A novel aberrant splice site mutation in COL27A1 is responsible for Steel syndrome and extension of the phenotype to include hearing loss

Am J Med Genet A. 2017 May;173(5):1257-1263. doi: 10.1002/ajmg.a.38153. Epub 2017 Mar 21.


Steel syndrome is an autosomal recessive disease characterized by skeletal abnormalities and dysmorphic features. The first mutation associated with this syndrome was reported in Puerto Rican children. In this study, we identified a novel homozygous splice site variant in COL27A1 (c.3556-2A>G) in a consanguineous Emirati family with a child affected by Steel syndrome. In addition, the affected child had severe non-progressive sensorineural hearing loss not reported previously. The variant segregated in the family in an autosomal recessive manner and we show that the variant alters mRNA splicing. Furthermore, relative quantitative analysis revealed a marked reduction in gene expression in the proposita compared to healthy controls. Segregation analysis of heterozygous variants, related to hearing loss, identified by whole exome sequencing in the child (ILDR1: c.1159T>C, SYNE4: c.313G>C, and GPR98: c.18746T>G) excluded them from being responsible for the hearing loss in the proposita. In addition, the products of these genes are not interacting in the same pathway and have only been reported to cause deafness in an autosomal recessive manner. Therefore, we conclude that the novel splice-site variant identified in COL27A1 is the most likely cause for Steel syndrome in this family and that the hearing loss is part of this syndrome's phenotype.

Keywords: COL27A1; Steel syndrome; deafness; exon skipping; multiple joint dislocations; whole-exome sequencing.

Publication types

  • Case Reports

MeSH terms

  • Asian Continental Ancestry Group
  • Base Sequence
  • Child, Preschool
  • Exome / genetics
  • Female
  • Fibrillar Collagens / genetics*
  • Hearing Loss, Sensorineural / genetics*
  • Hearing Loss, Sensorineural / physiopathology
  • Heterozygote
  • Humans
  • Male
  • Mutation
  • Pedigree
  • Protein Isoforms / genetics*
  • RNA Splicing / genetics


  • COL27A1 protein, human
  • Fibrillar Collagens
  • Protein Isoforms