Spondyloepiphyseal dysplasia congenita caused by double heterozygous mutations in COL2A1

Abstract

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.

Integrated analysis of COL2A1 variant data and classification of type II collagenopathies

“…In the data obtained from 663 probands with COL2A1 mutations, 535 and 114 cases of mutations were located in the CDS and intron regions of the COL2A1 , respectively. It is noteworthy that one patient with SEDC carried two mutations (p.Gly504Ser and p.Gly612Ala) on the same allele . This case was characterized by a more severe phenotype compared with previously reported cases involving a single p.Gly504Ser mutation …”

“…It is noteworthy that one patient with SEDC carried two mutations (p.Gly504Ser and p.Gly612Ala) on the same allele. 27 This case was characterized by a more severe phenotype compared with previously reported cases involving a single p.Gly504Ser mutation. 28 Interestingly, according to the analysis of the variant position and severity of the phenotype (Figure 2) (the classification criteria of severity were selected from Deng et al 52 ), we found two most likely genotypephenotype correlations.…”

Collagen Mutant Mouse Models Provide an Important Tool to Study Osteoarthritis

“…We have previously reported OA-like changes in a mouse model that bears a mutation in the Col2a1 gene, similar to that found in humans, that behaves as a recessive mutation resulting in no obvious phenotype in the heterozygote [9]. The mouse mutation was named spondyloepiphesial dysplasia congenita (sedc) [10] because when homozygous it produces features that resemble the most common clinical phenotypes of SED congenita in humans [11]. Thus in both mouse and human it is known that collagen gene mutations that lead to a wide variety of disorders of the skeletal system can also lead to premature osteoarthritis.…”

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

“…In this case, both mutations were located in the coding sequence for the triple helix domain and a severe phenotype was also reported. 16 An additional mutation was described in another Japanese patient with SMD-A phenotype who presented with short stature, severe leg deformity, severe genu valgum, myopia, and hearing impairment. This patient had a heterozygous missense mutation located in the triple helical domain (p.G861V) in COL2A1.…”