The power of homozygosity mapping:discovery of new genetic defects in patients with retinal dystrophy.

Contains fulltext : 82950.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 3 november 2010Promotor : Cremers, F.P.M. Co-promotores : Born, L.I. van den, Hollander, A.I. den239 p

The power of homozygosity mapping: discovery of new genetic defects in patients with retinal dystrophy

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Novel null mutations in the EYS gene are a frequent cause of autosomal recessive retinitis pigmentosa in the Israeli population.

Contains fulltext : 87206_pre.pdf (preprint version ) (Open Access) Contains fulltext : 87206_pub.pdf (publisher's version ) (Closed access)PURPOSE: To characterize the role of EYS, a recently identified retinal disease gene, in families with inherited retinal degenerations in the Israeli and Palestinian populations. METHODS: Clinical and molecular analyses included family history, ocular examination, full-field electroretinography (ERG), perimetry, autozygosity mapping, mutation detection, and estimation of mutation age. RESULTS: Autozygosity mapping was performed in 171 consanguineous Israeli and Palestinian families with inherited retinal degenerations. Large homozygous regions, harboring the EYS gene, were identified in 15 of the families. EYS mutation analysis in the 15 index cases, followed by genotyping of specific mutations in an additional 121 cases of inherited retinal degenerations, revealed five novel null mutations, two of which are founder mutations, in 10 Israeli and Palestinian families with autosomal recessive retinitis pigmentosa (arRP). The most common mutation identified was a founder mutation in the Moroccan Jewish subpopulation. The ESTIAGE program produced an estimate that the age of the most recent common ancestor was 26 generations. The retinal phenotype in most patients was typical yet relatively severe RP, with an early age of onset and nonrecordable ERGs on presentation. CONCLUSIONS: The results demonstrate that EYS is currently the most commonly mutated arRP gene in the Israeli population, mainly due to founder mutations. EYS mutations were associated with an RP phenotype in all patients. The authors concluded that the gene plays only a minor role in causing other retinal phenotypes.01 september 201

Mutations in the EYS gene account for approximately 5% of autosomal recessive retinitis pigmentosa and cause a fairly homogeneous phenotype.

Contains fulltext : 89418.pdf (publisher's version ) (Closed access)OBJECTIVE: To determine the prevalence of mutations in the EYS gene in a cohort of patients affected by autosomal recessive retinitis pigmentosa (RP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Two hundred forty-five patients affected by autosomal recessive RP. METHODS: All coding exons of EYS were screened for mutations by polymerase chain reaction amplification and sequence analysis. All 12 patients carrying mutations in EYS were re-examined, which included Goldmann kinetic perimetry, electroretinography, and high-resolution spectral-domain optical coherence tomography (OCT). MAIN OUTCOME MEASURES: DNA sequence variants, best-corrected visual acuity, fundus appearance, visual field assessments using Goldmann kinetic perimetry, electroretinogram responses, and OCT images. RESULTS: Nine novel truncating mutations and one previously described mutation in EYS were identified in 11 families. In addition, 18 missense changes of uncertain pathogenicity were found. Patients carrying mutations in EYS demonstrated classic RP with night blindness as the initial symptom, followed by gradual constriction of the visual field and a decline of visual acuity later in life. The onset of symptoms typically occurred between the second and fourth decade of life. The fundus displayed bone spicules increasing in density with age and generalized atrophy of the retinal pigment epithelium and choriocapillaris with relative sparing of the posterior pole until later in the disease process, when atrophic macular changes occurred. CONCLUSIONS: Mutations in EYS account for approximately 5% of autosomal recessive RP patients in a cohort of patients consisting predominantly of patients of western European ancestry. The EYS-associated RP phenotype is typical and fairly homogeneous in most patients.1 oktober 201

A Homozygous Frameshift Mutation in LRAT Causes Retinitis Punctata Albescens.

Item does not contain fulltextPURPOSE: To determine the genetic defect and to describe the clinical characteristics in patients with retinitis punctata albescens (RPA) and fundus albipunctatus (FAP). DESIGN: Case series/observational study. PARTICIPANTS: We included 13 patients affected by RPA or FAP. METHODS: Thirteen patients were collected from 8 families with a retinal dystrophy characterized by tiny, yellow-white dots on funduscopy, typical for FAP or RPA. All patients underwent full ophthalmologic examinations, including visual field assessment. Fundus photography, and electroretinography were performed in 12 patients, and optical coherence tomography and fundus autofluorescence were performed in 4 patients. DNA samples of all patients were screened for mutations in RLBP1 and for mutations in RDH5 in patients who did not carry mutations in RLBP1. DNA samples of 2 sibling pairs of nonconsanguineous families who carried mutations neither in RLBP1 nor in RDH5 were analyzed by genome-wide homozygosity mapping. Sequence analysis was performed of LRAT, a candidate gene in a shared homozygous region. MAIN OUTCOME MEASURES: We assessed DNA sequence variants, best-corrected visual acuity, fundus appearance, visual field measurements, electroretinogram responses, optical coherence tomography, and fundus autofluorescence. RESULTS: A homozygous frameshift mutation was identified in LRAT in 4 patients with RPA. Mutations in RLBP1 were identified in 7 patients with RPA and in 1 patient with FAP and cone dystrophy. One patient had compound heterozygous mutations in RDH5 and suffered from FAP with mild maculopathy. CONCLUSIONS: A genetic defect was identified in LRAT as a novel cause of RPA. LRAT is therefore the fourth gene involved in the visual cycle that may cause a white-dot retinopathy. We also revealed that mutations in RLBP1 may lead to FAP with cone dystrophy. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.1 september 201

A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype.

Contains fulltext : 87683.pdf (publisher's version ) (Closed access)PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP). METHODS. DNA samples of the affected family members were genotyped with 250 K genome-wide SNP microarrays. Genetic defects were localized by linkage analysis and homozygosity mapping, and candidate genes were analyzed by sequencing. Patients underwent a full ophthalmic examination. RESULTS. Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991+1655A>G founder mutation and a novel nonsense mutation in exon 7 (c.451C>T, p.Arg151X). The proband had nystagmus, hyperopia, a flat electroretinogram (ERG), and decreased visual acuity (20/250) from birth. The two cousins had minimal scotopic ERG responses at the age of 2. In one of these patients, visual acuity had reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA in affected individuals revealed altered splice forms in which either exon 7 or exons 7 and 8 were skipped. In both mutant cDNA products, the open reading frame was not disrupted. Furthermore, homozygosity mapping and mutation analysis in the distant family member affected by RP revealed a homozygous mutation in MERTK, but no CEP290 mutations. This MERTK mutation was heterozygously present in the most severely affected (LCA) patient, but was absent in the two more mildly affected cousins. CONCLUSIONS. A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. That the remaining open reading frame is intact may explain the less severe phenotype observed in the two affected cousins. The additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband. This study extends the phenotypic spectrum of CEP290-associated diseases at the mild end.1 juli 201

High-resolution homozygosity mapping is a powerful tool to detect novel mutations causative of autosomal recessive RP in the Dutch population

Contains fulltext : 96984.pdf (publisher's version ) (Closed access)PURPOSE: To determine the genetic defects underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch population and in a subset of patients originating from other countries. The hypothesis was that, because there has been little migration over the past centuries in certain areas of The Netherlands, a significant fraction of Dutch arRP patients carry their genetic defect in the homozygous state. METHODS: High-resolution genome-wide SNP genotyping on SNP arrays and subsequent homozygosity mapping were performed in a large cohort of 186 mainly nonconsanguineous arRP families living in The Netherlands. Candidate genes residing in homozygous regions were sequenced. RESULTS: In ~94% of the affected individuals, large homozygous sequences were identified in their genome. In 42 probands, at least one of these homozygous regions contained one of the 26 known arRP genes. Sequence analysis of the corresponding genes in each of these patients revealed 21 mutations and two possible pathogenic changes, 14 of which were novel. All mutations were identified in only a single family, illustrating the genetic diversity within the Dutch population. CONCLUSIONS: This report demonstrates that homozygosity mapping is a powerful tool for identifying the genetic defect underlying genetically heterogeneous recessive disorders like RP, even in populations with little consanguinity

BBS1 Mutations in a Wide Spectrum of Phenotypes Ranging From Nonsyndromic Retinitis Pigmentosa to Bardet-Biedl Syndrome

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