The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Abstract

Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.

Figure 1

Workflow showing the different steps and subjects enrolled in our study.

Figure 2

(a) Variant distribution according to the patients' phenotype. Achondrogenesis, type II or hypochondrogenesis (MIM#200610), Czech dysplasia (MIM#609162), Kniest dysplasia (MIM#156550), SEMD Strudwick type (MIM#184250), SpondyloEpiphyseal Dysplasia Congenita (MIM#183900), Stickler type 1 (MIM#108300; 609508). (b) Variant distribution among patients according to the type and effect of the variant. (c) Distribution of the variant type and effect according to the patients' phenotype.

Figure 3

Distribution of the 44 novel COL2A1 variants identified in 136 French patients with skeletal dysplasia. I, intron; E, exon; bp, base pair; aa, amino acid; bracket, large deletion; circle, premature stop codon; triangle, small rearrangement; square, glycine missense; diamond, nonglycine missense and asterisk, RNA processing.

Figure 4

Pedigree of two representative Stickler multiplex families. (a) Segregation of the p.(Gly366Alafs*263) (c.1095delT) frameshift deletion. (b) Segregation of the intronic c.2355+4A>C variant. Open and dark symbols denote asymptomatic and affected subjects, respectively. The year of birth and the variant status are shown below the symbols.