Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA)
1 MRC-Holland, Amsterdam, The Netherlands
2 East Anglian Regional Genetics Laboratory, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
3 Genetic Medicine, St Mary’s Hospital, Manchester, UK
4 Clinical Genetics, University Hospitals Bristol, NHS Trust, Bristol, UK
5 Department of Medical Genetics, Hospital de Dona Estefânia, Lisbon, Portugal
6 Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK
7 Vitreoretinal Service, Department of Ophthalmology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
8 Department of Pathology, University of Cambridge, Cambridge, UK
BMC Medical Genetics 2013, 14:48 doi:10.1186/1471-2350-14-48Published: 26 April 2013
COL11A1 is a large complex gene around 250 kb in length and consisting of 68 exons. Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis. Many of the mutations resulting in either Stickler or Marshall syndrome alter splice sites and result in exon skipping, which because of the exon structure of collagen genes usually leaves the message in-frame. The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products. To date only one large deletion of 40 kb in the COL11A1, which was detected by RT-PCR, has been characterized. However, commonly used screening protocols, utilizing genomic amplification and exon sequencing, are unlikely to detect such large deletions. Consequently the frequency of this type of mutation is unknown.
We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler syndrome, and have detected six novel deletions that were not found by exon sequencing alone.
Exon deletions appear to represent a significant proportion of type 2 Stickler syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing.