Clinical and genetic findings in TRPM1-related congenital stationary night blindness.

Abstract

PURPOSE:

Congenital stationary night blindness (CSNB) is a heterogeneous group of Mendelian retinal disorders that present in childhood. Biallelic variants altering the protein-coding region of the TRPM1 gene are one of the commonest causes of CSNB. Here, we report the clinical and genetic findings in 10 unrelated individuals with TRPM1-retinopathy.

METHODS:

Study subjects were recruited through a tertiary clinical ophthalmic genetic service at Manchester, UK. All participants underwent visual electrodiagnostic testing and panel-based genetic analysis.

RESULTS:

Study subjects had a median age of 8 years (range: 3-20 years). All probands were myopic and had electroretinographic findings in keeping with complete CSNB. Notably, three probands reported no night vision problems. Fourteen different disease-associated TRPM1 variants were detected. One individual was homozygous for the NM_001252024.2 (TRPM1):c.965 + 29G>A variant and a mini-gene assay highlighted that this change results in mis-splicing and premature protein termination. Additionally, two unrelated probands who had CSNB and mild neurodevelopmental abnormalities were found to carry a 15q13.3 microdeletion. This copy number variant encompasses seven genes, including TRPM1, and was encountered in the heterozygous state and in trans with a missense TRPM1 variant in each case.

CONCLUSION:

Our findings highlight the importance of comprehensive genomic analysis, beyond the exons and protein-coding regions of genes, for individuals with CSNB. When this characteristic retinal phenotype is accompanied by extraocular findings (including learning and/or behavioural difficulties), a 15q13.3 microdeletion should be suspected. Focused analysis (e.g. microarray testing) is recommended to look for large-scale deletions encompassing TRPM1 in patients with CSNB and neurodevelopmental abnormalities.

• Authors: Christos Iosifidis, Jingshu Liu, Theodora Gale, Jamie M Ellingford, Christopher Campbell, Stuart Ingram, Kate Chandler, Neil R A Parry, Graeme C Black, Panagiotis I Sergouniotis
• Journal: Acta ophthalmologica (Acta Ophthalmol) Vol. 100 Issue 6 Pg. e1332-e1339 (Sep 2022) ISSN: 1755-3768 [Electronic] England
• PMID: 35633130 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.

Chemical References

• TRPM Cation Channels
• TRPM1 protein, human

Topics

• Chromosome Deletion
• Chromosome Disorders
• Chromosomes, Human, Pair 15
• Electroretinography
• Eye Diseases, Hereditary (diagnosis, genetics)
• Genetic Diseases, X-Linked (diagnosis, genetics)
• Humans
• Intellectual Disability
• Mutation
• Myopia
• Night Blindness (congenital, diagnosis, genetics)
• Pedigree
• Seizures
• TRPM Cation Channels (genetics, metabolism)