A duplication on chromosome 16q12 affecting the IRXB gene cluster is associated with autosomal dominant cone dystrophy with early tritanopic color vision defect

Hum Mol Genet. 2021 Jun 17;30(13):1218-1229. doi: 10.1093/hmg/ddab117.


Cone dystrophies are a rare subgroup of inherited retinal dystrophies and hallmarked by color vision defects, low or decreasing visual acuity and central vision loss, nystagmus and photophobia. Applying genome-wide linkage analysis and array comparative genome hybridization, we identified a locus for autosomal dominant cone dystrophy on chromosome 16q12 in four independent multigeneration families. The locus is defined by duplications of variable size with a smallest region of overlap of 608 kb affecting the IRXB gene cluster and encompasses the genes IRX5 and IRX6. IRX5 and IRX6 belong to the Iroquois (Iro) protein family of homeodomain-containing transcription factors involved in patterning and regionalization of embryonic tissue in vertebrates, including the eye and the retina. All patients presented with a unique progressive cone dystrophy phenotype hallmarked by early tritanopic color vision defects. We propose that the disease underlies a misregulation of the IRXB gene cluster on chromosome 16q12 and demonstrate that overexpression of Irx5a and Irx6a, the two orthologous genes in zebrafish, results in visual impairment in 5-day-old zebrafish larvae.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosome Duplication*
  • Chromosomes, Human, Pair 16 / genetics*
  • Color Vision Defects / genetics*
  • Comparative Genomic Hybridization / methods
  • Cone Dystrophy / genetics*
  • Family Health
  • Female
  • Gene Expression Regulation
  • Genes, Dominant / genetics
  • Homeodomain Proteins / genetics*
  • Humans
  • Male
  • Multigene Family*
  • Pedigree
  • Sequence Analysis, DNA / methods
  • Transcription Factors / genetics*
  • Zebrafish / genetics


  • Homeodomain Proteins
  • IRX5 protein, human
  • IRX6 protein, human
  • Transcription Factors