Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders

Hum Mutat. 2019 Jun;40(6):765-787. doi: 10.1002/humu.23735. Epub 2019 Mar 28.


Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.

Keywords: CACNA1F; IRD; gene defect; icCSNB; intronic variants; minigene approach; synonymous variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channels, L-Type / genetics*
  • Eye Diseases, Hereditary / genetics*
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Predisposition to Disease
  • Hemizygote
  • Humans
  • Introns
  • Male
  • Mutation*
  • Myopia / genetics*
  • Night Blindness / genetics*
  • Pedigree
  • RNA Splicing
  • Sequence Analysis, DNA / methods*
  • Silent Mutation


  • CACNA1F protein, human
  • Calcium Channels, L-Type

Supplementary concepts

  • Night blindness, congenital stationary