Dataset Information

Clinical features and genetic spectrum of NMNAT1-associated retinal degeneration.

ABSTRACT:

Objectives

To systematically analyse the NMNAT1 variant spectrum and frequency, the associated phenotypic characteristics, and potential genotype-phenotype correlations based on our data and literature review.

Methods

Biallelic potential pathogenic variants (PPV) in NMNAT1 were collected from our in-house exome sequencing data. Whole-genome sequencing was conducted subsequently for patients with only one heterozygous PPV detected in NMNAT1. The clinical data were reviewed and evaluated in detail. Furthermore, the literature was reviewed for reports of NMNAT1 variants and their associated phenotypes.

Results

Eleven NMNAT1 variants, including two novel variants, were detected in 8 families from our cohort. All of the 9 available patients showed generalized tapetoretinal dystrophy at an early age (88.9% in the first decade), and disciform macular atrophy was identified in six patients from five unrelated families. Among a total of 125 patients from 8 families of our cohort and 91 families reported by the available literature, 92.9% patients showed onset of disease in the first year after birth, and 89.0% patients showed visual acuity of 0.05 or lower. All of the 39 patients with fundus photos available presented disciform macular atrophy with generalized tapetoretinal dystrophy. Most (54/80, 67.5%) of causative NMNAT1 variants were missense. The most frequent variants in Caucasian and Asian population are p.E257K and p.R237C, respectively.

Conclusions

Early-onset age, disciform macular atrophy with generalized tapetoretinal dystrophy, and poor visual acuity are the typical features of NMNAT1-associated retinal degeneration. Different variant hot spots of NMNAT1 were observed in different populations.

SUBMITTER: Yi Z

PROVIDER: S-EPMC9674661 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Clinical features and genetic spectrum of NMNAT1-associated retinal degeneration.

Yi Zhen Z Li Shiqiang S Wang Siyu S Xiao Xueshan X Sun Wenmin W Zhang Qingjiong Q

Eye (London, England) 20211126 12

<h4>Objectives</h4>To systematically analyse the NMNAT1 variant spectrum and frequency, the associated phenotypic characteristics, and potential genotype-phenotype correlations based on our data and literature review.<h4>Methods</h4>Biallelic potential pathogenic variants (PPV) in NMNAT1 were collected from our in-house exome sequencing data. Whole-genome sequencing was conducted subsequently for patients with only one heterozygous PPV detected in NMNAT1. The clinical data were reviewed and eval ...[more]

PMID: 34837036

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Project description:Importance:Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. Objective:To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. Design, Setting, and Participants:A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. Main Outcomes and Measures:Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. Results:There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. Conclusions and Relevance:This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

Dataset Information

Clinical features and genetic spectrum of NMNAT1-associated retinal degeneration.

Objectives

Methods

Results

Conclusions

Publications

Clinical features and genetic spectrum of NMNAT1-associated retinal degeneration.

Similar Datasets

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