Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement

Am J Hum Genet. 2020 Jun 4;106(6):859-871. doi: 10.1016/j.ajhg.2020.04.018. Epub 2020 May 28.


Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.

Keywords: CRSD; RIMS2; congenital cone-rod synaptic disorder; differential diagnosis; exome sequencing; neurodevelopmental or pancreatic involvement; stationary versus degenerative retinal disease; synaptic membrane exocytosis gene; syndromic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Alternative Splicing
  • Brain / metabolism
  • Cell Line
  • Child
  • Child, Preschool
  • Diagnosis, Differential
  • Eye Diseases, Hereditary / genetics*
  • Family Health
  • Female
  • France
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / genetics*
  • GTP-Binding Proteins / metabolism
  • Genetic Diseases, X-Linked / genetics*
  • Glucose / metabolism
  • Humans
  • Insulin Secretion
  • Loss of Function Mutation*
  • Male
  • Myopia / genetics*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Night Blindness / genetics*
  • Pancreas / metabolism
  • Pedigree
  • Retina / metabolism
  • Saudi Arabia
  • Senegal


  • Nerve Tissue Proteins
  • RIMS1 protein, human
  • GTP-Binding Proteins
  • Glucose

Supplementary concepts

  • Night blindness, congenital stationary