Expanding the Genetic Landscape of Usher-Like Phenotypes

Invest Ophthalmol Vis Sci. 2019 Nov 1;60(14):4701-4710. doi: 10.1167/iovs.19-27470.


Purpose: Usher syndrome (USH) is a rare disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss. Several genes are responsible for the disease, but not all cases are explained by mutations in any of these, supporting the fact that there remain other unknown genes that have a role in the syndrome. We aimed to find the genetic cause of presumed USH patients lacking pathogenic mutations in the known USH genes.

Methods: Whole exome sequencing was performed on a priori USH-diagnosed subjects from nine unrelated families, which had shown negative results for an USH-targeted panel in a previous study.

Results: We identified possible pathogenic variants in six of the studied families. One patient harbored mutations in REEP6 and TECTA, each gene tentatively causative of one of the two main symptoms of the disease, mimicking the syndrome. In three patients, only the retinal degeneration causative mutations were detected (involving EYS, WDR19, and CNGB1 genes). Another family manifested a dementia-linked retinal dystrophy dependent on an allele dosage in the GRN gene. Last, another case presented a homozygous mutation in ASIC5, a gene not yet associated with USH.

Conclusions: Our findings demonstrate that pending cases should be clinically and genetically carefully assessed, since more patients than expected may be either related phenocopies or affected by a more complex disease encompassing additional symptoms rather than classical USH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Sensing Ion Channels / genetics
  • Cyclic Nucleotide-Gated Cation Channels / genetics
  • Cytoskeletal Proteins / genetics
  • DNA Mutational Analysis
  • Extracellular Matrix Proteins / genetics
  • Eye Proteins / genetics*
  • Female
  • GPI-Linked Proteins / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Membrane Proteins / genetics*
  • Pedigree
  • Phenotype
  • Progranulins / genetics
  • Retinitis Pigmentosa / diagnosis
  • Retinitis Pigmentosa / genetics
  • Usher Syndromes / diagnosis
  • Usher Syndromes / genetics*
  • Whole Genome Sequencing*


  • ASIC5 protein, human
  • Acid Sensing Ion Channels
  • CNGB1 protein, human
  • Cyclic Nucleotide-Gated Cation Channels
  • Cytoskeletal Proteins
  • EYS protein, human
  • Extracellular Matrix Proteins
  • Eye Proteins
  • GPI-Linked Proteins
  • GRN protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Progranulins
  • REEP6 protein, human
  • TECTA protein, human
  • WDR19 protein, human