Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I

The significant variability in the clinical manifestations of COL2A1-associated skeletal dysplasias makes it necessary to conduct a clinical and genetic analysis of individual nosological variants, which will contribute to improving our understanding of the pathogenetic mechanisms and prognosis. We presented the clinical and genetic characteristics of 60 Russian pediatric patients with type II collagenopathies caused by previously described and newly identified variants in the COL2A1 gene. Diagnosis confirmation was carried out by new generation sequencing of the target panel with subsequent validation of the identified variants using automated Sanger sequencing. It has been shown that clinical forms of spondyloepiphyseal dysplasias predominate in childhood, both with more severe clinical manifestations (58%) and with unusual phenotypes of mild forms with normal growth (25%). However, Stickler syndrome, type I was less common (17%). In the COL2A1 gene, 28 novel variants were identified, and a total of 63% of the variants were found in the triple helix region resulted in glycine substitution in Gly-XY repeats, which were identified in patients with clinical manifestations of congenital spondyloepiphyseal dysplasia with varying severity, and were not found in Stickler syndrome, type I and Kniest dysplasia. In the C-propeptide region, five novel variants leading to the development of unusual phenotypes of spondyloepiphyseal dysplasia have been identified.

Pleiotropy of a Stickler syndrome genotype

Purpose: To report a case of pleiotropy in the COL2A1 gene typically associated with Stickler Syndrome Type 1. Observations: A patient with a confirmed mutation of the COL2A1 gene presented with an isolated retinitis pigmentosa phenotype. Conclusions: The mutated COL2A1 gene in Stickler Syndrome Type 1 represents a site of pleiotropy, highlighting a change in phenotype across the same genotype potentially due to tissue alternative splicing.

A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1

Spondylometaphyseal dysplasia Algerian type (MIM no.: 184253) is an uncommon autosomal dominant skeletal dysplasia caused by heterozygous mutations in the COL2A1 gene (MIM no.: 120140). In this case based review, we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum. Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures. The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the COL2A1 gene and a variant of unknown significance in c.1366–13C > A in intron 21. This latter sequence variant could partially or completely disrupt the natural splice acceptor site of intron 21/exon 22 in the COL2A1 gene leading to a potential modification of the phenotypic severity.

Stickler syndrome in the Czech Republic: phenotypic variability and genetic heterogeneity

Stickler syndrome (STL) is a progressive multisystemic disorder of connective tissue with an incidence of 1:7,500 newborns, which is probably underestimated due to its considerable clinical and genetic heterogeneity. STL symptoms include cleft palate or the Pierre-Robin sequence, hearing and/ or vision impairment, namely early high myopia and spontaneous retinal detachment, skeletal dysplasia, and a characteristic facial appearance, including a flat profile, protruding eyes, and micrognathia. STL symptoms show high inter- and even intrafamilial phenotypical variability. Variants in seven different collagen genes can cause STL. Autosomal dominant (AD) type 1 caused by a defect in the COL2A1 gene is the most common form of STL (80–90%); AD type 2 (involving COL11A1 gene defects) is much less common (10–20%). The third AD type and all autosomal recessive types are extremely rare. A genetically confirmed dia­gnosis of STL facilitates early treatment, prevention, and an accurate genetic risk estimation of STL in the family.

Polymorphisms in COL2A1 gene in Adolescents with Temporomandibular Disorders

Objectives: Temporomandibular disorder (TMD) is considered a functional disorder with multifactorial aspects. The goal of this study was to investigate if genetic polymorphisms in the COL2A1 gene could be associated with TMD in adolescents. Study design: The case group (TMD-affected) included individuals diagnosed with any of the following TMD subgroups according to the RDC/TMD criteria: myofascial pain, disc displacements and arthralgia. Genomic DNA for molecular analysis was extracted from buccal cells and genetic polymorphisms in COL2A1 were genotyped by real time polymerase chain reactions using the TaqMan assay. Data were analyzed using the Epi Info 3.5.7 and Stata software. Results: 249 subjects were included in this study (148 subjects “affected” by TMD). There were no significant differences between the affected and unaffected individual (p>0.05), for TMD, arthralgia and myofascial pain however, rs2276454 was borderline in the genotype distribution (p=0.07) and was associated with disc displacement (p=0.03) in the allelic distribution. Recessive model showed significant differences between groups for with disc displacement (p=0.02). Conclusions: Genetic polymorphisms in COL2A1 are not associated with myofascial pain, arthralgia or TMD in adolescents but this study provides evidence that rs2276454 is involved in the disc displacement of the temporomandibular joint.