TY - JOUR
T1 - Stickler syndrome caused by COL2A1 mutations
T2 - Genotype-phenotype correlation in a series of 100 patients
AU - Hoornaert, Kristien P.
AU - Vereecke, Inge
AU - Dewinter, Chantal
AU - Rosenberg, Thomas
AU - Beemer, Frits A.
AU - Leroy, Jules G.
AU - Bendix, Laila
AU - Björck, Erik
AU - Bonduelle, Maryse
AU - Boute, Odile
AU - Cormier-Daire, Valerie
AU - De Die-Smulders, Christine
AU - Dieux-Coeslier, Anne
AU - Dollfus, Hélène
AU - Elting, Mariet
AU - Green, Andrew
AU - Guerci, Veronica I.
AU - Hennekam, Raoul C.M.
AU - Hilhorts-Hofstee, Yvonne
AU - Holder, Muriel
AU - Hoyng, Carel
AU - Jones, Kristi J.
AU - Josifova, Dragana
AU - Kaitila, Ilkka
AU - Kjaergaard, Suzanne
AU - Kroes, Yolande H.
AU - Lagerstedt, Kristina
AU - Lees, Melissa
AU - Lemerrer, Martine
AU - Magnani, Cinzia
AU - Marcelis, Carlo
AU - Martorell, Loreto
AU - Mathieu, Michèle
AU - McEntagart, Meriel
AU - Mendicino, Angela
AU - Morton, Jenny
AU - Orazio, Gabrielli
AU - Paquis, Véronique
AU - Reish, Orit
AU - Simola, Kalle O.J.
AU - Smithson, Sarah F.
AU - Temple, Karen I.
AU - Van Aken, Elisabeth
AU - Van Bever, Yolande
AU - Van Den Ende, Jenneke
AU - Van Hagen, Johanna M.
AU - Zelante, Leopoldo
AU - Zordania, Riina
AU - De Paepe, Anne
AU - Leroy, Bart P.
AU - De Buyzere, Marc
AU - Coucke, Paul J.
AU - Mortier, Geert R.
N1 - Funding Information:
We are grateful to the patients and their families for their cooperation. We thank the following clinicians for the referral of samples: M Ausems, M Baumgartner, K Becker, S Bertok, F Betis, AM Bisgaard, K Bouman, H Brunner, O Calabrese, K Chandler, S De Almeida, T De Ravel, K Devriendt, M Drolenga, I Feenstra, JP Fryns, H Fryssira, F Goodman, BCJ Hamel, JM Hertz, T Homfray, J Hurst, S Janssens, D Johnson, J Kamphoven, WS Kerstjens-Frederikse, K Keymolen, I Liebaers, M Maas, F Malfait, H Malmgren, S Mancini, S Mansour, I Mathijssen, T McDevitt, EJ Meijers, F Meire, A Mendicino, N Mignone, A Muellner-Eidenbock, R Newbury-Ecob, A Nordgren, C Postma, EM Ruiter, P Schmidt, C Schrander-Stumpel, F Stanzial, A Superti-Furga, K Ten Berg, P Terhal, S Tinschert, A Tzschach, D van den Boogaard, I Van Der Burgt, P Van Kerrebroeck, L Van Maldergem, N Van Regemorter, J Vigneron, AMC Vos, M Wright and A Zankl. This study was made possible by Grant no. G.0331.03 from the Research Foundation-Flanders (FWO) and GOA grant no. 12051203 from the Ghent University. Geert R Mortier is senior clinical investigator at the Research Foundation – Flanders (FWO). The corresponding author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive license (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in the Journal of Medical Genetics and any other BMJPGL products to exploit all subsidiary rights, as set out in our license.
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
KW - COL2A1
KW - genotype-phenotype correlation
KW - splice site mutation
KW - Stickler syndrome
KW - type II collagenopathies
UR - http://www.scopus.com/inward/record.url?scp=77954959024&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2010.23
DO - 10.1038/ejhg.2010.23
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C2 - 20179744
AN - SCOPUS:77954959024
VL - 18
SP - 872
EP - 881
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 8
ER -