Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients.
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.
Hoornaert
Kristien P
KP
Center for Medical Genetics, Ghent University Hospital, Gent, Belgium. [corrected]
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
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
C499177:COL2A1 protein, human; D024043:Collagen Type II