The Stickler syndrome: Genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1

Liberfarb, Ruth M.; Levy, Howard P.; Rose, Peter S.; Wilkin, Douglas J.; Davis, Joie; Balog, Joan Z.; Griffith, Andrew J.; Szymko-Bennett, Yvonne M.; Johnston, Jennifer J.; Francomano, Clair A.

doi:10.1097/00125817-200301000-00004

Cited by 82 publications

(59 citation statements)

References 42 publications

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“…Extensive inter-and intrafamilial variability has also been reported for Stickler syndrome [20]. Variable penetrance and expressivity can be easily accounted for if we consider that a null mutation or deletion of one Dominance and gene dosage balance in health and disease 177 of the alleles at the relevant locus drives the concentration of monomers near the inflexion point of the sigmoid (see Figure 1b).…”

Section: Haploinsufficiency and Macromolecular Complexesmentioning

confidence: 91%

Dominance and gene dosage balance in health and disease: why levels matter!

Veitia

Birchler

2009

The Journal of Pathology

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The classical concept of genetic dominance is a simplification of a more quantitative reality. This is clearly exemplified by aneuploid syndromes, of which the best known case is trisomy 21. Moreover, there is an increasing number of clinical conditions due to reduced dosage (haploinsufficiency) of genes encoding transcription factors and other proteins involved in signal transduction and macromolecular complexes. In such genetic diseases, a high degree of phenotypic variability is observed, which calls for an explanation. The sources of dominance are heterogeneous and difficult to cover in a brief review. Here, we will focus on the molecular bases of dosage-sensitive syndromes from the perspective of the gene dosage balance hypothesis, which postulates that stoichiometric alterations of macromolecular complexes or cellular networks are responsible for dominant phenotypes, because of the existing non-linear relationships between the genotypic and phenotypic values with which they are associated.

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Section: Haploinsufficiency and Macromolecular Complexesmentioning

confidence: 91%

Dominance and gene dosage balance in health and disease: why levels matter!

Veitia

Birchler

2009

The Journal of Pathology

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“…Subsequently over 100 reports including more than a dozen review articles on this syndrome have expanded the details of the phenotype affecting the ocular, craniofacial, auditory, and musculoskeletal systems and the heart, and highlighted the intra-and inter-familial variability [Liberfarb et al, 1981[Liberfarb et al, , 2003Lucarini et al, 1987;Spallone, 1987;Seery et al, 1990;Snead et al, 1994Snead et al, , 1996Wilkin et al, 1998;Martin et al, 1999;Snead and Yates, 1999;Richards et al, 2000a,b;Stickler et al, 2001;Szymko-Bennett et al, 2001;Rose et al, 2001a,b;Donoso et al, 2003;Poulson et al, 2004].…”

Section: Introductionmentioning

confidence: 99%

“…Patients may develop myopia at a young age with vitreous abnormalities and predisposition to retinal lattice formation, holes, tears, and/or detachments and premature cataracts [Niffenegger et al, 1993]. Approximately one quarter have cleft palate, and another third have more subtle palatal abnormalities including submucous clefts or bifid uvulas [Stickler et al, 2001;Liberfarb et al, 2003]. Facial abnormalities include malar hypoplasia, flattening, or widening of the nasal bridge, and micro/retrognathia (Fig.…”

Section: Introductionmentioning

confidence: 99%

Stickler syndrome: Clinical characteristics and diagnostic criteria

Rose

Levy

Liberfarb

et al. 2005

American J of Med Genetics Pt A

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116

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The purpose of this study was to establish diagnostic criteria for Stickler syndrome. Ninety patients from 38 families had complete evaluations for possible Stickler syndrome. Molecular confirmation of COL2A1 mutation status (type I Stickler syndrome) was available on 25 patients from six families. In the remaining 65 patients, 47 from 25 families were affected with Stickler syndrome and 18 from seven families were unaffected with Stickler syndrome. A diagnostic nosology based on type I Stickler patients with known COL2A1 mutations was applied to clinically affected and unaffected patients. A diagnostic scale of 9 points evaluated molecular data or family history data and characteristic ocular, orofacial, auditory, and musculoskeletal findings. A score of > or =5 was diagnostic of Stickler syndrome. These criteria demonstrate 100% sensitivity when applied to type I Stickler syndrome patients with known COL2A1 mutations, 98% sensitivity when applied to clinically affected Stickler patients, and 86% specificity when applied to patients unaffected based on clinical and/or molecular analysis. We conclude that diagnostic criteria based on type I Stickler patients with molecularly confirmed COL2A1 mutations appear to be sensitive and specific for the diagnosis of this syndrome and should be helpful to clinicians when making the diagnosis.

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“…Thus, the phenotypic differences between the proband and his father suggest an intrafamilial variance in clinical expression, suggesting the involvement of modifiers. 23 These two deletions, which were both identified in Stickler cases, were also predicted to be subjected to NMD like the smaller rearrangement described above and would result in a haploinsufficiency. 19 The third large deletion was an in-frame deletion p.(Pro916_Gly1074del), c.2745_3221del, that was expected to result in a shortened peptide lacking 159 amino acids that would exert a dominant negative effect on the 'healthy' component of the trimeric collagen.…”

Section: Discussionmentioning

confidence: 93%

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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The Stickler syndrome: Genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1

Abstract: Purpose: To evaluate a cohort of clinically diagnosed Stickler patients in which the causative COL2A1 mutation has been identified, determine the prevalence of clinical features in this group as a whole and as a function

Cited by 82 publications

References 42 publications

Dominance and gene dosage balance in health and disease: why levels matter!

Dominance and gene dosage balance in health and disease: why levels matter!

Stickler syndrome: Clinical characteristics and diagnostic criteria

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

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