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Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant.

ABSTRACT: BACKGROUND:To describe the clinical phenotype and genetic cause underlying the disease pathology in a pedigree (affected n?=?9) with X-linked retinoschisis (XLRS1) due to a novel RS1 mutation and to assess suitability for novel therapies using multimodal imaging. METHODS:The Irish National Registry for Inherited Retinal Degenerations (Target 5000) is a program including clinical history and examination with multimodal retinal imaging, electrophysiology, visual field testing and genetic analysis. Nine affected patients were identified across 3 generations of an XLRS1 pedigree. DNA sequencing was performed for each patient, one carrier female and one unaffected relative. Pedigree mapping revealed a further 4 affected males. RESULTS:All affected patients had a history of reduced visual acuity and dyschromatopsia; however, the severity of phenotype varied widely between the nine affected subjects. The stage of disease was classified as previously described. Phenotypic severity was not linearly correlated with age. A novel RS1 (Xp22.2) mutation was detected (NM_000330: c.413C?>?A) resulting in a p.Thr138Asn substitution. Protein modelling demonstrated a change in higher order protein folding that is likely pathogenic. CONCLUSIONS:This family has a novel gene mutation in RS1 with clinical evidence of XLRS1. A proportion of the older generation has developed end-stage macular atrophy; however, the severity is variable. Confirmation of genotype in the affected grandsons of this pedigree in principle may enable them to avail of upcoming gene therapies, provided there is anatomical evidence (from multimodal imaging) of potentially reversible early stage disease.

SUBMITTER: Stephenson K

PROVIDER: S-EPMC6233547 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant.

Stephenson Kirk K Dockery Adrian A Wynne Niamh N Carrigan Matthew M Kenna Paul P Jane Farrar G G Keegan David D

BMC medical genetics 20181112 1

<h4>Background</h4>To describe the clinical phenotype and genetic cause underlying the disease pathology in a pedigree (affected n = 9) with X-linked retinoschisis (XLRS1) due to a novel RS1 mutation and to assess suitability for novel therapies using multimodal imaging.<h4>Methods</h4>The Irish National Registry for Inherited Retinal Degenerations (Target 5000) is a program including clinical history and examination with multimodal retinal imaging, electrophysiology, visual field testing and ge ...[more]

PMID: 30419843

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Project description:PURPOSE: To determine the clinical features and to identify mutations in the retinoschisis gene (RS1) in ten patients with X-linked retinoschisis (XLRS). METHODS: Ten male patients from nine Polish families were included in this study. Ophthalmologic examinations, including optical coherence tomography (OCT) and full-field electroretinography (ERG), were performed in all affected boys. The entire coding region encompassing six exons of the RS1 gene was amplified with PCR and directly sequenced in all the patients. RESULTS: All affected individuals showed typical retinoschisis signs and symptoms, and all appeared to have a mutation in the RS1 gene. Seven different mutations were identified, including two novel missense substitutions: c.176G>C (p.Cys59Ser), c.451T>A (p.Tyr151Asp); one novel nonsense substitution: c.218C>A (p.Ser73*); and one novel frameshift mutation: c.354_355delCA (p.Asp118Glufs*2). We also found two missense substitutions that had been previously described: c.214G>A (p.Glu72Lys) and c.626G>T (p.Arg209Leu) and one known splice site mutation in intron 5: c.522+1G>T (IVS5+1G>T). CONCLUSIONS: This study provides the first molecular genetic characteristics of patients with juvenile retinoschisis from the previously unexplored Polish population. We investigated the molecular background of XLRS in ten boys. The present study reports for the first time four novel mutations, including two missense substitutions, one nonsense substitution, and one frameshift deletion. One of these substitutions and 2-bp deletion created stop codons. Moreover, we described three substitutions that had been previously reported (one is a splicing mutation). Further genetic characterization of Polish patients with XLRS will be helpful in understanding the worldwide spectrum of RS1 mutations. Despite the mutation heterogeneity found in a small group of our patients, they presented a relatively uniform clinical picture. Identifying the causative mutation is helpful in confirming diagnosis and counseling, but cannot provide prognostic data.

Dataset Information

Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant.

Publications

Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant.

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