Identification of a new intron heterozygote variant in COL2A1 gene and its functional characteristics in relation to Stickler syndrome type I.. Identification and functional characteristics of a novel intron heterozygote variant of COL2A1 associated with Stickler syndrome type I

Background Stickler Syndrome type I (STL1) is an autosomal dominant disorder affecting vision, hearing, orofacial and skeletal anomalies. The main causes are variants in the COL2A1 gene that encodes the II type collagen precursor protein. In this study, we presented a newborn with STL1 from China and aimed to obtain new insights into the consequences of a novel COL2A1 intronic variant on pre-mRNA splicing. Methods Trio whole exome sequencing was used to identify causative variant in the family. The identified variant was validated by Sanger sequencing. Bioinformatics programs were conducted to predict the pathogenicity of candidate variant. In vitro minigene assay was applied to investigate its effect on RNA splicing. Results A heterozygote novel splicing variant in the intron 9 acceptor donor site of COL2A1 (c.655-2A>G) was identified in the proband with STL1. The splice junction variant leaded to aberrant COL2A1 mRNA splicing resulting in skipping of exon 10 (c.655_708del) to produce truncated protein which may lack the last 18 native amino acids (p.Gln221_Pro238del). Conclusion Our findings reveal that the c.655-2A>G variant in COL2A1 gene causes STL1 by aberrant 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 counseling of the disease.