Exon-Trapping Assay Improves Clinical Interpretation of COL11A1 and COL11A2 Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia

Genes (Basel). 2020 Dec 17;11(12):1513. doi: 10.3390/genes11121513.


Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in COL11A1 and COL11A2, respectively. In both genes, available database information indicates a high rate of potentially deleterious intronic variants, but published evidence of their biological effect is usually insufficient for a definite clinical interpretation. We report four previously unpublished intronic variants in COL11A1 (c.2241 + 5G>T, c.2809 - 2A>G, c.3168 + 5G>C) and COL11A2 (c.4392 + 1G>A) identified in type 2 SS/OSMED individuals. The pathogenic effect of these variants was first predicted in silico and then investigated by an exon-trapping assay. We demonstrated that all variants can induce exon in-frame deletions, which lead to the synthesis of shorter collagen XI α1 or 2 chains. Lacking residues are located in the α-triple helical region, which has a crucial role in regulating collagen fibrillogenesis. In conclusion, this study suggests that these alternative COL11A1 and COL11A2 transcripts might result in aberrant triple helix collagen. Our approach may help to improve the diagnostic molecular pathway of COL11-related disorders.

Keywords: COL11A1; COL11A2; stickler syndrome.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Collagen Type XI / chemistry
  • Collagen Type XI / deficiency*
  • Collagen Type XI / genetics
  • Connective Tissue Diseases / diagnosis
  • Connective Tissue Diseases / genetics*
  • Developmental Disabilities / genetics
  • Diagnosis, Differential
  • Dwarfism / diagnosis
  • Dwarfism / genetics*
  • Ehlers-Danlos Syndrome / diagnosis
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Infant, Newborn
  • Introns / genetics*
  • Male
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / genetics*
  • Point Mutation*
  • Protein Isoforms / genetics
  • Protein Structure, Secondary
  • RNA Splicing
  • RNA, Messenger / genetics
  • Vitreous Detachment / diagnosis
  • Vitreous Detachment / genetics*


  • COL11A1 protein, human
  • COL11A2 protein, human
  • Collagen Type XI
  • Protein Isoforms
  • RNA, Messenger

Supplementary concepts

  • Megaepiphyseal dwarfism
  • Stickler syndrome, type 2