Author: Maria del Pilar Martin Gutierrez (Spain)
Co-authors: Anthony G. Robson, Michel Michaelides, Andrew R. Webster, Omar A. Mahroo
Purpose
To describe phenotypic features and novel genotypes in a series of ten patients diagnosed with autosomal recessive complete congenital stationary night blindness (CSNB) with molecularly confirmed pathogenic variants in the gene TRPM1.
Setting/Venue
Our series of ten probands were assessed in the Genetics Service of Moorfields Eye Hospital, London, between 2001 and 2021.
Methods
Ten patients with a confirmed molecular diagnosis of autosomal recessive congenital stationary night blindness (CSNB) secondary to pathogenic variants in TRPM1 were found by retrospective search of the electronic patient record. The following clinical features were noted where available: reported nyctalopia; type of refractive error; visual acuity at first available visit; findings on multimodal retinal imaging and electrophysiology. Particular note was made of the ratio of b-wave to a-wave amplitude (b:a ratio) in the standard scotopic bright flash (DA10) and the standard photopic flash (LA3) in those patients who had undergone international standard electroretinogram (ERG) recording. A search using the PubMed database and the ClinVar resource was conducted to establish which missense variants had been previously reported.
Results
Of the 10 probands, six (60%) were male. Ages ranged from 9 months to 48 years, with a mean (SD) age of 14 (14) years. Mean (SD) best corrected logMAR visual acuity was 0.58 (0.19). Nine patients had myopic refractive error and fundus features compatible with myopia. One patient was reported to have hypermetropic refractive error. Congenital nyctalopia was reported in 9 patients (90%). ERG results were available for 8 patients: in 3 patients, a non-standard protocol was employed due to their young age; in the remaining 5 patients, standard testing was performed. All showed ERG features typical of complete CSNB. For the 5 patients undergoing standard testing, mean (SD) b:a ratio was 0.48 (0.04) for the DA10 stimulus, with a median of 0.47 (range 0.42 to 0.54); for the LA3 stimulus, mean (SD) b:a ratio was 2.6 (0.9), with a median of 2.6 (range 1.5 to 4.0). Two missense variants (found in two patients) were not found in previously reports: p.(Cys932Tyr) was found in heterozygosity in one patient; a second patient was homozygous for p.(Leu682Pro). These variants were absent from the gnomAD database.
Conlusions
We report phenotypic characteristics in a series of 10 patients with complete CSNB associated TRPM1 (each patient having with 2 molecularly confirmed variants). Two rare missense variants are reported that were not found in the published literature. All patients had typical ERG findings. Whilst the DA10 b:a ratio was very similar across patients, the LA3 b:a ratio varied, but was always well above 1. As pathogenic variants in TRPM1 affect ON bipolar cell responses, the latter finding is consistent with OFF bipolar cells contributing significantly to the b-wave in the LA3 flash response.
Financial Disclosure
All authors affiliated with Moorfields Eye Hospital and Institute of Ophthalmology are founded by the NIHR Biomedical Resource Centre at UCL Institute of Ophthalmology and Moorfields
Comments
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