Clinical and Molecular Characterization and Discovery of Novel Genetic Mutations of Chinese Patients with COL2A1-related Dysplasia

Abstract

COL2A1-related disorders represent a heterogeneous group of skeletal dysplasias with a wide phenotypic spectrum. Our aim is to characterize the clinical and molecular phenotypes of Chinese patients with COL2A1-related dysplasia and to explore their phenotype-genotype relations. Clinical data were collected, physical examinations were conducted, and X-ray radiography and genetic analyses were performed in ten families involving 29 patients with COL2A1-related dysplasia. Nine mutations were identified in COL2A1, including five novel (c.816+6C>T, p.Gly246Arg, p.Gly678Glu, p.Gly1014Val and p.Ter1488Gln) and four reported previously (p.Gly204Val, p.Arg275Cys, p.Gly504Ser and p.Arg719Cys). Based on clinical features and molecular mutations, the ten families were classified into five definite COL2A1-related disorders: four families with spondyloepiphyseal dysplasia congenita (SEDC), three with osteoarthritis with mild chondrodysplasia (OSCPD), one with Czech dysplasia, one with Kniest dysplasia, and one with epiphyseal dysplasia, multiple, with myopia and deafness (EDMMD). Based on genetic testing results, prenatal diagnosis and genetic counseling were accomplished for one female proband with OSCDP. Chinese patients with OSCDP, Czech dysplasia and EDMMD caused by COL2A1 mutations were first reported, expanding the spectrum of COL2A1 mutations and the phenotype of COL2A1-related disorders and providing further evidence for the phenotype-genotype relations, which may help improve procreative management of COL2A1-related disorders.

Discovery of sensorineural hearing loss and ossicle deformity in a Chinese Li nationality family with spondyloepiphyseal dysplasia congenita caused by p.G504S mutation of COL2A1

“…S2 and Additional File 1 : Table S2). The variation had been reported to be the pathogenic variation of SEDC, regarded as a hot spot variation [ 4 – 9 ]. The genotype frequency in the 1000 Genomes Project, ESP and ExAC was less than 0.001.…”

“…On the other hand, several manifestations, including disproportionate short stature and neck, spine malformation including scoliosis and kyphosis, acetabulum abnormal, and femoral head disease, were common symptoms among different families. The proband from Family 1 [ 9 ] had a pain, limitation in hip mobility and abnormal gait from 5 years old and the symptoms increased with age. Short heights, lower extremities and spines abnormal were his main clinical manifestations.…”

Exploring and expanding the phenotype and genotype diversity in seven Chinese families with spondylo-epi-metaphyseal dysplasia

“…Patients with C-propeptide glycine substitutions have been reported to be shorter than those with N-propeptide substitutions ( Terhal et al, 2012 ). Our center has reported that glycine to serine substitution caused milder phenotypes than glycine to nonserine substitutions ( Xu et al, 2020 ). In Kniest dysplasia, the classical phenotypes are short-trunk dwarfism due to severely affected skeletal growth, scoliosis, platyspondyly, and joint enlargement, while extraskeletal features mainly include myopia, prominent eyes, conductive hearing loss, and mid-face hypoplasia ( Barat-Houari et al, 2016a ).…”

Genetic testing and diagnostic strategies of fetal skeletal dysplasia: a preliminary study in Wu Han, China ​

“…The pathogenicity is closely associated with mutations of the genes encoding collagen (e. g. type I, II, IX, IX, XI collagen) [3] . Current scienti c study reported many pathogenic gene variations in the proband with skeletal dysplasia and variants occurred in causative genes of COL1A1, COL1A2, WNT1, OBSL1, FGFR3, IMPAD1, FBN2, and GORAB [4][5][6] . According to 2019 edition of the Nosology, 461 disorders classi ed within 42 different groups have been described based on radiologic, molecular and biochemical criteria [7] .…”