Buyzere
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D001168:Arthritis / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics* / Q000378:metabolism; D003240:Connective Tissue Diseases / Q000235:genetics* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics; D004252:DNA Mutational Analysis; D056726:Genetic Association Studies; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D012163:Retinal Detachment / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
chemical_list: C499177:COL2A1 protein, human; D024043:Collagen Type II