Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.

Targeted sequencing and in vitro splice assays shed light on ABCA4-associated retinopathies missing heritability.

The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrophy probands.

iPSC-derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function.

Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases.

Insights Into PROM1-Macular Disease Using Multimodal Imaging.

Purpose: To describe the features of genetically confirmed PROM1-macular dystrophy in multimodal images.

Methods: Thirty-six (36) eyes of 18 patients (5-66 years; mean age, 42.4 years) were prospectively studied by clinical examination and multimodal imaging.

Establishment of the iPSC line CUIMCi005-A from a patient with Stargardt disease for retinal organoid culture.

Pathogenic variation in the ABCA4 gene is the underlying cause of Stargardt disease, the most common inherited retinal degeneration. We established an induced pluripotent stem cell line for retinal organoid research from a patient with mild disease features who is compound heterozygous for the frequent c.5882G>A (p.

A pathogenic in-frame deletion-insertion variant in BEST1 phenocopies Stargardt disease.

Here, we describe affected members of a 2-generation family with a Stargardt disease-like phenotype caused by a 2-base pair deletion insertion, c.1014_1015delGAinsCT;p.(Trp338_Asn339delinsCysTyr), in BEST1.

Systems genomics in age-related macular degeneration.

Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics.

The human ATP-binding cassette (ABC) transporter superfamily.

The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intracellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. To provide tools to study the function of human ABC transporters we compiled data from multiple genomics databases.

Longitudinal Analysis of a Resolving Foveomacular Vitelliform Lesion in ABCA4 Disease.

Purpose: To describe the longitudinal progression and phenotypic association of bilateral foveomacular vitelliform lesions in the setting of ABCA4 disease.

Design: Case report and cross-sectional cohort study.

Participants: Nineteen patients with confirmed ABCA4 disease exhibiting an optical gap phenotype.

Expanding the phenotype of TTLL5-associated retinal dystrophy: a case series.

Background: Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone-rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5.

Comparisons Among Optical Coherence Tomography and Fundus Autofluorescence Modalities as Measurements of Atrophy in ABCA4-Associated Disease.

Purpose: In ABCA4-associated retinopathy, central atrophy was assessed by spectral domain optical coherence tomography (SD-OCT) and by short-wavelength (SW-AF) and near-infrared (NIR-AF) autofluorescence.

Methods: Patients exhibited a central atrophic lesion characterized by hypoautofluorescence (hypoAF) surrounded either by hyperautofluorescent (hyperAF) rings in both AF images (group 1, 4 patients); or a hyperAF ring in SW-AF but not in NIR-AF images (group 2, 11 patients); or hyperAF rings in neither AF images (group 3, 11 patients). Choroidal hypertransmission and widths of ellipsoid zone (EZ) loss were measured in foveal SD-OCT scans, and in AF images hypoAF and total hypo+hyperAF widths were measured along the same axis.

A genotype-phenotype correlation matrix for ABCA4 disease based on long-term prognostic outcomes.

BackgroundMore than 1500 variants in the ATP-binding cassette, sub-family A, member 4 (ABCA4), locus underlie a heterogeneous spectrum of retinal disorders ranging from aggressive childhood-onset chorioretinopathy to milder late-onset macular disease. Genotype-phenotype correlation studies have been limited in clinical applicability as patient cohorts are typically small and seldom capture the full natural history of individual genotypes. To overcome these limitations, we constructed a genotype-phenotype correlation matrix that provides quantifiable probabilities of long-term disease outcomes associated with specific ABCA4 genotypes from a large, age-restricted patient cohort.

Targeted long-read sequencing identifies missing disease-causing variation.

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.

Shared Features in Retinal Disorders With Involvement of Retinal Pigment Epithelium.

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.

Cis-acting modifiers in the ABCA4 locus contribute to the penetrance of the major disease-causing variant in Stargardt disease.

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.

Reevaluating the Association of Sex With ABCA4 Alleles in Patients With Stargardt Disease.

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.

Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease.

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.

Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder.

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), 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.