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ABSTRACT: OBJECTIVE: To investigate the relative frequency of the genetic causes of the Schubert-Bornschein type of congenital stationary night blindness (CSNB) and to determine the genotype-phenotype correlations in CSNB1 and CSNB2. DESIGN: Clinic-based, longitudinal, multicenter study. PARTICIPANTS: A total of 39 patients with CSNB1 from 29 families and 62 patients with CSNB2 from 43 families. METHODS: Patients underwent full ophthalmologic and electrophysiologic examinations. On the basis of standard electroretinograms (ERGs), patients were diagnosed with CSNB1 or CSNB2. Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in NYX, TRPM1, GRM6, and GPR179 in patients with CSNB1 and CACNA1F and CABP4 in patients with CSNB2. MAIN OUTCOME MEASURES: Data included genetic cause of CSNB, refractive error, visual acuity, nystagmus, strabismus, night blindness, photophobia, color vision, dark adaptation (DA) curve, and standard ERGs. RESULTS: A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a "square-wave" appearance in CSNB1 and a decreased b-wave in CSNB2. Mutations causing CSNB1 were found in NYX (20 patients, 13 families), TRPM1 (10 patients, 9 families), GRM6 (4 patients, 3 families), and GPR179 (2 patients, 1 family). Congenital stationary night blindness 2 was primarily caused by mutations in CACNA1F (55 patients, 37 families). Only 3 patients had causative mutations in CABP4 (2 families). Patients with CSNB1 mainly had rod-related problems, and patients with CSNB2 had rod- and cone-related problems. The visual acuity on average was better in CSNB1 (0.30 logarithm of the minimum angle of resolution [logMAR]) than in CSNB2 (0.52 logMAR). All patients with CSNB1 and only 54% of the patients with CSNB2 reported night blindness. The dark-adapted threshold was on average more elevated in CSNB1 (3.0 log) than in CSNB2 (1.8 log). The 3 patients with CABP4 had a relative low visual acuity, were hyperopic, had severe nonspecific color vision defects, and had only 1.0 log elevated DA threshold. CONCLUSIONS: Congenital stationary night blindness 1, despite different causative mutations, shows 1 unique CSNB1 phenotype. Congenital stationary night blindness 2 caused by mutations in CABP4 merely shows cone-related problems and therefore appears to be distinct from CSNB2 caused by mutations in CACNA1F. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Ophthalmology 05/2013; · 5.45 Impact Factor
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ABSTRACT: Abstract Purpose: To determine which color vision test is most appropriate for the identification of cone disorders. Methods: In a clinic-based study, four commonly used color vision tests were compared between patients with cone dystrophy (n = 37), controls with normal visual acuity (n = 35), and controls with low vision (n = 39) and legal blindness (n = 11). Mean outcome measures were specificity, sensitivity, positive predictive value and discriminative accuracy of the Ishihara test, Hardy-Rand-Rittler (HRR) test, and the Lanthony and Farnsworth Panel D-15 tests. Results: In the comparison between cone dystrophy and all controls, sensitivity, specificity and predictive value were highest for the HRR and Ishihara tests. When patients were compared to controls with normal vision, discriminative accuracy was highest for the HRR test (c-statistic for PD-axes 1, for T-axis 0.851). When compared to controls with poor vision, discriminative accuracy was again highest for the HRR test (c-statistic for PD-axes 0.900, for T-axis 0.766), followed by the Lanthony Panel D-15 test (c-statistic for PD-axes 0.880, for T-axis 0.500) and Ishihara test (c-statistic 0.886). Discriminative accuracies of all tests did not further decrease when patients were compared to controls who were legally blind. Conclusions: The HRR, Lanthony Panel D-15 and Ishihara all have a high discriminative accuracy to identify cone disorders, but the highest scores were for the HRR test. Poor visual acuity slightly decreased the accuracy of all tests. Our advice is to use the HRR test since this test also allows for evaluation of all three color axes and quantification of color defects.
Ophthalmic epidemiology 04/2013; 20(2):114-22. · 1.93 Impact Factor
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Susanne Roosing, L Ingeborgh van den Born,
Carel B Hoyng,
Alberta A H J Thiadens,
Elfride de Baere,
Rob W J Collin,
Robert K Koenekoop,
Bart P Leroy,
Norka van Moll-Ramirez,
Hanka Venselaar,
Frans C C Riemslag,
Frans P M Cremers,
Caroline C W Klaver,
Anneke I den Hollander
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ABSTRACT: PURPOSE: The majority of the genetic causes of autosomal recessive (ar) cone dystrophy (CD) and cone-rod dystrophy (CRD) are currently unknown. We used a high-resolution homozygosity mapping approach in a cohort of patients with CD or CRD to identify new genes for ar cone disorders. DESIGN: Case series. PARTICIPANTS: A cohort of 159 patients with ar CD and 91 patients with CRD. METHODS: The genomes of 83 patients with ar CD and 73 patients with CRD were analyzed for homozygous regions using single nucleotide polymorphism (SNP) microarrays. One patient showed homozygosity of SNPs across chromosome 6, and segregation analysis was performed using microsatellite markers. Direct sequencing of all retinal disease genes on chromosome 6 revealed a novel pathogenic TULP1 mutation in this patient. A cohort of 159 individuals with CD and 91 individuals with CRD was screened for this particular mutation using the restriction enzyme HhaI. The medical history of patients carrying the TULP1 mutation was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence (FAF), and fundus photography. MAIN OUTCOME MEASURES: TULP1 mutations, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, FAF, and OCT findings. RESULTS: In 1 patient, homozygosity mapping and subsequent segregation analysis revealed maternal uniparental disomy (UPD) of chromosome 6. A novel homozygous missense mutation (p.Arg420Ser) was identified in TULP1, whereas no mutations were detected in other retinal disease genes on chromosome 6. The mutation affects a highly conserved amino acid residue in the Tubby domain and is predicted to be pathogenic. The same homozygous mutation was also identified in an additional, unrelated patient with CRD. Both patients carrying the p.Arg420Ser mutation presented with a bull's eye maculopathy. The first patient had progressive loss of visual acuity with a relatively preserved ERG, whereas the second patient developed loss of visual acuity, peripheral degeneration, and severely reduced ERG responses in a cone-rod pattern. CONCLUSIONS: Maternal UPD of chromosome 6 unmasked a mutation in the TULP1 gene as a novel cause of cone dysfunction. This expands the disease spectrum of TULP1 mutations from Leber congenital amaurosis and early-onset retinitis pigmentosa to cone-dominated disease. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Ophthalmology 03/2013; · 5.45 Impact Factor
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ABSTRACT: OBJECTIVE: To describe the clinical and genetic characteristics of patients with autosomal recessive bestrophinopathy (ARB). DESIGN: Retrospective case series. PARTICIPANTS: Ten patients with ARB from 7 different families. METHODS: All patients underwent a complete ophthalmic examination, including dilated fundus examination, fundus photography, and fluorescein angiography (FA). In all probands, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), electro-oculography (EOG), and Goldmann perimetry were performed. In selected patients, multifocal ERG was performed. Blood samples were obtained to analyze the BEST1 gene for biallelic mutations that confirmed the diagnosis of ARB. MAIN OUTCOME MEASURES: Age at onset; visual acuity; fundus appearance; characteristics on FA, FAF, OCT, full-field ERG, and EOG; BEST1 gene mutations; and genotype-phenotype correlation. RESULTS: The age at onset varied widely, from 2 to 54 years. A spectrum of fundus abnormalities was observed, such as multifocal yellowish subretinal deposits, subretinal fibrous scars, and cystoid intraretinal fluid collections in the macula. All ARB patients were hyperopic, and some had shallow anterior chamber angles that predisposed them to angle-closure glaucoma. The EOG results were abnormal in all patients. The full-field ERG results were abnormal in 8 ARB patients, whereas 2 patients demonstrated normal cone and rod responses on full-field ERG. Nine ARB patients carried biallelic mutations in the BEST1 gene, and in 1 patient with a characteristic ARB phenotype, only 1 mutation could be identified. Seven different mutations were detected, including 4 novel mutations. CONCLUSIONS: Autosomal recessive bestrophinopathy is a recognizable phenotype caused by autosomal recessively inherited mutations in the BEST1 gene. A differential diagnosis with other conditions can be made on the basis of marked autofluorescence changes in combination with an absent light rise on the EOG that outweighs the full-field ERG abnormalities, which point to the BEST1-related hereditary nature of the disease. A number of currently available therapeutic options should be considered in ARB, a disease that seems to be a suitable candidate for future gene therapy. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Ophthalmology 01/2013; · 5.45 Impact Factor
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Karin W Littink,
Maria M van Genderen,
Mary J van Schooneveld,
Linda Visser,
Frans C C Riemslag,
Jan E E Keunen,
Bjorn Bakker,
Marijke N Zonneveld,
Anneke I den Hollander,
Frans P M Cremers, L Ingeborgh van den Born
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ABSTRACT: To determine the genetic defect and to describe the clinical characteristics in patients with retinitis punctata albescens (RPA) and fundus albipunctatus (FAP).
Case series/observational study.
We included 13 patients affected by RPA or FAP.
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.
We assessed DNA sequence variants, best-corrected visual acuity, fundus appearance, visual field measurements, electroretinogram responses, optical coherence tomography, and fundus autofluorescence.
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.
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.
Ophthalmology 05/2012; 119(9):1899-906. · 5.45 Impact Factor
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Kornelia Neveling,
Rob W J Collin,
Christian Gilissen,
Ramon A C van Huet,
Linda Visser,
Michael P Kwint,
Sabine J Gijsen,
Marijke N Zonneveld,
Nienke Wieskamp,
Joep de Ligt, [......],
Ulrich Kellner,
Kari E Branham,
Anneke I den Hollander,
Alexander Hoischen,
Carel Hoyng,
B Jeroen Klevering, L Ingeborgh van den Born,
Joris A Veltman,
Frans P M Cremers,
Hans Scheffer
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ABSTRACT: Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retinal disease genes (n = 111) were captured and simultaneously analyzed using NGS in 100 RP patients without a molecular diagnosis. A systematic data analysis pipeline was developed and validated to prioritize and predict the pathogenicity of all genetic variants identified in each patient, which enabled us to reduce the number of potential pathogenic variants from approximately 1,200 to zero to nine per patient. Subsequent segregation analysis and in silico predictions of pathogenicity resulted in a molecular diagnosis in 36 RP patients, comprising 27 recessive, six dominant, and three X-linked cases. Intriguingly, De novo mutations were present in at least three out of 28 isolated cases with causative mutations. This study demonstrates the enormous potential and clinical utility of NGS in molecular diagnosis of genetically heterogeneous diseases such as RP. De novo dominant mutations appear to play a significant role in patients with isolated RP, having major implications for genetic counselling.
Human Mutation 02/2012; 33(6):963-72. · 5.69 Impact Factor
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Alberta A H J Thiadens,
T My Lan Phan,
Renate C Zekveld-Vroon,
Bart P Leroy, L Ingeborgh van den Born,
Carel B Hoyng,
Caroline C W Klaver,
Susanne Roosing,
Jan-Willem R Pott,
Mary J van Schooneveld,
Norka van Moll-Ramirez,
Maria M van Genderen,
Camiel J F Boon,
Anneke I den Hollander,
Arthur A B Bergen,
Elfride De Baere,
Frans P M Cremers,
Andrew J Lotery
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ABSTRACT: To evaluate the clinical course, genetic etiology, and visual prognosis in patients with cone dystrophy (CD) and cone-rod dystrophy (CRD).
Clinic-based, longitudinal, multicenter study.
Consecutive probands with CD (N = 98), CRD (N = 83), and affected relatives (N = 41 and N = 17, respectively) from various ophthalmogenetic clinics in The Netherlands, Belgium, and the United Kingdom.
Data on best-corrected Snellen visual acuity, color vision, ophthalmoscopy, fundus photography, Goldmann perimetry, and full-field standard electroretinogram (ERG) from all patients were registered from medical charts over a mean follow-up of 19 years. The ABCA4, CNGB3, KCNV2, PDE6C, and RPGR genes were analyzed by direct sequencing in autosomal recessive (AR) and X-linked (XL), respectively. Genotyping was not undertaken for autosomal-dominant cases.
The 10-year progression of all clinical parameters and cumulative lifetime risk of low vision and legal blindness were assessed.
The mean age onset for CD was 16 years (standard deviation, 11), and of CRD 12 years (standard deviation, 11; P = 0.02). The pattern of inheritance was AR in 92% of CD and 90% of CRD. Ten years after diagnosis, 35% of CD and 51% of CRD had a bull's eye maculopathy; 70% of CRD showed absolute peripheral visual field defects and 37% of CD developed rod involvement on ERG. The mean age of legal blindness was 48 (standard error [SE], 3.1) years in CD, and 35 (SE, 1.1; P<0.001) years in CRD. ABCA4 mutations were found in 8 of 90 (9%) of AR-CD, and in 17 of 65 (26%) of AR-CRD. Other mutations were detected in CNGB3 (3/90; 3%), KCNV2 (4/90; 4%), and in PDE6C (1/90; 1%). The RPGR gene was mutated in the 2 XL-CD and in 4 of 5 (80%) of XL-CRD. ABCA4 mutations as well as age of onset <20 years were significantly associated with a faster progression to legal blindness (P<0.001).
Although CD had a slightly more favorable clinical course than CRD, both disorders progressed to legal blindness in the majority of patients. Mutations in the ABCA4 gene and early onset of disease were independent prognostic parameters for visual loss. Our data may serve as an aid in counseling patients with progressive cone disorders.
Ophthalmology 01/2012; 119(4):819-26. · 5.45 Impact Factor
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ABSTRACT: This study investigated the centrosomal protein, 290-KD (CEP290) associated genotype and ocular and extra-ocular phenotype in 18 patients with Leber congenital amaurosis (LCA).
Eighteen patients with LCA from 14 families with mutations in the CEP290 gene were identified with sequencing or with heteroduplex analysis. Ophthalmic examinations were performed on all patients. Scans of the central nervous system were reassessed in three patients and obtained in two. Renal function was evaluated in all patients. Ultrasonography of the kidneys was performed in six patients.
Eight patients (from five families) carried the c.2991+1655A>G mutation homozygously. Nine solitary patients carried this variant combined with a nonsense, frameshift, or splice site mutation on the second allele. One new nonsense mutation was identified: c.1078C>T. Fourteen patients (from 12 families) had been completely blind from birth or had light perception. The best-recorded visual acuity was 20/200. Peripheral fundus changes appeared to be progressive with a relatively preserved posterior pole. Novel ophthalmic features for the CEP290 phenotype were Coats-like exudative vasculopathy in two patients, a small chorioretinal coloboma in one patient, and well defined, small, atrophic spots at the level of the retinal pigment epithelium causing a dot-like appearance in five patients. Some CEP290 patients exhibited systemic abnormalities. We found abnormal proprioception in two patients and mild mental retardation in one. One patient was infertile due to immobile spermatozoa. No renal abnormalities were detected.
CEP290-associated LCA has a severe, progressive, and clinically identifiable phenotype. Distinct extra-ocular findings were noted, which may be attributed to ciliary dysfunction.
Molecular vision 01/2012; 18:412-25. · 2.20 Impact Factor
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ABSTRACT: Mutations in the retinitis pigmentosa 1 (RP1) gene are a common cause of autosomal dominant retinitis pigmentosa (adRP), and have also been found to cause autosomal recessive RP (arRP) in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39) are located in the 4(th) and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3(rd) exon of RP1 (c.686delC; p.P229QfsX35) found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated Rp1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as Rp1 transgenic mice carrying a wild-type BAC Rp1 transgene. The Rp1-Q662X allele produces a truncated Rp1 protein, and homozygous Rp1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC Rp1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled.
PLoS ONE 01/2012; 7(8):e43251. · 4.09 Impact Factor
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ABSTRACT: Mutations in the RPGR gene predominantly cause rod photoreceptor disorders with a large variability in clinical course. In this report, we describe two families with mutations in this gene and cone involvement.
We investigated an X-linked cone dystrophy family (1) with 25 affected males, 25 female carriers, and 21 non-carriers, as well as a small family (2) with one affected and one unaffected male. The RPGR gene was analyzed by direct sequencing. All medical records were evaluated, and all available data on visual acuity, color vision testing, ophthalmoscopy, fundus photography, fundus autofluorescence, Goldmann perimetry, SD-OCT, dark adaptation, and full-field electroretinography (ERG) were registered. Cumulative risks of visual loss were studied with Kaplan-Meier product-limit survival analysis.
Both families had a frameshift mutation in ORF15 of the RPGR gene; family 1 had p.Ser1107ValfsX4, and family 2 had p.His1100GlnfsX10. Mean follow up was 13 years (SD 10). Virtually all affected males showed reduced photopic and normal scotopic responses on ERG. Fifty percent of the patients had a visual acuity of <0.5 at age 35 years (SE 2.2), and 75% of the patients was legally blind at age 60 years (SE 2.3). Female carriers showed no signs of ocular involvement.
This report describes the clinical course and visual prognosis in two families with cone dystrophy due to RPGR mutations in the 3' terminal region of ORF15. Remarkable features were the consistent, late-onset phenotype, the severe visual outcome, and the non-expression in female carriers. Expression of RPGR mutations in this particular region appears to be relatively homogeneous and predisposed to cones.
Albrecht von Graæes Archiv für Ophthalmologie 08/2011; 249(10):1527-35. · 2.17 Impact Factor
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Rıza Köksal Ozgül,
Anna M Siemiatkowska,
Didem Yücel,
Connie A Myers,
Rob W J Collin,
Marijke N Zonneveld,
Avigail Beryozkin,
Eyal Banin,
Carel B Hoyng, L Ingeborgh van den Born,
Ron Bose,
Wei Shen,
Dror Sharon,
Frans P M Cremers,
B Jeroen Klevering,
Anneke I den Hollander,
Joseph C Corbo
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ABSTRACT: A fundamental challenge in analyzing exome-sequence data is distinguishing pathogenic mutations from background polymorphisms. To address this problem in the context of a genetically heterogeneous disease, retinitis pigmentosa (RP), we devised a candidate-gene prioritization strategy called cis-regulatory mapping that utilizes ChIP-seq data for the photoreceptor transcription factor CRX to rank candidate genes. Exome sequencing combined with this approach identified a homozygous nonsense mutation in male germ cell-associated kinase (MAK) in the single affected member of a consanguineous Turkish family with RP. MAK encodes a cilium-associated mitogen-activated protein kinase whose function is conserved from the ciliated alga, Chlamydomonas reinhardtii, to humans. Mutations in MAK orthologs in mice and other model organisms result in abnormally long cilia and, in mice, rapid photoreceptor degeneration. Subsequent sequence analyses of additional individuals with RP identified five probands with missense mutations in MAK. Two of these mutations alter amino acids that are conserved in all known kinases, and an in vitro kinase assay indicates that these mutations result in a loss of kinase activity. Thus, kinase activity appears to be critical for MAK function in humans. This study highlights a previously underappreciated role for CRX as a direct transcriptional regulator of ciliary genes in photoreceptors. In addition, it demonstrates the effectiveness of CRX-based cis-regulatory mapping in prioritizing candidate genes from exome data and suggests that this strategy should be generally applicable to a range of retinal diseases.
The American Journal of Human Genetics 08/2011; 89(2):253-64. · 10.60 Impact Factor
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ABSTRACT: To investigate COL9A1 in two families suggestive of autosomal recessive Stickler syndrome and to delineate the associated phenotype.
The probands of two consanguineous autosomal recessive Stickler families were evaluated for homozygosity using SNP microarray in one and haplotype analysis in the other. Subsequently, the entire COL9A1 open reading frame was analyzed by DNA sequencing in all members of the respective families. Several family members were investigated for dysmorphic features as well as ophthalmic, audiologic, and radiologic abnormalities.
A novel homozygous COL9A1 mutation (p.R507X) was identified in two affected Turkish sisters, and the previously published mutation (p.R295X) was found in a Moroccan boy. Ophthalmic assessment revealed myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Intervertebral disc bulging was observed in one patient and in two heterozygous carriers of the p.R507X mutation.
A second, novel mutation was identified in COL9A1, causing autosomal recessive Stickler syndrome together with the previously described nucleotide change in two separate families. Although the overall phenotype was comparable to autosomal dominant Stickler, vitreous changes that may enable recognition of patients who are likely to carry mutations in COL9A1 were identified, and exudative retinal detachment was observed as a new finding in Stickler syndrome.
Investigative ophthalmology & visual science 03/2011; 52(7):4774-9. · 3.43 Impact Factor
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Rob W J Collin, L Ingeborgh van den Born,
B Jeroen Klevering,
Marta de Castro-Miró,
Karin W Littink,
Kentar Arimadyo,
Maleeha Azam,
Volkan Yazar,
Marijke N Zonneveld,
Codrut C Paun,
Anna M Siemiatkowska,
Tim M Strom,
Jayne Y Hehir-Kwa,
Hester Y Kroes,
Jan-Tjeerd H N de Faber,
Mary J van Schooneveld,
John R Heckenlively,
Carel B Hoyng,
Anneke I den Hollander,
Frans P M Cremers
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ABSTRACT: 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.
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.
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.
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.
Investigative ophthalmology & visual science 01/2011; 52(5):2227-39. · 3.43 Impact Factor
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Karin W Littink,
Robert K Koenekoop, L Ingeborgh van den Born,
Rob W J Collin,
Luminita Moruz,
Joris A Veltman,
Susanne Roosing,
Marijke N Zonneveld,
Amer Omar,
Mahshad Darvish,
Irma Lopez,
Hester Y Kroes,
Maria M van Genderen,
Carel B Hoyng,
Klaus Rohrschneider,
Mary J van Schooneveld,
Frans P M Cremers,
Anneke I den Hollander
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ABSTRACT: To determine the genetic defect and to describe the clinical characteristics in a cohort of mainly nonconsanguineous cone-rod dystrophy (CRD) patients.
One hundred thirty-nine patients with diagnosed CRD were recruited. Ninety of them were screened for known mutations in ABCA4, and those carrying one or two mutations were excluded from further research. Genome-wide homozygosity mapping was performed in the remaining 108. Known genes associated with autosomal recessive retinal dystrophies located within a homozygous region were screened for mutations. Patients in whom a mutation was detected underwent further ophthalmic examination.
Homozygous sequence variants were identified in eight CRD families, six of which were nonconsanguineous. The variants were detected in the following six genes: ABCA4, CABP4, CERKL, EYS, KCNV2, and PROM1. Patients carrying mutations in ABCA4, CERKL, and PROM1 had typical CRD symptoms, but a variety of retinal appearances on funduscopy, optical coherence tomography, and autofluorescence imaging.
Homozygosity mapping led to the identification of new mutations in consanguineous and nonconsanguineous patients with retinal dystrophy. Detailed clinical characterization revealed a variety of retinal appearances, ranging from nearly normal to extensive retinal remodeling, retinal thinning, and debris accumulation. Although CRD was initially diagnosed in all patients, the molecular findings led to a reappraisal of the diagnosis in patients carrying mutations in EYS, CABP4, and KCNV2.
Investigative ophthalmology & visual science 11/2010; 51(11):5943-51. · 3.43 Impact Factor
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ABSTRACT: Achromatopsia (ACHM) is a congenital autosomal recessive cone disorder with a presumed stationary nature and only a few causative genes. Animal studies suggest that ACHM may be a good candidate for corrective gene therapy. Future implementation of this therapy in humans requires the presence of viable cone cells in the retina. In this study the presence of cone cells in ACHM was determined, as a function of age.
The appearance and thickness of all retinal layers were evaluated by spectral-domain optical coherence tomography (SD-OCT) in 40 ACHM patients (age range, 4-70 years) with known mutations in the CNGB3, CNGA3, and PDE6C genes. A comparison was made with 55 healthy age-matched control subjects.
The initial feature of cone cell decay was loss of inner and outer segments with disruption of the ciliary layer on OCT, which was observed as early as 8 years of age. Cone cell loss further progressed with age and occurred in 8 (42%) of 19 patients below 30 years and in 20 (95%) of 21 of those aged 30+ years. Retinal thickness was significantly thinner in the fovea of all patients (126 μm in ACHM vs. 225 μm in the control; P < 0.001) and correlated with age (β = 0.065; P = 0.011). Foveal hypoplasia was present in 24 (80%) of 30 patients and in 1 of 55 control subjects.
ACHM is not a stationary disease. The first signs of cone cell loss occur in early childhood. If intervention becomes available in the future, the present results imply that it should be applied in the first decade.
Investigative ophthalmology & visual science 11/2010; 51(11):5952-7. · 3.43 Impact Factor
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Karin W Littink, L Ingeborgh van den Born,
Robert K Koenekoop,
Rob W J Collin,
Marijke N Zonneveld,
Ellen A W Blokland,
Hayat Khan,
Thomas Theelen,
Carel B Hoyng,
Frans P M Cremers,
Anneke I den Hollander,
B Jeroen Klevering
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ABSTRACT: 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.
Case series.
Two hundred forty-five patients affected by autosomal recessive RP.
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).
DNA sequence variants, best-corrected visual acuity, fundus appearance, visual field assessments using Goldmann kinetic perimetry, electroretinogram responses, and OCT images.
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.
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.
Ophthalmology 10/2010; 117(10):2026-33, 2033.e1-7. · 5.45 Impact Factor
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The British journal of ophthalmology 10/2010; 95(1):153; author reply 153-4. · 2.92 Impact Factor
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Alejandro Estrada-Cuzcano,
Robert K Koenekoop,
Frauke Coppieters,
Susanne Kohl,
Irma Lopez,
Rob W J Collin,
Elfride B W De Baere,
Debbie Roeleveld,
Jonah Marek,
Antje Bernd,
Klaus Rohrschneider, L Ingeborgh van den Born,
Françoise Meire,
Irene H Maumenee,
Samuel G Jacobson,
Carel B Hoyng,
Eberhart Zrenner,
Frans P M Cremers,
Anneke I den Hollander
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ABSTRACT: Leber congenital amaurosis (LCA) is genetically heterogeneous, with 15 genes identified thus far, accounting for ∼70% of LCA patients. The aim of the present study was to identify new genetic causes of LCA.
Homozygosity mapping in >150 LCA patients of worldwide origin was performed with high-density SNP microarrays to identify new disease-causing genes.
In three isolated LCA patients, the authors identified large homozygous regions on chromosome 3 encompassing the IQCB1 gene, which has been associated with Senior-Loken syndrome (SLSN), characterized by nephronophthisis and retinal degeneration. Mutation analysis of IQCB1 in these three patients and a subsequent cohort of 222 additional LCA patients identified frameshift and nonsense mutations in 11 patients diagnosed with LCA. On re-inspection of the patient's disease status, seven were found to have developed SLSN, but four maintained the diagnosis of LCA as the kidney function remained normal.
Results show that the onset of renal failure in patients with IQCB1 mutations is highly variable, and that mutations are also found in LCA patients without nephronophthisis, rendering IQCB1 a new gene for LCA. However, these patients are at high risk for developing renal failure, which in early stages is often not recognized and can cause sudden death from fluid and electrolyte imbalance. It is therefore recommended that all LCA patients be screened for IQCB1 mutations, to follow them more closely for kidney disease.
Investigative ophthalmology & visual science 09/2010; 52(2):834-9. · 3.43 Impact Factor
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Dikla Bandah-Rozenfeld,
Rob W J Collin,
Eyal Banin, L Ingeborgh van den Born,
Karlien L M Coene,
Anna M Siemiatkowska,
Lina Zelinger,
Muhammad I Khan,
Dirk J Lefeber,
Inbar Erdinest, [......],
Francesca Simonelli,
Krysta Voesenek,
Ellen A W Blokland,
Tim M Strom,
Caroline C W Klaver,
Raheel Qamar,
Sandro Banfi,
Frans P M Cremers,
Dror Sharon,
Anneke I den Hollander
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ABSTRACT: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP.
The American Journal of Human Genetics 08/2010; 87(2):199-208. · 10.60 Impact Factor
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Karin W Littink,
Jan-Willem R Pott,
Rob W J Collin,
Hester Y Kroes,
Joke B G M Verheij,
Ellen A W Blokland,
Marta de Castro Miró,
Carel B Hoyng,
Caroline C W Klaver,
Robert K Koenekoop,
Klaus Rohrschneider,
Frans P M Cremers, L Ingeborgh van den Born,
Anneke I den Hollander
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ABSTRACT: 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.
Investigative ophthalmology & visual science 07/2010; 51(7):3646-52. · 3.43 Impact Factor
