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2.
Invest Ophthalmol Vis Sci ; 60(10): 3432-3446, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390656

RESUMO

Purpose: Cone/cone-rod dystrophy is a large group of retinal disorders with both phonotypic and genetic heterogeneity. The purpose of this study was to characterize the phenotype of eight patients from seven families harboring POC1B mutations in a cohort of the Japan Eye Genetics Consortium (JEGC). Methods: Whole-exome sequencing with targeted analyses identified homozygous or compound heterozygous mutations of the POC1B gene in 7 of 548 families in the JEGC database. Ophthalmologic examinations including the best-corrected visual acuity, perimetry, fundus photography, fundus autofluorescence imaging, optical coherence tomography, and full-field and multifocal electroretinography (ERGs) were performed. Results: There were four men and four women whose median age at the onset of symptoms was 15.6 years (range, 6-23 years) and that at the time of examination was 40.3 years (range, 22-67 years). The best-corrected visual acuity ranged from -0.08 to 1.52 logMAR units. The funduscopic appearance was normal in all the cases except in one case with faint mottling in the fovea. Optical coherence tomography revealed an absence of the interdigitation zone and blurred ellipsoid zone in the posterior pole, but the foveal structures were preserved in three cases. The full-field photopic ERGs were reduced or extinguished with normal scotopic responses. The central responses of the multifocal ERGs were preserved in two cases. The diagnosis was either generalized cone dystrophy in five cases or cone dystrophy with foveal sparing in three cases. Conclusions: Generalized or peripheral cone dystrophy with normal funduscopic appearance is the representative phenotype of POC1B-associated retinopathy in our cohort.

3.
BMC Cardiovasc Disord ; 19(1): 174, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337358

RESUMO

BACKGROUND: We aimed to determine the mutation yield and clinical applicability of "molecular autopsy" following sudden arrhythmic death syndrome (SADS) by validating and utilizing low-cost high-throughput technologies: Fluidigm Access Array PCR-enrichment with Illumina HiSeq 2000 next generation sequencing (NGS). METHODS: We validated and optimized the NGS platform with a subset of 46 patients by comparison with Sanger sequencing of coding exons of major arrhythmia risk-genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2). A combined large multi-ethnic international SADS cohort was sequenced utilizing the NGS platform to determine overall molecular yield; rare variants identified by NGS were subsequently reconfirmed by Sanger sequencing. RESULTS: The NGS platform demonstrated 100% sensitivity for pathogenic variants as well as 87.20% sensitivity and 99.99% specificity for all substitutions (optimization subset, n = 46). The positive predictive value (PPV) for NGS for rare substitutions was 16.0% (27 confirmed rare variants of 169 positive NGS calls in 151 additional cases). The overall molecular yield in 197 multi-ethnic SADS cases (mean age 22.6 ± 14.4 years, 68% male) was 5.1% (95% confidence interval 2.0-8.1%), representing 10 cases carrying pathogenic or likely pathogenic risk-mutations. CONCLUSIONS: Molecular autopsy with Fluidigm Access Array and Illumina HiSeq NGS utilizing a selected panel of LQTS/BrS and CPVT risk-genes offers moderate diagnostic yield, albeit requiring confirmatory Sanger-sequencing of mutational variants.

4.
Ann Neurol ; 86(3): 368-383, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31298765

RESUMO

OBJECTIVE: Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality. METHODS: Linkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model. RESULTS: We defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied. INTERPRETATION: SSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.

6.
Am J Ophthalmol ; 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31077665

RESUMO

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity. Design; Retrospective case-series METHODS: Twelve patients (ten families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS). RESULTS: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and two missense variants were identified. Subsequent bone density measurement, identified osteoporosis in one proband.Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other two had bilateral retinal folds. Four heterozygous variants were found, including two large deletions not identified on Sanger sequencing or WES.Finally, a family of two children with learning difficulties, abnormal peripheral retinal vasculogenesis and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6.Three families remain unsolved following WES and WGS. CONCLUSIONS: Molecular diagnosis has been achieved in seven of ten families investigated including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in three families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.

7.
Ophthalmology ; 126(10): 1432-1444, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31028767

RESUMO

PURPOSE: To describe the clinical and genetic characteristics of the cohort enrolled in the East Asian studies of occult macular dystrophy (OMD). DESIGN: International, multicenter, retrospective cohort studies. PARTICIPANTS: A total of 36 participants from 21 families with a clinical diagnosis of OMD and harboring pathogenic RP1L1 variants (i.e., Miyake disease) were enrolled from 3 centers in Japan, China, and South Korea. METHODS: A detailed history was obtained, and comprehensive ophthalmological examinations including spectral-domain OCT were performed. All detected sequence variants in the RP1L1 gene were reviewed, and in silico analysis was performed, including allele frequency analyses and pathogenicity predictions. MAIN OUTCOME MEASURES: Onset of disease, visual acuity (VA) converted to the logarithm of the minimum angle of resolution (logMAR), OCT findings, and effect of detected variants. RESULTS: Eleven families from Japan, 6 from South Korea, and 4 from China were recruited. There were 12 female and 24 male participants. The median age of onset was 25.5 years (range, 2-73), and the median age at the latest examination was 46.0 years (range, 11-86). The median VA (logMAR) was 0.65 (range, -0.08-1.22) in the right eye and 0.65 (-0.08-1.10) in the left eye. A significant correlation between onset of disease and VA was revealed. The Classical morphologic phenotype showing both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors was demonstrated in 30 patients (83.3%), and subtle photoreceptor architectural changes were demonstrated in 6 patients (16.6%). Eight pathogenic RP1L1 variants were identified, including 6 reported variants and 1 novel variant: p.R45W, p.T1194M/p.T1196I (complex), p.S1199C, p.G1200A, p.G1200D, p.V1201G, and p.S1198F, respectively. Two variants were recurrent: p.R45W (11 families, 52.4%) and p.S1199C (5 families, 23.8%). The pathogenic missense variants in 10 families (47.6%) were located within the previously reported unique motif, including 6 amino acids (1196-1201). CONCLUSIONS: There is a large spectrum of clinical findings in Miyake disease, including various onset of disease and VA, whereas the characteristic photoreceptor microstructures were shared in most cases. Two hot spots including amino acid numbers 45 and 1196-1201 in the RP1L1 gene were confirmed in the East Asian population.

8.
Hum Mutat ; 40(5): 578-587, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30710461

RESUMO

The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14-16.2 that overlaps the North Carolina macular dystrophy (NCMD) locus MCDR1. NCMD is a nonprogressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Whole genome sequencing was performed to interrogate structural variants (SVs) and single nucleotide variants (SNVs) in eight individuals, six affected individuals from two families with PBCRA, and two individuals from an additional family with a related developmental macular dystrophy. A SNV (chr6:100,046,804T>C), located 7.8 kb upstream of the PRDM13 gene, was shared by all PBCRA-affected individuals in the disease locus. Haplotype analysis suggested that the variant arose independently in the two families. The two affected individuals from Family 3 were screened for rare variants in the PBCRA and NCMD loci. This revealed a de novo variant in the proband, 21 bp from the first SNV (chr6:100,046,783A>C). This study expands the noncoding variant spectrum upstream of PRDM13 and suggests altered spatio-temporal expression of PRDM13 as a candidate disease mechanism in the phenotypically distinct but related conditions, NCMD and PBCRA.

9.
Genet Med ; 21(8): 1761-1771, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30670881

RESUMO

PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.

10.
Genet Med ; 21(8): 1751-1760, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30643219

RESUMO

PURPOSE: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability. METHODS: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects. RESULTS: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects. CONCLUSION: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

11.
Genome Med ; 10(1): 95, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30526634

RESUMO

BACKGROUND: Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. METHODS: We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. RESULTS: We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. CONCLUSIONS: Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.


Assuntos
Genoma Humano , Variação Estrutural do Genoma , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Proteínas Serina-Treonina Quinases/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética
12.
Ophthalmic Genet ; 39(6): 763-770, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30451557

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is a common sight threatening condition. However, there are a number of monogenic macular dystrophies that are clinically similar to AMD, which can potentially provide pathogenetic insights. METHODS: Three siblings from a non-consanguineous Greek-Cypriot family reported central visual disturbance and nyctalopia. The patients had full ophthalmic examinations and color fundus photography, spectral-domain ocular coherence tomography and scanning laser ophthalmoscopy. Targeted polymerase chain reaction (PCR) was performed as a first step to attempt to identify suspected mutations in C1QTNF5 and TIMP3 followed by whole genome sequencing. RESULTS: The three patients were noted to have symptoms of nyctalopia, early paracentral visual field loss and, in older patients, central vision loss. Imaging identified pseudodrusen, retinal atrophy and RPE-Bruch's membrane separation. Whole genome sequencing of the proband revealed two novel heterozygous variants in C1QTNF5, c.556C>T, and c.569C>G. The mutation segregated with disease in this family, occurred in cis, and resulted in missense amino acid changes P186S and S190W in C1QTNF5. In silico modeling of the variants revealed that the S190W mutations was likely to have the greatest pathologic effect and that the combination of the mutations was likely to have an additive effect. CONCLUSIONS: The novel mutations in C1QTNF5 identified here expand the genotypic spectrum of mutations causing late-onset retinal dystrophy.

13.
Invest Ophthalmol Vis Sci ; 59(12): 4812-4820, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347075

RESUMO

Purpose: We describe the clinical features in two pedigrees with dominantly inherited retinopathy segregating the previously reported frameshifting mutation, c.836dupG (p.Ile280Asn*78) in the terminal exon of the RGR gene, and compare their haplotypes to that of the previously reported pedigree. Methods: The probands were ascertained at West Virginia University Eye Institute (WVU) and Moorfields Eye Hospital (MEH) through next generation sequencing (NGS) and whole genome sequencing (WGS) respectively. Clinical data included visual acuity (VA), visual fields, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Haplotype analysis was performed using Sanger sequencing of the DNA from the molecularly ascertained individuals from the three pedigrees. Results: Nine heterozygous mutation carriers were identified in two families. Four carriers were asymptomatic; five carriers had variable VA reduction, visual field constriction, and experienced difficulty under dim illumination. Fundus examination of the asymptomatic carriers showed diffuse or reticular pigmentation of the retina; the symptomatic carriers had chorioretinal atrophy. FAF imaging showed widespread signal loss in advanced retinopathy, and reticular hyperautofluorescence in mild cases. OCT showed loss of outer retinal lamina in advanced disease. ERG showed moderate-to-severe rod-cone dysfunction in two symptomatic carriers; and was normal in three asymptomatic carriers. A shared haplotype flanking the mutation of up to 6.67 Mb was identified in both families. Within this region, 1.27 Mb were shared with the first family reported with this retinopathy. Conclusions: The clinical data suggest a variable and slow degeneration of the RPE. A shared chromosomal segment surrounding the RGR gene suggests a single ancestral mutational event underlying all three families.

14.
Mol Vis ; 24: 603-612, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210231

RESUMO

Purpose: Mutations in ARL2BP, encoding ADP-ribosylation factor-like 2 binding protein, have recently been implicated as a cause of autosomal recessive retinitis pigmentosa (arRP), with three homozygous variants identified to date. In this study, we performed next-generation sequencing to reveal additional arRP cases associated with ARL2BP variants. Methods: Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in 1,051 unrelated individuals recruited for the UK Inherited Retinal Disease Consortium and NIHR-BioResource Rare Diseases research studies. Sanger sequencing was used to validate the next-generation sequencing data, and reverse transcriptase (RT)-PCR analysis was performed on RNA extracted from blood from affected individuals to test for altered splicing of ARL2BP. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography. Results: Homozygous variants in ARL2BP (NM_012106.3) were identified in two unrelated individuals with RP. The variants, c.207+1G>A and c.390+5G>A, at conserved splice donor sites for intron 3 and intron 5, respectively, were predicted to alter the pre-mRNA splicing of ARL2BP. RT-PCR spanning the affected introns revealed that both variants caused abnormal splicing of ARL2BP in samples from affected individuals. Conclusions: This study identified two homozygous variants in ARL2BP as a rare cause of arRP. Further studies are required to define the underlying disease mechanism causing retinal degeneration as a result of mutations in ARL2BP and any phenotype-genotype correlation associated with residual levels of the wild-type transcript.


Assuntos
Proteínas de Transporte/genética , Mutação , Retinite Pigmentosa/genética , Adulto , Análise Mutacional de DNA , Eletrorretinografia , Exoma , Feminino , Genes Recessivos , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , História do Século XVI , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Processamento de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tomografia de Coerência Óptica , Sequenciamento Completo do Genoma
15.
Eur J Hum Genet ; 26(11): 1713-1718, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30089822

RESUMO

1. NAME OF THE DISEASE (SYNONYMS): Primary congenital glaucoma (PCG). Glaucoma, congenital (GLC). 2. OMIM# OF THE DISEASE: 231300- GLC3A. 600975- GLC3B. 613085- GLC3C. 613086- GLC3D. 617272- GLC3E. 3. NAME OF THE ANALYSED GENES OR DNA/CHROMOSOME SEGMENTS: CYP1B1. LTBP2. MYOC. FOXC1. TEK. 4. OMIM# OF THE GENE(S): CYP1B1 MIM# 601771. LTBP2 MIM# 602091. MYOC MIM# 601652. FOXC1 MIM# 601090. TEK MIM# 600221. Review of the analytical and clinical validity, as well as of the clinical utility of DNA-based testing for variants in the CYP1B1, LTBP2 and MYOC gene(s) in ⊠ diagnostic, ⊠ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.

16.
PLoS Genet ; 14(8): e1007504, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30157172

RESUMO

We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.

18.
Eur J Hum Genet ; 26(5): 687-694, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29391521

RESUMO

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

19.
Retina ; 38(3): 620-628, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28234808

RESUMO

BACKGROUND: Albinism refers to a group of disorders primarily characterized by hypopigmentation. Affected individuals usually manifest both ocular and cutaneous features of the disease, but occasionally hair and skin pigmentation may appear normal. This is the case in ocular albinism, an X chromosome linked disorder resulting from mutation of GPR143. Female carriers may be recognized by a "mud-splatter" appearance in the peripheral retina. The macula is thought to be normal, however. METHODS: Obligate female carriers of pathogenic GPR143 alleles were recruited. Molecular confirmation of disease was performed only for atypical cases. Detailed retinal imaging was performed (colour fundus photography, optical coherence tomography, fundus autofluorescence. RESULTS: Eight individuals were ascertained. A novel GPR143 mutation was identified in one family (p.Gln328Ter). Foveal fundus autofluorescence was subjectively reduced in 6/6 patients imaged. A "tapetal-like" pattern of autofluorescence was visible at the macula in 3/6. Persistence of the inner retinal layers at the fovea was observed in 6/8 females. CONCLUSION: Female carriers of ocular albinism may manifest signs of retinal pigment epithelium mosaicism at the macula and the peripheral fundus. A tapetal-like reflex on fundus autofluorescence may be considered the macular correlate of "mud-splatter."


Assuntos
Albinismo Ocular/patologia , Retina/patologia , Adulto , Albinismo Ocular/genética , Proteínas do Olho/genética , Feminino , Heterozigoto , Humanos , Macula Lutea/patologia , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Estudos Prospectivos , Epitélio Pigmentado da Retina/patologia
20.
Hum Mutat ; 39(1): 80-91, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28967191

RESUMO

Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.


Assuntos
Genes Ligados ao Cromossomo X , Mutação de Sentido Incorreto , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/genética , Ribose-Fosfato Pirofosfoquinase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Ribose-Fosfato Pirofosfoquinase/química , Adulto Jovem
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