A Homozygous Missense Mutation in NEUROD1 Is Associated With Nonsyndromic Autosomal Recessive Retinitis Pigmentosa

Abstract

Citation: Wang F, Li H, Xu M, et al. A homozygous missense mutation in NEUROD1 is associated with nonsyndromic autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2015;56:150-155. DOI: 10.1167/iovs.14-15382 PURPOSE. Mutations in the same gene can lead to different clinical phenotypes. In this study, we aim to identify novel genotype-phenotype correlations and novel disease genes by analyzing an unsolved autosomal recessive retinitis pigmentosa (ARRP) Han Chinese family.METHODS. Whole exome sequencing was performed for one proband from the consanguineous ARRP family. Stringent variants filtering and prioritizations were applied to identify the causative mutation. RESULTS.A homozygous missense variant, c.724G>A; p.V242I, in NEUROD1 was identified as the most likely cause of disease. This allele perfectly segregates in the family and affects an amino acid, which is highly conserved among mammals. A previous study showed that a homozygous null allele in NEUROD1 causes severe syndromic disease with neonatal diabetes, systematic neurological abnormalities, and early-onset retinal dystrophy. Consistent with these results, our patients who are homozygous for a less severe missense allele presented only late-onset retinal degeneration without any syndromic symptoms.CONCLUSIONS. We identified a potential novel genotype-phenotype correlation between NEUROD1 and nonsyndromic ARRP. Our study supports the idea that NEUROD1 is important for maintenance of the retina function and partial loss-of-function mutation in NEUROD1 is likely a rare cause of nonsyndromic ARRP.

The phenotypic variability of HK1-associated retinal dystrophy

“…IRDs demonstrate both extensive clinical and genetic heterogeneity. To date, nearly 300 genes have been identified that associate with various forms of IRDs ( https://sph.uth.edu/retnet/ ) (accessed Jun 23 rd , 2017) and they are involved in a wide range of biological pathways such as photo-transduction 1 , 2 , ciliogenesis 3 , 4 , pre-mRNA splicing 5 , 6 , transcription regulation 7 and protein transport/quality control 8 , 9 . Nevertheless, novel disease-causing genes and pathways are still being identified by whole exome sequencing or whole genome sequencing, adding to the pathological mechanisms of retinal dystrophy.…”

Permanent neonatal diabetes mellitus and neurological abnormalities due to a novel homozygous missense mutation inNEUROD1

“…This variant was identified by whole‐exome sequencing and was predicted to affect a highly conserved amino acid. Different in silico analysis algorithms yielded prediction scores ranging from “damaging” to “benign.” Segregation analysis was consistent with the variant being causative, supporting the essential role of NEUROD1 in maintaining adult photoreceptors in humans . It is interesting that these cases had isolated retinitis pigmentosa with no neurological features or disorders in glucose metabolism.…”

“…Recently, a NEUROD1 homozygous missense mutation, p.Val242Ile, has been identified in a consanguineous family with autosomal recessive non‐syndromic retinitis pigmentosa . This variant was identified by whole‐exome sequencing and was predicted to affect a highly conserved amino acid.…”

Clinically-guided mutation screening of two families with hereditary retinal disease

“…In the HRD field, the molecular diagnosis of disease cases also benefits a lot from a variety of NGS-based methods, including whole exome sequencing and targeted capture sequencing. Correspondingly, the molecular diagnosis rate of HRD cases has been significantly improved [4][5][6][7][8][9][10][11][12][13] , and a series of novel HRD-associated genes have been identified [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] .…”