Dataset Information

Clinical Characteristics and Genetic Variants in Taiwanese Patients With PROM1-Related Inherited Retinal Disorders.

ABSTRACT:

Purpose

This study investigated the clinical characteristics of patients with PROM1-related inherited retinal diseases (IRDs).

Methods

Patients diagnosed with IRDs who had mutations in PROM1 were identified at Linkou Chang Gung Memorial Hospital and Kaohsiung Medical University Hospital in Taiwan. Information on clinical characteristics and best-corrected visual acuity was recorded. Color fundus (CF) images, fundus autofluorescence photography (FAF), spectral-domain optical coherence tomography (SD-OCT), and electroretinograms (ERGs) were analyzed to examine patient phenotypes. PROM1 variants were detected using whole exome sequencing and verified by Sanger sequencing.

Results

Fourteen patients from nine families with PROM1-related IRDs were analyzed. Most patients exhibited chorioretinal atrophy in the macular area, with or without extramacular involvement on CF. Similarly, hypo-autofluorescence confined to the macular area, with or without extramacular involvement, was present for most patients on FAF. Furthermore, SD-OCT revealed outer retinal tubulations and focal or diffuse retinal thinning. ERGs showed variable findings, including maculopathy with normal ERG, subnormal cone response, and extinguished rod and cone responses. We detected five variants of the PROM1 gene, including c.139del, c.794del, c.1238T>A, c.2110C>T, and c.1117C>T.

Conclusions

In this study, we evaluated 14 Taiwanese patients with five PROM1 variants. Additionally, incomplete penetrance of heterozygous PROM1 variants was observed. Furthermore, patients with autosomal dominant PROM1 variants had lesions in the macular area and the peripheral region of the retina. SD-OCT serves as a useful tool for early detection of PROM1-related IRDs, as it captures certain signs of such diseases.

SUBMITTER: Lin TY

PROVIDER: S-EPMC10664721 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Clinical Characteristics and Genetic Variants in Taiwanese Patients With PROM1-Related Inherited Retinal Disorders.

Lin Tzu-Yi TY Wu Pei-Liang PL Kang Eugene Yu-Chuan EY Chi Yi-Chun YC Jenny Laura A LA Lin Pei-Hsuan PH Lee Chia-Ying CY Liu Chun-Hsiu CH Liu Laura L Yeh Lung-Kun LK Chen Kuan-Jen KJ Hwang Yih-Shiou YS Wu Wei-Chi WC Lai Chi-Chun CC Hsiao Meng-Chang MC Liu Pei-Kang PK Wang Nan-Kai NK

Investigative ophthalmology & visual science 20231101 14

<h4>Purpose</h4>This study investigated the clinical characteristics of patients with PROM1-related inherited retinal diseases (IRDs).<h4>Methods</h4>Patients diagnosed with IRDs who had mutations in PROM1 were identified at Linkou Chang Gung Memorial Hospital and Kaohsiung Medical University Hospital in Taiwan. Information on clinical characteristics and best-corrected visual acuity was recorded. Color fundus (CF) images, fundus autofluorescence photography (FAF), spectral-domain optical cohere ...[more]

PMID: 37975849

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Project description:ImportanceThe PROM1 gene, commonly associated with cone-rod dystrophies, may have dominant or recessive phenotypes that influence disease onset and severity.ObjectiveTo characterize the clinical phenotype and molecular genetic variations in patients with PROM1 variants.Design, setting, and participantsThis case-series study was conducted at 2 specialist retinal genetics clinics and examined 19 consecutively enrolled patients with PROM1-related retinal degeneration. Data were collected and analyzed from May 2018 to December 2018.Main outcomes and measuresResults of ophthalmic examination, retinal imaging, and molecular genetic analysis by next-generation sequencing.ResultsOf 19 patients, 13 (68%) were women, and age ranged from 11 to 70 years. All patients presented with central visual loss, with or without photophobia. Individuals with recessive variants commonly had severe loss of visual acuity by their 20s, whereas the dominant variant was associated with a milder phenotype, with most patients retaining good vision into late adulthood. The recessive cases were associated with a panretinal dystrophy of cone-rod phenotype with early macular involvement, whereas the dominant variants were associated with a cone-rod phenotype that was restricted to the macula with predominantly cone dysfunction. Next-generation sequencing identified 3 novel and 9 previously reported variants in PROM1. Recessive mutations included 6 truncating variants (3 nonsense and 3 frameshift), 4 splice site variants, and 1 missense variant. All 6 dominant variants were associated with a c.1117C>T missense variant. The variants were distributed throughout the PROM1 genomic sequence with no specific clustering on protein domains.Conclusions and relevanceIn this case-series study, PROM1 recessive variants were associated with early-onset, severe panretinal degeneration. The similar phenotypes observed in patients with homozygous missense variants and splice site variants compared with similarly aged patients with truncating variants suggests that all recessive variants have a null (or loss of function close to null) outcome on PROM1 function. In contrast, the dominant missense cases were associated with a milder, cone-driven phenotype, suggesting that the dominant disease is preferentially associated with cones. This has implications for the development of treatments for this severely blinding disease, and adeno-associated viral vector-based gene therapy and optogenetics could become successful treatment options.

Project description:Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Dataset Information

Clinical Characteristics and Genetic Variants in Taiwanese Patients With PROM1-Related Inherited Retinal Disorders.

Purpose

Methods

Results

Conclusions

Publications

Clinical Characteristics and Genetic Variants in Taiwanese Patients With PROM1-Related Inherited Retinal Disorders.

Similar Datasets

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