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1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
Invest Ophthalmol Vis Sci ; 62(7): 15, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34115091

RESUMO

When using spectral domain optical coherence tomography (SD-OCT) to inform the status of outer retina, we have noted discrete hyperreflective lesions extending through photoreceptor-attributable bands that have a similar presentation in multiple retinal diseases. These lesions present as either corrugated thickenings of interdigitation zone and ellipsoid zone bands or in later stages as rectangular or pyramidal shaped foci that extend radially through photoreceptor cell-attributable bands. In ABCA4-related and peripherin-2/RDS-disease (PRPH2/RDS), monogenic forms of retinopathy caused by mutations in proteins expressed in photoreceptor cells, these punctate lesions colocalize with fundus flecks in en face images. In fundus albipunctatus and retinitis punctata albescens, diseases caused by mutations in genes (retinol dehydrogenase 5, RDH5; and retinaldehyde-binding protein 1, RLBP1) encoding proteins of the visual cycle, these lesions manifest as white dot-like puncta. Similar aberrations in photoreceptor cell-attributable SD-OCT reflectivity layers manifest as reticular pseudodrusen (RPD) in short-wavelength fundus autofluorescence and near-infrared fundus autofluorescence fundus images and are linked to age-related macular degeneration a complex disease. Despite differences in the etiologies of retinal diseases presenting as fundus flecks, dots and RPD, underlying degenerative processes in photoreceptor cells are signified in SD-OCT scans by the loss of structural features that would otherwise define healthy photoreceptor cells at these foci.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Oxirredutases do Álcool/genética , Proteínas de Transporte/genética , Imagem Óptica/métodos , Doenças Retinianas , Epitélio Pigmentado da Retina , Adolescente , Correlação de Dados , Diagnóstico Diferencial , Progressão da Doença , Feminino , Fundo de Olho , Humanos , Masculino , Mutação , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Drusas Retinianas/patologia , Drusas Retinianas/fisiopatologia , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/fisiopatologia , Tomografia de Coerência Óptica/métodos
3.
Hum Mol Genet ; 30(14): 1293-1304, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-33909047

RESUMO

Over 1200 variants in the ABCA4 gene cause a wide variety of retinal disease phenotypes, the best known of which is autosomal recessive Stargardt disease (STGD1). Disease-causing variation encompasses all mutation categories, from large copy number variants to very mild, hypomorphic missense variants. The most prevalent disease-causing ABCA4 variant, present in ~ 20% of cases of European descent, c.5882G > A p.(Gly1961Glu), has been a subject of controversy since its minor allele frequency (MAF) is as high as ~ 0.1 in certain populations, questioning its pathogenicity, especially in homozygous individuals. We sequenced the entire ~140Kb ABCA4 genomic locus in an extensive cohort of 644 bi-allelic, i.e. genetically confirmed, patients with ABCA4 disease and analyzed all variants in 140 compound heterozygous and 10 homozygous cases for the p.(Gly1961Glu) variant. A total of 23 patients in this cohort additionally harbored the deep intronic c.769-784C > T variant on the p.(Gly1961Glu) allele, which appears on a specific haplotype in ~ 15% of p.(Gly1961Glu) alleles. This haplotype was present in 5/7 of homozygous cases, where the p.(Gly1961Glu) was the only known pathogenic variant. Three cases had an exonic variant on the same allele with the p.(Gly1961Glu). Patients with the c.[769-784C > T;5882G > A] complex allele exhibit a more severe clinical phenotype, as seen in compound heterozygotes with some more frequent ABCA4 mutations, e.g. p.(Pro1380Leu). Our findings indicate that the c.769-784C > T variant is major cis-acting modifier of the p.(Gly1961Glu) allele. The absence of such additional allelic variation on most p.(Gly1961Glu) alleles largely explains the observed paucity of affected homozygotes in the population.

4.
JAMA Ophthalmol ; 139(6): 654-657, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792637

RESUMO

Importance: Probing differences in disease prevalence between sexes is challenging, especially in mendelian diseases. Independent replication of any association study is warranted. Objective: To evaluate whether the recently reported association between sex and mild ABCA4 alleles among patients with autosomal recessive Stargardt disease (STGD1) is reproducible. Design, Setting, and Participants: Sequencing and clinical data from 644 unrelated patients with genetically confirmed STGD1 were analyzed in a cross-sectional study at the Department of Ophthalmology, Columbia University, New York, New York. Data were collected from June 1999 to October 2020. Main Outcomes and Measures: Sex, best-corrected visual acuity, and age at onset among patients with STGD1 with and without mild ABCA4 alleles. Results: A total of 644 patients with STGD1 with at least 2 pathogenic variants were included in the study. The mean (SD) age was 38.6 (17.2) years, and 352 participants (54.7%) were female. The proportion of women was slightly higher in the entire cohort and in most allele categories, although none of the differences were statistically significant. The proportion of women carrying the c.5603A>T p.(Asn1868Ile) allele was 7% (95% CI, -9 to 23) higher than in the subgroup not carrying any mild alleles (P = .32). The proportion of women carrying the c.5882G>A p.(Gly1961Glu) allele was 2% (95% CI, -12 to 15) higher than in the subgroup not carrying any mild alleles (P = .77). The difference between the total mild allele subcohort and the no mild allele subcohort was 3% (95% CI, -8 to 14; P = .48). Compared with patients in the no mild allele category, patients with mild alleles exhibited significantly delayed disease onset (mean [SD] age, 23.1 [11.6] for those with the c.5882G>A allele and 31.7 [13.5] years for those with the c.5603A>T allele vs 18.6 [11.8] years for those with no mild alleles; P < .001) and preserved visual acuity (5882G>A subgroup: mean [SD] logMAR, 0.65 [0.66]; 95% CI, 0.63-0.68; c.5603A>T subgroup: 0.64 [0.39]; 95% CI, 0.58-0.70; those with no mild alleles: 1.00 [0.57]; 95% CI, 0.96-1.03; P < .001). Conclusions and Relevance: This independent analysis of a larger cohort of individuals with Stargardt disease did not support the association between sex and certain mild ABCA4 alleles. While sex is undoubtedly an important variable in medicine, its putative association with clinical outcomes should be rigorously scrutinized.

6.
Commun Biol ; 4(1): 274, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33654266

RESUMO

Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci (p < 5 × 10-8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR = 3.9 × 10-47) and glycine depletion (FDR = 0.006) as well as alanine abundance (FDR = 0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p = 0.009). This represents the largest genetic study on MacTel to date and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health.


Assuntos
Metabolismo Energético/genética , Polimorfismo de Nucleotídeo Único , Retina/metabolismo , Telangiectasia Retiniana/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Locos de Características Quantitativas , Telangiectasia Retiniana/diagnóstico , Telangiectasia Retiniana/metabolismo , Medição de Risco , Fatores de Risco , Transcriptoma
7.
Nat Metab ; 3(3): 366-377, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33758422

RESUMO

Macular telangiectasia type 2 (MacTel) is a progressive, late-onset retinal degenerative disease linked to decreased serum levels of serine that elevate circulating levels of a toxic ceramide species, deoxysphingolipids (deoxySLs); however, causal genetic variants that reduce serine levels in patients have not been identified. Here we identify rare, functional variants in the gene encoding the rate-limiting serine biosynthetic enzyme, phosphoglycerate dehydrogenase (PHGDH), as the single locus accounting for a significant fraction of MacTel. Under a dominant collapsing analysis model of a genome-wide enrichment analysis of rare variants predicted to impact protein function in 793 MacTel cases and 17,610 matched controls, the PHGDH gene achieves genome-wide significance (P = 1.2 × 10-13) with variants explaining ~3.2% of affected individuals. We further show that the resulting functional defects in PHGDH cause decreased serine biosynthesis and accumulation of deoxySLs in retinal pigmented epithelial cells. PHGDH is a significant locus for MacTel that explains the typical disease phenotype and suggests a number of potential treatment options.


Assuntos
Haploinsuficiência , Fosfoglicerato Desidrogenase/genética , Telangiectasia Retiniana/genética , Serina/biossíntese , Estudos de Coortes , Humanos , Fenótipo , Epitélio Pigmentado da Retina/metabolismo
8.
Transl Vis Sci Technol ; 10(1): 3, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33505770

RESUMO

Purpose: To compare the detection of retinal pigment epithelium (RPE) atrophy in short-wavelength (SW-AF) and near-infrared autofluorescence (NIR-AF) images in Stargardt disease (STGD1) patients. Methods: SW-AF and NIR-AF images (115 eyes from 115 patients) were analyzed by two independent graders. Hypoautofluorescent (hypoAF) areas, indicative of RPE atrophy, were measured, and the two modalities were compared. Results: Patients were segregated into four groups: nascent (6 [5%]), widespread (21 [18%]), discrete (55 [48%]), and chorioretinal atrophy (33 [29%]). The areas of hypoAF were larger in NIR-AF compared to SW-AF images in discrete (3.9 vs. 2.2 mm2, P < 0.001) and chorioretinal atrophy (12.7 vs. 11.4 mm2, P = 0.015). Similar findings were observed qualitatively in nascent and widespread atrophy patients. Using the area linear model (ALM), lesion area increased at similar rates in SW-AF and NIR-AF images of discrete atrophy (0.20 vs. 0.32 mm2/y, P = 0.275) and chorioretinal atrophy (1.30 vs. 1.74 mm2/y, P = 0.671). Using the radius linear model (RLM), the lesion effective radius also increased similarly in SW-AF and NIR-AF images in discrete (0.03 vs. 0.05 mm2/y, P = 0.221) and chorioretinal atrophy (0.08 vs. 0.10 mm2/y, P = 0.754) patients. Conclusions: NIR-AF reveals a larger area of RPE atrophy in STGD1 patients compared to SW-AF images, but rates of lesion enlargement in the two modalities are similar. Translational Relevance: Measurements of RPE atrophy by AF imaging are crucial for monitoring STGD1 disease progression and given our findings we advocate greater use of NIR-AF for patients.


Assuntos
Epitélio Pigmentado da Retina , Tomografia de Coerência Óptica , Atrofia/patologia , Angiofluoresceinografia , Humanos , Epitélio Pigmentado da Retina/patologia , Doença de Stargardt
9.
Eur J Ophthalmol ; : 1120672120957599, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32927963

RESUMO

INTRODUCTION: Mutations in the cone-rod homeobox (CRX) gene, a known cause of inherited retinal dystrophy, are characterized by extensive phenotypic heterogeneity. We describe a novel presentation of rod-cone dystrophy (RCD) phenocopying pigmented paravenous retinochoroidal atrophy associated with a mutation in CRX. CASE DESCRIPTION: A 53-year-old man and his 48-year-old brother presented with a history of progressive vision loss and nyctalopia. Fundus examination revealed a bull's eye lesion with chorioretinal atrophy and intraretinal pigment migration, while spectral-domain optical coherence tomography (SD-OCT) demonstrated retinal thinning with outer retinal atrophy. On short-wavelength autofluorescence (SW-AF) imaging, an atypical paravenous pattern of atrophy with a surrounding hyperautofluorescent border was observed. Full-field electroretinogram (ffERG) revealed a rod-cone pattern of dysfunction. A heterozygous pathogenic variant, c.119G>A:p.(Arg40Gln), in the CRX gene was identified in both brothers and segregated in their family. CONCLUSION: This case report broadens the currently known phenotypic presentations of CRX-associated retinopathy and suggests that mutations in CRX may be associated with pigmented paravenous retinochoroidal atrophy.

10.
Am J Ophthalmol ; 218: 40-53, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32445700

RESUMO

PURPOSE: To characterize the progression of optical gaps and expand the known etiologies of this phenotype. DESIGN: Retrospective cohort study. METHODS: Thirty-six patients were selected based on the identification of an optical gap on spectral-domain optical coherence tomography (OCT) from a large cohort of patients (N = 746) with confirmed diagnoses of inherited retinal dystrophy. The width and height of the gaps in 70 eyes of 36 patients were measured by 2 independent graders using the caliper tool on Heidelberg Explorer. Measurements of outer and central retinal thickness were also evaluated and correlated with gap dimensions. RESULTS: Longitudinal analysis confirmed the progressive nature of optical gaps in patients with Stargardt disease, achromatopsia, occult macular dystrophy, and cone dystrophies (P < .003). Larger changes in gap width were noted in patients with Stargardt disease (78.1 µm/year) and cone dystrophies (31.9 µm/year) compared with patients with achromatopsia (16.2 µm/year) and occult macular dystrophy (15.4 µm/year). Gap height decreased in patients with Stargardt disease (6.5 µm/year; P = .02) but increased in patients with achromatopsia (3.3 µm/year) and occult macular dystrophy (1.2 µm/year). Gap height correlated with measurements of central retinal thickness at the fovea (r = 0.782, P = .00012). Interocular discordance of the gap was observed in 7 patients. Finally, a review of all currently described etiologies of optical gap was summarized. CONCLUSION: The optical gap is a progressive phenotype seen in an increasing number of etiologies. This progressive nature suggests a use as a biomarker in the understanding of disease progression. Interocular discordance of the phenotype may be a feature of Stargardt disease and cone dystrophies.


Assuntos
Biomarcadores , Defeitos da Visão Cromática/diagnóstico por imagem , Distrofias de Cones e Bastonetes/diagnóstico por imagem , Degeneração Macular/diagnóstico por imagem , Retinite Pigmentosa/diagnóstico por imagem , Doença de Stargardt/diagnóstico por imagem , Tomografia de Coerência Óptica , Adolescente , Adulto , Idoso , Proteínas de Ligação ao Cálcio/genética , Criança , Defeitos da Visão Cromática/fisiopatologia , Distrofias de Cones e Bastonetes/fisiopatologia , Progressão da Doença , Eletrorretinografia , Feminino , Humanos , Degeneração Macular/fisiopatologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fenótipo , Retina/fisiopatologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/fisiopatologia , Estudos Retrospectivos , Doença de Stargardt/fisiopatologia , Acuidade Visual/fisiologia , Proteínas rab de Ligação ao GTP/genética
11.
Invest Ophthalmol Vis Sci ; 61(4): 13, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32298433

RESUMO

Purpose: To analyze the progression of choriocapillaris (CC) impairment in recessive Stargardt disease (STGD) and compare it to the progression of retinal pigment epithelium (RPE) atrophy. Methods: Fifty-five patients with a clinical diagnosis of STGD and genetic confirmation of pathogenic biallelic variants in ABCA4 were imaged with short-wavelength fundus autofluorescence (SW-AF) and optical coherence tomography angiography (OCTA) at a single clinic visit, whereas a subset of 12 patients were imaged with the same modalities at two different clinic visits. Results: We observed three stages of CC impairment: an area of bright yet intact macular CC (11 patients), regions of vascular rarefaction and incomplete CC atrophy within an area of bright CC (10 patients), and areas of extensive CC atrophy (26 patients). These changes correlated to the degree of RPE atrophy observed in SW-AF imaging. Furthermore, 8 patients presented with early changes on SW-AF, but healthy CC. Quantitative analyses of the atrophic changes revealed that the area of RPE atrophy is larger (9.6 ± 1.7 mm2 vs. 6.9 ± 1.3 mm2, P < 0.001) and that it progresses at a faster rate (1.1 ± 0.1 mm2/year vs. 0.8 ± 0.2 mm2/year, P = 0.004) than the corresponding area of CC atrophy. Conclusions: CC impairment is progressive and OCTA imaging can be used to demonstrate the stages, which culminate in extensive CC atrophy. Furthermore, CC impairment is secondary to RPE atrophy in STGD. We further advocate the use of SW-AF and OCTA imaging in monitoring the progression of STGD.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Corioide/patologia , Epitélio Pigmentado da Retina/patologia , Doença de Stargardt/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia , Criança , Progressão da Doença , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Óptica , Estudos Retrospectivos , Doença de Stargardt/genética , Tomografia de Coerência Óptica , Adulto Jovem
12.
Prog Retin Eye Res ; 79: 100861, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32278709

RESUMO

The ABCA4 protein (then called a "rim protein") was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types - missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy - clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , DNA/genética , Terapia Genética/métodos , Mutação , Doenças Retinianas/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Humanos , Fenótipo , Doenças Retinianas/metabolismo , Doenças Retinianas/terapia
13.
Proc Natl Acad Sci U S A ; 117(16): 9001-9012, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32265282

RESUMO

The interplay of transcription factors and cis-regulatory elements (CREs) orchestrates the dynamic and diverse genetic programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. We took advantage of the retina, a well-characterized region of the CNS known to be affected by pathogenic variants in CREs, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive analysis of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, and retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines regulatory elements with the potential to contribute to Mendelian and complex disorders of human vision.


Assuntos
Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Sequências Reguladoras de Ácido Nucleico/genética , Retina/patologia , Doenças Retinianas/genética , Adulto , Animais , Análise Mutacional de DNA , Epigenômica , Feminino , Variação Genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , RNA-Seq , Retina/crescimento & desenvolvimento , Doenças Retinianas/patologia , Especificidade da Espécie
14.
Ophthalmic Genet ; 40(4): 369-375, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31576780

RESUMO

Background: The extensive phenotypic heterogeneity of monogenic diseases can be largely traced to intragenic variation; however, recent advances in clinical detection and gene sequencing have uncovered the emerging role of non-allelic variation (i.e. genetic trans-modifiers) in shaping disease phenotypes. Identifying these associations are not only of significant diagnostic value, but also provides scientific insight into the expanded molecular etiology of rare diseases. This reports describes the discordant clinical manifestation of a family segregating mutations in ABCA4 and PROM1. Methods: Three patients across a two generation family underwent multimodal imaging and functional testing of the retina including color photography, fundus autofluorescence (AF), spectral domain-optical coherence tomography (SD-OCT) and full-field electroretinography (ffERG). Genetic characterization was carried out by direct Sanger and whole exome sequencing. Results: Clinical examination revealed similar retinal degenerative phenotypes in the proband and her mother. Despite being younger, the proband's phenotype was more advanced and exhibited additional features related to Stargardt disease not found in the mother. Whole exome sequencing identified a pathogenic missense variant in PROM1, c.400C > T, p.(Arg134Cys), as the underlying cause of retinal disease in both the proband and mother. Sequencing of the ABCA4 locus uncovered a single disease-causing variant, c.5714 + 5G > A in the daughter segregating from the father who, surprisingly, also exhibited very subtle disease changes associated with STGD1 despite being a heterozygous carrier. Conclusions: Harboring an additional heterozygous ABCA4 mutation increases severity and confers STGD1-like features in patients with PROM1 disease which provides supporting evidence for their shared pathophysiology and potential treatment prospects.


Assuntos
Antígeno AC133/genética , Transportadores de Cassetes de Ligação de ATP/genética , Degeneração Macular/patologia , Mutação , Degeneração Retiniana/patologia , Doença de Stargardt/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prognóstico , Degeneração Retiniana/genética , Doença de Stargardt/genética , Adulto Jovem
15.
N Engl J Med ; 381(15): 1422-1433, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509666

RESUMO

BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS: Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).


Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas/genética , Mutação , Telangiectasia Retiniana/genética , Serina C-Palmitoiltransferase/genética , Serina/metabolismo , Esfingolipídeos/metabolismo , Adulto , Idoso , Animais , Análise Mutacional de DNA , Modelos Animais de Doenças , Exoma/genética , Feminino , Neuropatias Hereditárias Sensoriais e Autônomas/complicações , Neuropatias Hereditárias Sensoriais e Autônomas/metabolismo , Humanos , Metabolismo dos Lipídeos , Macula Lutea/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem , Telangiectasia Retiniana/complicações , Telangiectasia Retiniana/metabolismo , Fatores de Risco , Serina/sangue , Esfingosina/análogos & derivados , Esfingosina/análise , Adulto Jovem
16.
Am J Ophthalmol ; 207: 77-86, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31181178

RESUMO

PURPOSE: To characterize and bring awareness to the disease spectrum of female choroideremia patients, as severity can vary from mild to severe disease, comparable to that observed in male patients. DESIGN: Retrospective cohort study. METHODS: Twelve female carriers of disease-causing variants in the CHM gene confirmed by molecular genetic sequencing were characterized clinically and imaged with short-wave fundus autofluorescence (SW-FAF), spectral-domain optical coherence tomography (OCT), and color fundus imaging. RESULTS: Twelve unrelated female patients with a clinical and genetic diagnosis of choroideremia carriers were included in this study. Disease severity among these phenotypes ranged from mild to severe, resembling the typical presentation of choroideremia in male patients. Mild disease presented with retinal pigment epithelium mottling, a patchy pattern of hypoautofluorescent speckles on SW-FAF, and intact retinal layers on spectral-domain OCT. Severe disease presented with widespread chorioretinal atrophy as shown by SW-FAF and spectral-domain OCT. Each of the identified genetic variants in CHM was predicted to be disease-causing according to in silico prediction software. Disease progression analysis of 4 patients with follow-up showed a decline in visual acuity for 2 patients, with progression observed on spectral-domain OCT in 1 of the patients. No significant disease progression on SW-FAF was observed for any of the patients. CONCLUSIONS: Female carriers of choroideremia can present with a wide range of clinical phenotypes and disease severity, from mild to severe disease, similar to male subjects. Symptomatic female subjects should be considered for current and upcoming gene replacement therapy clinical trials.


Assuntos
Coroideremia/diagnóstico , Angiofluoresceinografia/métodos , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Coroideremia/genética , Feminino , Seguimentos , Fundo de Olho , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Oftalmoscopia/métodos , Fenótipo , Estudos Retrospectivos , Sequenciamento Completo do Genoma/métodos , Adulto Jovem
17.
Invest Ophthalmol Vis Sci ; 60(6): 2347-2356, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136651

RESUMO

Purpose: To define characteristic ocular features in a group of patients with autosomal recessive (AR) PROM1 cone-rod dystrophy (CRD). Methods: Three males and one female from three unrelated families were first seen at the ages of 15 to 22 years and diagnosed with CRD. Clinical testing available for review included full-field electroretinogram (ERG) in three patients, as well as near-infrared autofluorescence (NIR-AF), spectral-domain optical coherence tomography (SD-OCT), and color fundus photography in all four patients. Whole exome sequencing (WES) was performed on all cases, and whole genome sequencing (WGS) was performed in two families. Results: WES found compound heterozygous PROM1 variants in one isolated male, plus heterozygous variants in the remaining patients. WGS uncovered deleterious PROM1 variants in these two families. ERG showed markedly reduced cone-isolated amplitudes and variably reduced rod-isolated amplitudes. The dark-adapted combined rod and cone responses demonstrated notably reduced a-wave amplitudes and moderately reduced b-waves, and the resultant waveform resembled the normal rod-isolated response. On fundus examination, oval-shaped macular lesions were observed, as were several small, circular hypoautofluorescent lesions within the posterior pole on NIR-AF. Three patients showed extramacular circular atrophic lesions. Conclusions: The autofluorescence changes, peripheral retinal abnormalities, and ERG findings have not been emphasized in previous reports of AR PROM1, but they became a recognizable phenotype in this cohort of patients. A similar constellation of findings may be observed in CRD due to CDHR1, a functionally related gene. The pattern of abnormalities reported herein may help to focus genetic screening in patients with these findings.


Assuntos
Antígeno AC133/genética , Distrofias de Cones e Bastonetes , Adolescente , Adulto , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/patologia , Distrofias de Cones e Bastonetes/fisiopatologia , Adaptação à Escuridão/fisiologia , Eletrorretinografia , Feminino , Humanos , Masculino , Imagem Óptica/métodos , Fenótipo , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Tomografia de Coerência Óptica/métodos , Adulto Jovem
18.
Sci Rep ; 9(1): 6436, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015497

RESUMO

Fundus autofluorescence (FAF) imaging is crucial to the diagnosis and monitoring of recessive Stargardt disease (STGD1). In a retrospective cohort study of 34 patients, we compared FAF imaging platforms varying in field size (30° and 55°: blue/SW-AF and NIR-AF; 200°: ultrawide-field, UWF-AF), excitation wavelength (488 nm, blue/SW-AF; 532 nm, UWF-AF and 787 nm, NIR-AF) and image processing. Due to reduced absorption of 532 nm and 787 nm light by macular pigment, foveal sparing was more readily demonstrable by green/UWF-AF and NIR-AF imaging. Prominent in green/UWF-AF images is a central zone of relatively elevated AF that is continuous inferonasal with a demarcation line bordering lower AF nasally and higher AF temporally. This zone and border are more visible in STGD1 than in healthy eyes and more visible with green/UWF-AF. With the development of AF flecks, inferonasal retina is initially spared. Central atrophic areas were larger in NIR-AF images than in blue/SW-AF and green/UWF-AF images and the presence of a contiguous hyperAF ring varied with imaging modality. Flecks visible as hyperAF foci in blue/SW-AF images were also visible in green/UWF-AF but were often hypoAF in NIR-AF. Since disease in STGD1 often extends beyond the 30° and 55° fields, green/UWF-AF has advantages including for pediatric patients. The imaging platforms examined provided complementary information.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Fóvea Central/diagnóstico por imagem , Imagem Óptica/métodos , Epitélio Pigmentado da Retina/diagnóstico por imagem , Doença de Stargardt/diagnóstico por imagem , Doença de Stargardt/genética , Transportadores de Cassetes de Ligação de ATP/deficiência , Adolescente , Adulto , Idoso , Criança , Feminino , Fóvea Central/metabolismo , Fóvea Central/patologia , Fundo de Olho , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Estudos Retrospectivos , Doença de Stargardt/metabolismo , Doença de Stargardt/patologia
19.
Genet Med ; 21(10): 2336-2344, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30926958

RESUMO

PURPOSE: Variants in the ABCA4 gene are causal for a variety of retinal dystrophy phenotypes, including Stargardt disease (STGD1). However, 15% of patients who present with symptoms compatible with STGD1/ABCA4 disease do not have identifiable causal ABCA4 variants. We hypothesized that a case-control collapsing analysis in ABCA4-negative patients with compatible symptoms would provide an objective measure to identify additional disease genes. METHODS: We performed a genome-wide enrichment analysis of "qualifying variants"-ultrarare variants predicted to impact protein function-in protein-coding genes in 79 unrelated cases and 9028 unrelated controls. RESULTS: Despite modest sample size, two known retinal dystrophy genes, PRPH2 and CRX, achieved study-wide significance (p < 1.33 × 10-6) under a dominant disease model, and eight additional known retinal dystrophy genes achieved nominal significance (p < 0.05). Across these ten genes, the excess of qualifying variants explained up to 36.8% of affected individuals. Furthermore, under a recessive model, the cone-rod dystrophy gene CERKL approached study-wide significance. CONCLUSION: Our results indicate that case-control collapsing analyses can efficiently identify pathogenic variants in genes in non-ABCA4 retinal dystrophies. The genome-wide collapsing analysis framework is an objective discovery method particularly suitable in settings with overlapping disease phenotypes.


Assuntos
Proteínas de Homeodomínio/genética , Periferinas/genética , Distrofias Retinianas/genética , Transativadores/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Genes Recessivos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Mutação , Linhagem , Periferinas/metabolismo , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Doença de Stargardt/genética , Doença de Stargardt/fisiopatologia , Transativadores/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-30630813

RESUMO

ROM1 (retinal outer segment membrane protein 1) is a 351-amino acid integral membrane protein on Chromosome 11q, with high structural similarity to PRPH2/RDS. Localized at the rims of photoreceptor outer segments (OSs), it is required for the maintenance of OS structure. Here, we describe a case with a phenotypic manifestation of a homozygous single-base pair deletion, c.712delC (p.Leu238Cysfs*78) in the ROM1 gene, resulting in early termination at exon 2. The variant was detected by whole-exome sequencing (WES) in a 63-yr-old Caucasian woman with late-onset pattern macular dystrophy. Notably, although the phenotype resembles those caused by pathogenic variants in ABCA4 or RDS/PRPH2, no pathogenic variants in these, or any other plausible candidate genes, were identified by WES. Clinical features include the presence of hyperautofluorescent flecks, relative sparing of the central macula, and preserved visual acuity. Reduced visual sensitivity was detected among flecked regions in the retina; however, full-field electroretinogram testing revealed no generalized cone dysfunction. The described first case of the complete loss of ROM1 protein function in the retina suggests its sufficiency for late-onset macular dystrophy. ROM1 and PRPH2 pattern macular dystrophies exhibit phenotype overlap, which may be attributable to their shared role in maintenance of the photoreceptor outer segment structure.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Proteínas do Olho/genética , Degeneração Macular/genética , Periferinas/genética , Tetraspaninas/genética , Eletrorretinografia , Feminino , Mutação da Fase de Leitura , Homozigoto , Humanos , Degeneração Macular/diagnóstico por imagem , Degeneração Macular/patologia , Pessoa de Meia-Idade , Fenótipo , Retina/diagnóstico por imagem , Retina/patologia , Sequenciamento Completo do Exoma
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