High efficiency of mutation detection in type 1 Stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1

Richards, Allan J.; Laidlaw, Maureen; Whittaker, Joanne; Treacy, Becky; Rai, Harjeet; Bearcroft, P.W.P.; Baguley, David; Poulson, Arabella; Ang, Alan; Scott, John D.; Snead, Martin P.

doi:10.1002/humu.20438

Cited by 16 publications

(41 citation statements)

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“…Forty-four of these were novel, which substantially adds to an approximate 300 COL2A1 variants previously reported in the LOVD database (Table 1) and in the literature. 1,2 No variant hotspot was observed in our study, as previously reported. 1 Glycine changes represented 19 of 44 (43%) of the novel variants and were all located in a triple helical region of the collagen 2 (Table 1, Figure 3).…”

Section: Discussionsupporting

confidence: 89%

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Barat‐Houari

Dumont²,

Fabre³

et al. 2015

Eur J Hum Genet

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Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.

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Section: Discussionsupporting

confidence: 89%

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Barat‐Houari

Dumont²,

Fabre³

et al. 2015

Eur J Hum Genet

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“…The COL2A1 gene was analysed for mutations by amplifying large multi exon regions from a single member of each family, and direct sequencing as previously described (Richards et al, 2006). The cDNA NM_001844.3 and protein NP_001835.2 sequences were used for mutation nomenclature.…”

Section: Mutation Detectionmentioning

confidence: 99%

“…Dermal fibroblasts were used to amplify illegitimate transcripts and cells were incubated with or without emetine which inhibits nonsense mediated decay (NMD). Two previously characterised mutations S9X and a splicing mutation in intron 51 c.3886+1G>T, were used as controls, with the S9X mutation also residing within exon 1 (Richards et al, 2006). In genomic DNA, all 3 cell lines were heterozygous for a polymorphism in exon 36.…”

Section: Family Ms101mentioning

confidence: 99%

“…Minigenes consisting of exons 29-34 were transfected into primary skin fibroblasts and a retinal pigment epithelial cell line ARPE-19. Although use of the strong CMV promoter in these minigenes has previously been shown to overwhelm the nonsense mediated decay pathway (Richards et al, 2006) cells were also incubated with emetine to ensure inhibition of NMD. Amplification of minigene specific cDNA from both NMD inhibited and uninhibited cell lines had the same banding profile, with a faint product migrating just below the normal cDNA, consistent with deletion of 35bp, predicted by the creation of an alternative donor splice site within exon 30 by the C>T mutation (Fig.…”

Section: Family Ms203mentioning

confidence: 99%

“…These heterotypic collagen fibrils consist mainly of type II collagen with an inner core of the quantitatively minor type XI collagen. In type II collagen (COL2A1) these mutations almost always result in haploinsufficiency, via nonsense mediated decay (Richards et al, 2006). This is because most dominant negative changes within the type II collagen triple helix usually result in much more severe disorders such as achondrogenesis II, SEDC, SEMD and Kniest dysplasia (MIM#s 600610, 183990, 184250, 156550).…”

Section: Introductionmentioning

confidence: 99%

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Missense and silent mutations in COL2A1 result in Stickler syndrome but via different molecular mechanisms

et al. 2007

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Stickler syndrome due to mutations in COL2A1 is usually the result of premature termination codons and nonsense mediated decay resulting in haploinsufficiency of type II collagen. Here we present two missense mutations and one apparently silent mutation that each result in Stickler syndrome, but via different molecular mechanisms. One alters the translation initiating ATG codon. The second mutation is a unique glycine substitution in the minor collagen helix of the procollagen. To our knowledge a glycine substitution has not previously been reported in this region of fibrillar procollagens. The third mutation appears to be a silent change altering a GGC codon to GGT both for glycine, but use of a splicing reporter assay demonstrates that it results in missplicing and a shift in the reading frame.

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Vitreous phenotype: A key diagnostic sign in Stickler syndrome types 1 and 2 complicated by double heterozygosity

Ang

Ung

Puvanachandra

et al. 2007

American J of Med Genetics Pt A

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We describe the clinical findings in two patients with double heterozygosity, both involving Stickler syndrome. In case 1, the proposita had Albright hereditary osteodystrophy which was inherited from her mother and type 1 Stickler syndrome which was a new mutation. The combination of manifestations from the two syndromes had resulted in initial diagnostic confusion. Diagnosis of the latter syndrome was made only following ophthalmic examination which documented the presence of a membranous vitreous anomaly characteristic of type 1 Stickler syndrome. Subsequent confirmation was achieved by mutation analysis of the COL2A1 gene. The propositus in case 2 inherited Treacher Collins syndrome paternally and type 2 Stickler syndrome maternally. The overlap of facial anomalies may have resulted in a more severe phenotype for the patient. The diagnosis of Stickler syndrome in the propositus was confirmed initially by vitreous assessment and later by demonstration of mutation in the COL11A1 gene. These two patients highlight the key role of vitreous examination and vitreoretinal phenotyping in the differential diagnosis of Stickler syndrome and its subtypes in cases where the clinical picture is complicated by double heterozygosity.

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High efficiency of mutation detection in type 1 Stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1

Cited by 16 publications

References 0 publications

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Missense and silent mutations in COL2A1 result in Stickler syndrome but via different molecular mechanisms

Vitreous phenotype: A key diagnostic sign in Stickler syndrome types 1 and 2 complicated by double heterozygosity

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