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

Nesrin Gariballa, Afif Ben-Mahmoud, Makanko Komara, Aisha M. Al-Shamsi, Anne John, Bassam R. Ali, Lihadh Al-Gazali

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1257-1263
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Volume173
Issue number5
DOIs
Publication statusPublished - May 2017

Keywords

  • COL27A1
  • Steel syndrome
  • deafness
  • exon skipping
  • multiple joint dislocations
  • whole-exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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