Mutation Update for COL2A1 Gene Variants Associated with Type II Collagenopathies.

Mutations in the COL2A1 gene cause a spectrum of rare autosomal-dominant conditions characterized by skeletal dysplasia, short stature, and sensorial defects. An early diagnosis is critical to providing relevant patient care and follow-up, and genetic counseling to affected families. There are no recent exhaustive descriptions of the causal mutations in the literature. Here, we provide a review of COL2A1 mutations extracted from the Leiden Open Variation Database (LOVD) that we updated with data from PubMed and our own patients. Over 700 patients were recorded, harboring 415 different mutations. One-third of the mutations are dominant-negative mutations that affect the glycine residue in the G-X-Y repeats of the alpha 1 chain. These mutations disrupt the collagen triple helix and are common in achondrogenesis type II and hypochondrogenesis. The mutations resulting in a premature stop codon are found in less severe phenotypes such as Stickler syndrome. The p.(Arg275Cys) substitution is found in all patients with COL2A1-associated Czech dysplasia. LOVD-COL2A1 provides support and potential collaborative material for scientific and clinical projects aimed at elucidating phenotype-genotype correlation and differential diagnosis in patients with type II collagenopathies.

Short stature, platyspondyly, hip dysplasia, and retinal detachment: an atypical type II collagenopathy caused by a novel mutation in the C-propeptide region of COL2A1: a case report.

BACKGROUND: Heterozygous mutations in COL2A1 create a spectrum of clinical entities called type II collagenopathies that range from in utero lethal to relatively mild conditions which become apparent only during adulthood. We aimed to characterize the clinical, radiological, and molecular features of a family with an atypical type II collagenopathy. CASE PRESENTATION: A family with three affected males in three generations was described. Prominent clinical findings included short stature with platyspondyly, flat midface and Pierre Robin sequence, severe dysplasia of the proximal femora, and severe retinopathy that could lead to blindness. By whole exome sequencing, a novel heterozygous deletion, c.4161_4165del, in COL2A1 was identified. The phenotype is atypical for those described for mutations in the C-propeptide region of COL2A1. CONCLUSIONS: We have described an atypical type II collagenopathy caused by a novel out-of-frame deletion in the C-propeptide region of COL2A1. Of all the reported truncating mutations in the C-propeptide region that result in short-stature type II collagenopathies, this mutation is the farthest from the C-terminal of COL2A1.

Spondyloepiphyseal dysplasia congenita caused by double heterozygous mutations in COL2A1.

Spondyloepiphyseal dysplasia congenita (SEDC) is a group of rare inherited chondrodysplasias characterized by short stature, abnormal epiphyses, and flattened vertebral bodies. SEDC is usually caused by substitution of glycine residue with another amino acid in the triple helical domains of alpha 1 chains, which consist of type II collagen (COL2A1). Herein, we describe a unique case of SEDC with mild coxa vara (SEDC-M) caused by double de novo COL2A1 mutations located on the same allele. One mutation, p.G504S, was previously described in patients with SEDC, whereas the other, p.G612A, was a novel mutation; both were located in the triple helical domain. Neither mutation was identified in the parents and appeared to be de novo. To the best of our knowledge, this is the first study involving a patient with a type II collagenopathy with two COL2A1 mutations on the same allele. The case was characterized by a more severe phenotype compared with previously reported cases involving a single p.G504S mutation, which may have been the result of the double mutation.

Identification and functional characteristics of a novel splicing heterozygote variant of COL2A1 associated with Stickler syndrome type I.

Background: Stickler syndrome type I (STL1) is an autosomal dominant disorder characterized by ocular, auditory, orofacial, and skeletal anomalies. The main causes of STL1 are variants in the COL2A1 gene, which encodes a type II collagen precursor protein. The specific focus of this study was on a newborn from China diagnosed with STL1, with the aim of providing novel insights into the effects of a newly identified intronic variant in the COL2A1 gene on pre-mRNA splicing. Methods: Trio whole exome sequencing was used to identify the causative variant in the family. The identified variant was validated using Sanger sequencing. Bioinformatics programs were used to predict the pathogenicity of the candidate variant. Additionally, an in vitro minigene assay was used to investigate the effects of the identified variant on RNA splicing. Results: The proband with STL1 had a novel heterozygous splicing variant in the intron nine acceptor donor site of COL2A1 (c.655-2A>G). This splice junction variant resulted in aberrant COL2A1 mRNA splicing, leading to the skipping of exon 10 and the production of a shorter protein that may lack the last 18 native amino acids. Conclusion: The c.655-2A>G variant in the COL2A1 gene leads to STL1 through abnormal splicing. By expanding the spectrum of variants in the COL2A1 gene, this finding improves the clinical understanding of STL1 and provides guidance for early diagnosis and disease counseling.

Clinical and functional characterization of COL2A1 p.Gly444Ser variant: From a fetal phenotype to a previously undisclosed postnatal phenotype.

COL2A1 gene encodes the alpha-1 chain of type-II procollagen. Heterozygous pathogenic variants are associated with the broad clinical spectrum of genetic diseases known as type-II collagenopathies. We aimed to characterize the NM_001844.5:c.1330G>A;p.Gly444Ser variant detected in the COL2A1 gene through trio-based prenatal exome sequencing in a fetus presenting a severe skeletal phenotype at 31 Gestational Weeks and in his previously undisclosed mild-affected father. Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. Extracellular matrix showed a disorganized fibronectin network. These results showed that p.Gly444Ser variant alters procollagen molecules processing and the assembly of mature type-II collagen fibrils, according to COL2A1-chain disorganization, displayed by protein modeling. Clinical assessment at 38 y.o., through a reverse-phenotyping approach, revealed limp gait, short and stocky appearance. X-Ray and MRI showed pelvis asymmetry with severe morpho-structural alterations of the femoral heads bilaterally, consistent with a mild form of type-II collagenopathy. This study shows how the fusion of genomics and clinical expertise can drive a diagnosis supported by cellular and bioinformatics studies to effectively establish variants pathogenicity.

A novel homozygous variant of COL2A1 in a Chinese male with type II collagenopathy: a case report.

BACKGROUND: Type II collagenopathies are a spectrum of diseases and skeletal dysplasia is one of the prominent features of collagenopathies. Molecular defects of the COL2A1 gene cause type II collagenopathies that is mainly an autosomal dominant disease, whereas some rare cases with autosomal recessive inheritance of mode have also been identified. CASE PRESENTATION: The patient was a 5-year-old male with a short neck, flat face, epiphyseal dysplasia, irregular vertebral endplates, and osteochondritis. Sequencing result indicated NM_001844.4: c.3662C > T; p. (Ser1221Phe) a novel missense variant, leading to a serine-to-phenylalanine substitution. Sanger sequencing confirmed the variant compared to his parents and brother. CONCLUSIONS: We identified a novel homozygous variant of the COL2A1 gene as the cause of type II collagenopathies in a Chinese male, enriching the spectrum of genotypes. This is the first case of type II collagenopathies inherited in an autosomal recessive manner in China and East Asia, and it is the first case that resulted from serine substitution in the world.

Multiple occurrence of premature polyarticular osteoarthritis in an early medieval Bohemian cemetery (Prague, Czech Republic).

OBJECTIVES: To highlight conditions that may cause early-onset degenerative joint disease, and to assess the possible impact of such diseases upon everyday life. MATERIAL: Four adults aged under 50 years from a medieval skeletal collection of Prague (Czechia). METHODS: Visual, osteometric, X-ray, and histological examinations, stable isotope analysis of bone collagen. RESULTS: All four individuals showed multiple symmetrical degenerative changes, affecting the majority of joints of the postcranial skeleton. Associated dysplastic deformities were observed in all individuals, including bilateral hip dysplasia (n = 1), flattening of the femoral condyles (n = 3), and substantial deformation of the elbows (n = 3). The diet of the affected individuals differed from the contemporary population sample. CONCLUSIONS: We propose the diagnosis of a mild form of skeletal dysplasia in these four individuals, with multiple epiphyseal dysplasia or type-II collagenopathy linked to premature osteoarthritis as the most probable causes. SIGNIFICANCE: Combining the skeletal findings with information from the medical literature, this paper defines several characteristic traits which may assist with the diagnosis of skeletal dysplasia in the archaeological record. LIMITATIONS: As no genetic analysis was performed to confirm the possible kinship of the individuals, it is not possible to definitively assess whether the individuals suffered from the same hereditary condition or from different forms of skeletal dysplasia. SUGGESTIONS FOR FURTHER RESEARCH: Further studies on premature osteoarthritis in archaeological skeletal series are needed to correct the underrepresentation of these mild forms of dysplasia in past populations.

Molecular genetics of the COL2A1-related disorders.

Type II collagen, comprised of three identical alpha-1(II) chains, is the major collagen synthesized by chondrocytes, and is found in articular cartilage, vitreous humour, inner ear and nucleus pulposus. Mutations in the collagen type II alpha-1 gene (COL2A1) have been reported to be responsible for a series of abnormalities, known as type II collagenopathies. To date, 16 definite disorders, inherited in an autosomal dominant or recessive pattern, have been described to be associated with the COL2A1 mutations, and at least 405 mutations ranging from point mutations to complex rearrangements have been reported, though the underlying pathogenesis remains unclear. Significant clinical heterogeneity has been reported in COL2A1-associated type II collagenopathies. In this review, we highlight current knowledge of known mutations in the COL2A1 gene for these disorders, as well as genetic animal models related to the COL2A1 gene, which may help us understand the nature of complex phenotypes and underlying pathogenesis of these conditions.

Skeletal dysplasias.

The skeletal dysplasias are a group of more than 450 heritable disorders of bone. They frequently present in the newborn period with disproportion, radiographic abnormalities, and occasionally other organ system abnormalities. For improved clinical care, it is important to determine a precise diagnosis to aid in management, familial recurrence, and identify those disorders highly associated with mortality. Long-term management of these disorders is predicated on an understanding of the associated skeletal system abnormalities, and these children are best served by a team approach to health care surveillance.

COL2A1 mutation as a cause of premature osteoarthritis in a 13-year-old child.

Diagnostic assessment of osteoarthritis in children and adolescents is difficult. Here, we report the sixth family with a COL2A1 mutation R275C. The index patient, her mother and her three brothers had severe coxarthrosis, in some cases requiring surgery. Only the mother was hard of hearing, and only her children had brachydactyly of the fourth digit. The index patient suffered a femoral neck fracture after minor trauma at a time when osteoarthritis was not yet radiologically detectable. Hip fracture or osteoarthritis of unclear origin in childhood should prompt genetic work-up for the purposes of correct classification and genetic counseling.