Rando Allikmets's research while affiliated with Columbia University and other places
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Publications (249)
Purpose:
To compare longitudinal changes in en face spectral domain-optical coherence tomography (SD-OCT) measurements of ellipsoid zone (EZ) and retinal pigment epithelium (RPE) loss to changes in the hypoautofluorescent and hyperautofluorescent (AF) areas detected with short-wavelength (SW)-AF in ABCA4-associated retinopathy.
Methods:
SD-OCT v...
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 screen...
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. Short-wavelength autofluorescence (SW-AF) and quantitative fundus autofluorescence (qAF...
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. T...
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.Gly1961Glu) missense variant and...
We describe affected members of a two-generation family segregating a Stargardt disease-like phenotype caused by a two base pair deletion-insertion, c.1014_1015delGAinsCT;p(Trp338_Asn339delinsCysTyr), in BEST1. The variant was identified by whole exome sequencing and its pathogenicity was verified through chloride channel recording using wild-type...
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 hig...
Inherited retinal diseases (IRDs) represent a spectrum of clinically and
genetically heterogeneous disorders. Our study describes an IRD patient
carrying ABCA4 and USH2A pathogenic biallelic mutations as a result of
paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-
year-old girl born from non-consanguineous parents. Both parent...
The ATP‐binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra‐ and intra‐cellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport...
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
19 patients with confirmed ABCA4 disease exhibiting the optical gap phenotype
Methods
Multi-modal retinal imaging across multipl...
Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, are not well-understood. We hypothes...
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...
The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intra-cellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport...
Background
More 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 coh...
Importance
Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD.
Objective
To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with in...
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 pathoge...
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 ell...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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 varian...
A Correction to this paper has been published: https://doi.org/10.1038/s42003-021-01972-y
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 r...
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 t...
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...
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...
BACKGROUND
Despite widespread availability of clinical genetic testing, many individuals with suspected genetic conditions do not have a precise diagnosis. This limits their opportunity to take advantage of state-of-the-art treatments. In such instances, testing sometimes reveals difficult-to-evaluate complex structural differences, candidate varia...
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<5E-8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcr...
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-wavel...
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...
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 o...
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 famil...
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...
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 males.
Design:
Retrospective cohort study.
Methods:
12 female carriers of disease-causing variants in the CHM gene confirmed by molecular genetic sequencing were...
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...
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-A...
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...
There is a lack of studies which seek to discern disease expression in patients with mutations that alter retinal ceramide metabolism, specifically in the ceramide kinase like (CERKL) gene. This cross-sectional case series reports a novel phenotypic manifestation of CERKL-associated retinopathy. Four unrelated patients with homozygous CERKL mutatio...
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 singl...
Cis-regulatory elements (CREs) orchestrate the dynamic and diverse transcriptional 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. However,...
Purpose:
To investigate the Stargardt disease phenotype associated with an unusually common and "extremely hypomorphic" ABCA4 variant, p.N1868I.
Methods:
The charts of 27 patients with p.N1868I on one allele and a severe/deleterious mutation on the other allele were reviewed. Subjective age of onset, best-corrected visual acuity, and stage of di...
[This corrects the article DOI: 10.1099/jmmcr.0.005145.].
A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneratio...
Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of the ABCA4 locus in STGD1 patients identifies two expected disease-causing alleles in ~75% of patients and only one mutation in ~15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of ABCA4 ha...
Purpose
We sought to advance interpretations and quantification of short-wavelength fundus autofluorescence (SW-AF) emitted from bisretinoid lipofuscin and near-infrared autofluoresence (NIR-AF) originating from melanin.
Methods
Carriers of mutations in X-linked GPR143/OA1, a common form of ocular albinism; patients with confirmed mutations in ABC...
Bisretinoid fluorophores form in photoreceptor outer segments from nonenzymatic reactions of vitamin A aldehyde. The short‐wavelength autofluorescence (SW‐AF) of fundus flecks in recessive Stargardt disease (STGD1) suggests a connection to these fluorophores. Through multimodal imaging, we sought to elucidate this link. Flecks observed in SW‐AF ima...
Significance
Genetic variation of the complement factor H ( CFH ) gene family is associated with several complex diseases. Here, we have performed both long- and short-read sequencing of multiple humans and nonhuman primates in an effort to understand its complex evolutionary history. We find that this locus has evolved predominantly through incomp...
Introduction
Although the current Zika virus (ZIKV) epidemic is a major public health concern, most reports have focused on congenital ZIKV syndrome, its most devastating manifestation. Severe ocular complications associated with ZIKV infections and possible pathogenetic factors are rarely described. Here, we describe three Venezuelan patients who...
Purpose:
Mutations in the eyes shut homolog (EYS) gene are a frequent cause of autosomal recessive retinitis pigmentosa (arRP). This study used multi-modal retinal imaging to elucidate genotype-phenotype relationships in EYS-related RP (EYS-RP).
Design:
Cross-sectional study.
Method:
Multimodal retinal imaging and electrophysiologic testing wa...
Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. D...
Purpose:
To determine which nocturnal blood pressure (BP) parameters (low levels or extreme dipper status) are associated with an increased risk of glaucomatous damage in Hispanics.
Design:
Observational cross-sectional study.
Participants:
A subset (n = 93) of the participants from the Maracaibo Aging Study (MAS) who met the study eligibility...
Purpose
To compare morphologic changes on en face images derived from wide-field swept-source optical coherence tomography (ssOCT) to hypo- and hyperautofluorescent (hypoAF, hyperAF) areas on short-wavelength autofluorescence (SW-AF), and near-infrared (NIR)-AF in recessive Stargardt disease (STGD1).
Methods
Wide-field ssOCT cube scans were obtain...
Purpose:
To describe an unusual manifestation of hyperreflective deposits in the subretinal space in a group of patients with clinically and genetically confirmed Stargardt disease.
Methods:
Retrospective review of color fundus, autofluorescence, infrared reflectance, red-free images, and spectral domain optical coherence tomography in 296 clini...
Purpose:
To characterize patients affected by a uniquely severe, rapid-onset chorioretinopathy (ROC) phenotype of ABCA4 disease.
Design:
Comparative cohort study.
Participants:
Sixteen patients were selected from a large clinically diagnosed and genetically confirmed cohort (n = 300) of patients diagnosed with ABCA4 disease.
Main outcome meas...
Purpose:
The purpose of our study was to investigate morpho-functional features of the preferred retinal location (PRL) and the transition zone (TZ) in a series of patients with recessive Stargardt disease (STGD1).
Methods:
Fifty-two STGD1 patients with at least one ABCA4 mutation, atrophy of the central macula (MA) and an eccentric PRL were rec...
Purpose
Choroidal thinning has been associated with reticular pseudodrusen (RPD) and β-peripapillary atrophy (β-PPA), which have been linked to normal-tension glaucoma (NTG). This analysis sought to determine whether RPD are independently associated with β-PPA in early AMD patients. Secondary outcomes included the association of RPD and preexisting...
Background:
Peripapillary sparing is a characteristic that is traditionally described as pathognomonic for Stargardt disease.
Materials and methods:
We present a multimodal assessment of four Leber congenital amaurosis (LCA) cases with congenital macular atrophy and severely attenuated electroretinogram findings caused by bilallelic mutations in...
Background:
Variation in the ABCA4 gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such as age-related macular degeneration (AMD). Despite substantial progress in determining the causal genetic variation, even complete sequencing of the entire open re...
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Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent...
Purpose
Using quantitative fundus autofluorescence (qAF), we analyzed short-wavelength autofluorescent (SW-AF) rings in RP.
Methods
Short-wavelength autofluorescent images (486 nm excitation) of 40 patients with RP (69 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. Mean qAF was me...
Variants in the ABCA4 gene are the most common cause of juvenile-onset blindness affecting close to 1 in 10 000 people worldwide. Disease severity varies largely according to genotype, which can be specific to ethnic and racial groups. Here we investigate the spectrum of ABCA4 variation and its phenotypic expression in 38 patients of South Asian de...
Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent...
Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5...
Variants in the ABCA4 gene are associated with a spectrum of inherited retinal diseases (IRDs), most prominently with autosomal recessive Stargardt disease (STGD1) and cone-rod dystrophy (arCRD). The clinical outcome to a large degree depends on the severity of the variants. To provide an accurate prognosis and to select patients for novel treatmen...
Nutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, and light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in CYP26B1, one of the major RA-metabolizing enzymes, cause advanced bone age, premature epiphyseal fusion, and craniosynostosis. In this paper,...
