Robert K Koenekoop

Robert K Koenekoop
McGill University | McGill · Division of Paediatric Ophthalmology

MD, PhD

About

197
Publications
23,685
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9,155
Citations
Additional affiliations
January 1995 - January 2016
McGill University
Position
  • Chief Paediatric Ophthalmology

Publications

Publications (197)
Article
Purpose This study aimed to investigate the clinical and genetic aspects of solute carrier (SLC) genes in inherited retinal diseases (IRDs). Methods Exome sequencing data were filtered to identify pathogenic variants in SLC genes. Analysis of transcript and protein expression was performed on fibroblast cell lines and retinal sections. Results Co...
Article
Purpose To report Phase 1b/2 interim results of QR-421a RNA therapy promoting USH2A exon 13 skipping. USH2A exon 13 mutations lead to non-syndromic Retinitis Pigmentosa & Usher syndrome type 2. Methods Stellar (NCT03780257) is a 24-month, multicenter Phase 1b/2 single-dose trial assessing 3 dose levels (50, 100, 200 μg) of QR-421a in patients aged...
Article
PCDH12 is a member of the non-clustered protocadherins that mediate cell-cell adhesion, playing crucial roles in many biological processes. Among these, PCDH12 promotes cell-cell interactions at inter-endothelial junctions, exerting essential functions in vascular homeostasis and angiogenesis. However, its exact role in eye vascular and brain devel...
Article
Full-text available
Purpose: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome. Methods: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fun...
Article
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Purpose: Despite the extensive use of next-generation sequencing (NGS) technology to identify disease-causing genomic variations, a major gap in our understanding of Mendelian diseases is the unidentified molecular lesion in a significant portion of patients. For inherited retinal degenerations (IRDs), although currently close to 300 disease-assoc...
Article
Full-text available
Purpose: Leber congenital amaurosis due to CEP290 mutations (LCA10) is an inherited retinal disease that often results in severe visual impairment or blindness in early childhood. Currently there are no approved treatments, highlighting the considerable unmet medical need associated with LCA10. We aimed to review the clinical characteristics of LC...
Article
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Recent literature has reported a higher occurrence of cognitive impairment among individuals with Age-related Macular Degeneration (AMD) compared to older adults with normal vision. This pilot study explored potential links between single nucleotide polymorphisms (SNPs) in AMD and cognitive status. Individuals with AMD (N = 21) and controls (N = 18...
Article
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Purpose: To investigate the precision of visual fields (VFs) from semiautomated kinetic perimetry (SKP) on Octopus 900 perimeters, for children and adults with inherited retinal degenerations (IRDs). Goldmann manual kinetic perimetry has long been used in the diagnosis and follow-up of these patients, but SKP is becoming increasingly common. Octop...
Article
Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function. However, a small number of patients carrying the CNGB3/c.1208G>A;p.R403Q mutation present with a variable retinal phenotype...
Article
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Importance Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti–vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for per...
Article
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Most genetically distinct inherited retinal degenerations are primary photoreceptor degenerations. We selected a severe early onset form of Leber congenital amaurosis (LCA), caused by mutations in the gene LCA5, in order to test the efficacy of gene augmentation therapy for a ciliopathy. The LCA5 encoded protein, Lebercilin, is essential for the tr...
Article
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The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS's) tha...
Article
Full-text available
Purpose To evaluate consanguineous pedigrees from Pakistan with a clinical diagnosis of nonsyndromic congenital retinal nonattachment (NCRNA) and identify genes responsible for the disease as currently only one NCRNA gene is known (atonal basic helix-loop-helix transcription factor 7: ATOH7). Methods We implemented a three-step genotyping platform...
Article
This article is dedicated to Irene Hussels-Maumenee, Professor of Human Genetics and Ophthalmology, Johns Hopkins’ Wilmer Eye Institute, Ocular Genetics Fellowship director in 1994–1995. Leber congenital amaurosis (LCA) has almost come full circle, from a profound and molecularly uncharacterized form of congenital retinal blindness to one in which...
Article
Full-text available
Pooled DNA based GWAS to determine genetic association of SNPs with visual acuity (VA) outcome in anti-vascular endothelial growth factor (anti-VEGF) treated neovascular age-related macular degeneration (nAMD) patients. We performed pooled DNA based GWAS on 285 anti-VEGF treated nAMD patients using high density Illumina 4.3 M array. Primary outcome...
Article
Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a sixgeneration family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing re...
Conference Paper
Full-text available
Purpose : Retinitis pigmentosa (RP) is a hereditary group of clinically and genetically heterogeneous retinal dystrophies that eventually lead to blindness. The genetics of RP are still incomplete despite intense studies. Currently, about 50 genes explain ~50% of cases. We studied a Canadian family of Syrian origin with adRP and aimed to identify t...
Article
Purpose: A patient initially presented with constricted visual field, attenuated retinal vasculature, pigmentary clumping and reduced ERG in OS only, suggestive of unilateral retinitis pigmentosa (RP). This patient was subsequently seen on eight occasions (over three decades), and, with time, the initially normal eye (OD) gradually showed signs of...
Article
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Background: SPATA7 mutations have been associated with different autosomal recessive retinal degeneration phenotypes. Long-term follow-up has not been described in detail. Materials and methods: A Hispanic patient with SPATA7 mutations was evaluated serially over a 12-year period with kinetic and static chromatic perimetry, optical coherence tom...
Article
Purpose: Leber congenital amaurosis (LCA) is an early-onset form of retinal degeneration. Six of the 22 known LCA genes encode photoreceptor ciliary proteins. Despite the identification of 22 LCA genes, the genetic basis of ~30% of LCA patients remains unknown. We sought to investigate the cause of disease in the remaining 30% by examining cilia-a...
Article
Full-text available
A growing number of human diseases have been linked to defects in protein glycosylation that affects a wide range of organs. Among them, O-mannosylation is an unusual type of protein glycosylation that is largely restricted to the muscular and nerve system. Consistently, mutations in genes involved in the O-mannosylation pathway result in infantile...
Data
Supplementary Figure S1 The fundi of proband MOGL3628 appear normal. The right and left eyes are shown in these colored retinal photos illustrating normal appearing discs, fovea, and maculae. The retinal arteries are very subtly narrowed.
Data
Supplementary Table S1: 349 rare protein-altering variants in 335 genes
Data
Supplementary Figure S2 The proband’s mutation in CLUAP1 does not prevent its ciliary localization when transiently overexpressed in hTERT-RPE1 cells. Immunohistochemistry analysis was performed using anti-FLAG (red), anti-acetylated α-tubulin (green), and DAPI (blue). (A) FLAG-CLUAP1 and (B) FLAG-CLUAP1Mut are both observed weakly throughout the c...
Article
Purpose: The French Canadian population of Quebec is a unique, well-known founder population with religious, linguistic, and geographic isolation. The genetics of retinitis pigmentosa (RP) in Quebec is not well studied thus far. The purpose of our study was to establish the genetic architecture of autosomal dominant RP (adRP) and to characterize t...
Article
Full-text available
Purpose: Photoreceptor neuronal degenerations are common, incurable causes of human blindness affecting 1 in 2000 patients worldwide. Only half of all patients are associated with known mutations in over 250 disease genes, prompting our research program to identify the remaining new genes. Most retinal degenerations are restricted to the retina, b...
Article
Full-text available
Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m²/day QLT091001 for 7 consecut...
Data
Scatterplots Showing Individual ETDRS Letter Score at Every Visit for All Eyes Against Baseline. (PDF)
Data
Onset and Duration of Visual Acuity Response in Responding Eyes by Patient. (PDF)
Data
Full-Field Standard Electroretinography (ERG): Original Tracings and Fourier Analysis of the 31-Hz Photopic Flicker ERG of Subject #601 at Baseline and Post-Treatment (2 months). (PDF)
Data
Scatterplots Showing Individual Functional Retinal Area (GVF Retinal Area of Primary Isopter) at Every Visit for All Eyes Against Baseline. (PDF)
Data
Onset and Duration of Visual Field Response in Responding Eyes by Patient. (PDF)
Data
Calculation of Functional Retinal Area. (PDF)
Data
Summary of All Adverse Drug Reactions. (PDF)
Data
Details for Functional Magnetic Resonance Imaging. (PDF)
Article
Full-text available
Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecut...
Article
Full-text available
Objective The aim of the study was to investigate the role of single-nucleotide polymorphisms (SNPs) located in the neuropilin-1 (NRP1) gene in treatment response to antivascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (nvAMD). Methods Four SNPs in the NRP1 gene (rs2229935, rs2247383, rs2070296, an...
Article
Full-text available
Introduction Sleep is important for optimal physical health and vitality. Recent studies have shown that individuals with visual impairments may be at risk for sleep problems. This research examines the prevalence of sleep problems among those with retinal disorders and the possibility of a genetic link. Methods Subjects with retinitis pigmentosa...
Article
Full-text available
An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), is identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is likely influenced by when in the diagnostic process WES is used. The Finding Of R...
Article
Full-text available
Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activatin...
Article
Full-text available
Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy o...
Article
Full-text available
Purpose This study aimed to identify the genetic defects in 2 families with autosomal recessive macular dystrophy with central cone involvement. Design Case series. Participants Two families and a cohort of 244 individuals with various inherited maculopathies and cone disorders. Methods Genome-wide linkage analysis and exome sequencing were perf...
Article
Full-text available
Purpose: Stargardt macular dystrophy (STGD) results in early central vision loss. We sought to explain the genetic cause of STGD in a cohort of 88 patients from three different cultural backgrounds. Methods: Next-generation sequencing using a novel capture panel was used to search for disease-causing mutations. Patients with undetermined causes...
Article
Photoreceptor neuronal degenerations are common and incurable causes of human blindness with one in 2000 affected. Approximately, half of all patients are associated with known mutations in more than 200 disease genes. Most retinal degenerations are restricted to the retina (primary retinal degeneration) but photoreceptor degeneration can also be f...
Article
Background Leber congenital amaurosis, caused by mutations in RPE65 and LRAT, is a severe form of inherited retinal degeneration leading to blindness. We aimed to assess replacement of the missing chromophore 11-cis retinal with oral QLT091001 (synthetic 9-cis-retinyl acetate) in these patients. Methods In our open-label, prospective, phase 1b tri...
Article
Full-text available
Background CYP1B1 is the most commonly mutated gene in primary congenital glaucoma (PCG). This study was undertaken to identify mutations in CYP1B1 in the Western region of Saudi Arabia.Methods Blood of patients who had typical findings of PCG, were screened by direct sequencing of all coding exons and splice junctions of the CYP1B1 gene.Results34...
Data
Conditions and primer sequences.
Data
Fundus photographs of CYP4V2-negative patients. Shown are fundus photographs of five CYP4V2-negative Bietti crystalline dystrophy patients. As in those with identified CYP4V2 mutations, predominant findings include choroidal sclerosis with or without visible crystalline deposits, pigment deposition, and vascular attenuation.
Data
Optical coherence tomography images of CYP4V2-negative patients. OCT images of five CYP4V2-negative patients, with presence of small hyperreflective intraretinal crystals and larger subretinal crystals (red arrows).
Article
Full-text available
Purpose: To identify the cause of retinitis pigmentosa (RP) in UTAD003, a large, six-generation Louisiana family with autosomal dominant retinitis pigmentosa (adRP). Methods: A series of strategies, including candidate gene screening, linkage exclusion, genome-wide linkage mapping, and whole-exome next-generation sequencing, was used to identify...
Article
Full-text available
Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2. In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underwent ophthalmic examinations and were screened for...
Article
Background: With progressively brighter stimuli, the amplitude of the b-wave of the human photopic electroretinogram (ERG) first increases to a maximal value (Vmax) and then decreases to finally reach a plateau, a phenomenon known as the photopic hill (PH). A mathematical model combining a Gaussian (G) and a logistic (L) growth function was previo...
Article
Full-text available
Usher syndrome (USH) is a heterogeneous group of inherited retinitis pigmentosa (RP) and sensorineural hearing loss (SNHL) caused by mutations in at least 12 genes. Our aim is to identify additional USH-related genes. Clinical examination included visual acuity test, funduscopy and electroretinography. Genetic analysis included homozygosity mapping...
Article
Full-text available
Retinitis pigmentosa (RP) is the most frequent inherited retinal disease, which shows a relatively high incidence of the autosomal-recessive form in Pakistan. Genome-wide high-density single-nucleotide polymorphism (SNP) microarrays were used to identify homozygous regions shared by affected individuals of one consanguineous family. DNA of three af...