Clinical and Molecular Spectrum of Nonsyndromic Early‐Onset Osteoarthritis

Ruault, Valentin; Yauy, Kévin; Fabre, Aurélie; Fradin, Mélanie; Van-Gils, Julien; Angelini, C.; Baujat, Geneviève; Blanchet, P.; Cuinat, Silvestre; Isidor, Bertrand; Jørgensen, Christian; Lacombe, Didier; Moutton, Sébastien; Odent, Sylvie; Sanchez, Elodie; Sigaudy, Sabine; Touitou, Isabelle; Willems, Marjolaine; Apparailly, Florence; Geneviève, David; Barat‐Houari, Mouna

doi:10.1002/art.41387

Cited by 10 publications

(6 citation statements)

References 19 publications

(25 reference statements)

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“…However, other features present in our patients such as tall stature, dural ectasia, high arched palate, dolichocephaly, malar hypoplasia, foot deformity, dolichostenomelia, and pectus deformity are not in line with this differential diagnosis (Table 2 ). Notably, COL2A1 variants have been recently identified as the main monogenic cause of nonsyndromic early-onset OA 37 . Nonetheless, it remains to be determined if the joint manifestations in subjects 1A and 1B are solely attributed to the COL2A1 p.(Lys1312Asn) variant.…”

Section: Discussionmentioning

confidence: 99%

Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype

Demal¹,

Scholz

Schuler³

et al. 2022

Sci Rep

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MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. We report four patients from three families presenting with a MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants. However, it revealed likely pathogenic missense variants in three individuals [c.3936G > T p.(Lys1312Asn), c.193G > A p.(Asp65Asn)] and a missense variant of unknown significance in the fourth patient [c.4013G > A p.(Ser1338Asn)] in propeptide coding regions of COL2A1. Pathogenic COL2A1 variants are associated with type II collagenopathies comprising a remarkable clinical variablility. Main features include skeletal dysplasia, ocular anomalies, and auditory defects. A MASS-like phenotype has not been associated with COL2A1 variants before. Thus, the identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. We compare the phenotypes of our patients with related disorders of connective tissue and discuss possible pathomechanisms and genotype–phenotype correlations for the identified COL2A1 variants. Our data recommend COL2A1 sequencing in FBN1-negative patients suggestive for MASS/Marfan-like phenotype (without aortopathy).

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Section: Discussionmentioning

confidence: 99%

Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype

Demal¹,

Scholz

Schuler³

et al. 2022

Sci Rep

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“…Although prior studies have associated tobacco use with less hand OA (31), to our knowledge this is the CMCJ OA is highly heritable (14)(15)(16)), yet few coding variants have been definitively linked to CMCJ OA (17,18,(20)(21)(22)34). Using the UPDB enabled us to discover a rare coding variant in a high-risk pedigree, a potentially powerful way to define pathways with a determinant effect on disease development (23,24,35,36). To our knowledge, our study is the first to identify a large number of multigenerational severe CMCJ OA pedigrees, determine relative risk among relatives and identify a coding variant associated with CMCJ OA.…”

Section: Discussionmentioning

confidence: 99%

Familial Clustering and Genetic Analysis of Severe Thumb Carpometacarpal Joint Osteoarthritis in a Large Statewide Cohort

Gavile

Kazmers

Novak

et al. 2022

Preprint

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Objectives: The objectives of this study are to 1) identify individuals that required surgery for thumb carpometacarpal osteoarthritis (CMCJ OA), 2) determine if CMCJ OA clusters in multigenerational families, 3) define the magnitude of familial risk of CMCJ OA, 4) identify risk factors associated with CMCJ OA and 5) identify rare genetic variants that segregate with familial CMCJ OA. Methods: We searched the Utah Population Database to identify a cohort of CMCJ OA patients that required a surgical procedure (CMC fusion or arthroplasty). Affected individuals were mapped to pedigrees to identify high-risk multigenerational families with excess clustering of CMCJ OA. Cox regression models were used to calculate familial risk of CMCJ OA in related individuals. Risk factors were evaluated using logistic regression models. Whole exome sequencing was used to identify a rare coding variant associated with familial CMCJ OA. Results: We identified 550 pedigrees with excess clustering of severe CMCJ OA. The relative risk of developing CMCJ OA requiring surgical treatment was significantly elevated in first- and third-degree relatives of affected individuals, and significant associations with advanced age, female sex, obesity, and tobacco use were observed. A dominantly segregating, rare variant in CHSY3 was associated with familial CMCJ OA. Conclusions: Familial clustering of severe CMCJ OA was observed in a statewide population. Identification of a candidate gene indicates a genetic contribution to the etiology of the disease. Our data indicate the genetic and environmental factors contribute to the disease process, further highlighting the multifactorial nature of the disease.

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“…The appropriate age of early-onset osteoarthritis based on literatures is considered to be under 50 years. 9 , 10 The Australian patients presented with similar symptoms including generalized stiffness, pain and restricted motion affecting multiple joints. 8 Two patients received hip replacements at age 23 and 33 years respectively and one patient underwent an ankle arthroscopy at age 16 years.…”

Section: Discussionmentioning

confidence: 99%

COL2A1 Mutation (c.611G>C) Leads to Early-Onset Osteoarthritis in a Chinese Family

Li¹,

Wang²,

Li³

et al. 2021

IJGM

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Mutations in the gene coding collagen type II α1 chain ( COL2A1 ) are associated with a series of human disorders mainly involving the skeletal system. Here, we describe the second family with COL2A1 mutation, c.611G>C, Gly204Ala, leading to a replacement of glycine in the core triple helical (Gly-X-Y) domain of COL2A1 gene. The replacements of glycine in every third position of the triple with other amino acids will cause failure in the structure of type II collagen. The affected family members manifested early-onset osteoarthritis involving multiple joints. We propose that the COL2A1 gene should be taken into consideration for genetic counseling for patients with hereditary premature osteoarthritis and individuals carrying this mutation should receive early interventions for osteoarthritis.

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Clinical and Molecular Spectrum of Nonsyndromic Early‐Onset Osteoarthritis

Cited by 10 publications

References 19 publications

Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype

Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype

Familial Clustering and Genetic Analysis of Severe Thumb Carpometacarpal Joint Osteoarthritis in a Large Statewide Cohort

COL2A1 Mutation (c.611G>C) Leads to Early-Onset Osteoarthritis in a Chinese Family

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