Mutated CCDC51 Coding for a Mitochondrial Protein, MITOK Is a Candidate Gene Defect for Autosomal Recessive Rod-Cone Dystrophy

The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA of the female patient originating from a consanguineous family revealed no large duplication or deletion, but several large homozygous regions. In one of these, a homozygous frameshift variant, c.244_246delins17 p.(Trp82Valfs*4); predicted to lead to a nonfunctional protein, was identified in CCDC51. CCDC51 encodes the mitochondrial coiled-coil domain containing 51 protein, also called MITOK. MITOK ablation causes mitochondrial dysfunction. Here we show for the first time that CCDC51/MITOK localizes in the retina and more specifically in the inner segments of the photoreceptors, well known to contain mitochondria. Mitochondrial proteins have previously been implicated in IRD, although usually in association with syndromic disease, unlike our present case. Together, our findings add another ultra-rare mutation implicated in non-syndromic IRD, whose pathogenic mechanism in the retina needs to be further elucidated.

Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials

Within the last decade, continuous advances in molecular biological techniques have made it possible to develop causative therapies for inherited retinal disorders (IRDs). Some of the most promising options are gene-specific approaches using adeno-associated virus-based vectors to express a healthy copy of the disease-causing gene in affected cells of a patient. This concept of gene supplementation therapy is already advocated for the treatment of retinal dystrophy in RPE65-linked Leberʼs congenital amaurosis (LCA) patients. While the concept of gene supplementation therapy can be applied to treat autosomal recessive and X-linked forms of IRD, it is not sufficient for autosomal dominant IRDs, where the pathogenic gene product needs to be removed. Therefore, for autosomal dominant IRDs, alternative approaches that utilize CRISPR/Cas9 or antisense oligonucleotides to edit or deplete the mutant allele or gene product are needed. In recent years, research retinal gene therapy has intensified and promising approaches for various forms of IRD are currently in preclinical and clinical development. This review article provides an overview of current clinical trials for the treatment of IRDs.

A Mild Phenotype Caused by Two Novel Compound Heterozygous Mutations in CEP290

CEP290 is a ciliary gene frequently mutated in ciliopathies, resulting in a broad range of phenotypes, ranging from isolated inherited retinal disorders (IRDs) to severe or lethal syndromes with multisystemic involvement. Patients with non-syndromic CEP290-linked disease experience profound and early vision loss due to cone-rod dystrophy, as in Leber congenital amaurosis. In this case report, we describe two novel loss-of-function heterozygous alterations in the CEP290 gene, discovered in a patient suffering from retinitis pigmentosa using massive parallel sequencing of a molecular inversion probes library constructed for 108 genes involved in IRDs. A milder phenotype than expected was found in the individual, which serves to prove that some CEP290-associated disorders may display preserved cone function.

Novel Homozygous TULP1 and RPE65 Variants Underlies Recessive Retinitis Pigmentosa

Retinitis pigmentosa (RP) clinically and genetically heterogeneous group of inherited retinal disorders (IRD) that result in retinal degeneration. This study aimed to identify the genetic findings of patients with autosomal recessive retinitis pigmentosa (arRP). Whole exome sequencing (WES) was performed in two unrelated Pakistani families underlying arRP. Data analysis and mutation screening was performed for all the known RP genes following bi-directional Sanger sequencing to determine whether any of the candidate variants co-segregated with the disease phenotype in the families. WES data analysis revealed a novel homozygous missense variant (c.1274T>C) in the in Tubby like Protein 1 (TULP1 NM_003322.6) gene in family 1 and a novel homozygous frameshift variant (c.351delC) in the retinoid isomerohydrolase 65 (RPE65 NM_000329.3) gene in family 2. The identified variants perfectly co-segregated with the disease phenotype within the families. Our results strongly suggest that mutations in TULP1 and RPE65 are responsible for the retinal phenotype in the affected individuals. These mutations will increase the mutation spectrum of these genes; furthermore, it will enhance our knowledge and understanding of the underlying molecular mechanisms of retinitis pigmentosa.

Findings from a Genotyping Study of over 1000 People with Inherited Retinal Disorders in Ireland

The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical assessment, which includes clinical history and analysis with multimodal retinal imaging, electrophysiology, and visual field testing. If suitable for recruitment, a sample is taken and used for genetic analysis. Genetic analysis is conducted by use of a retinal gene panel target capture sequencing approach. With over 1000 participants from 710 pedigrees now screened, there is a positive candidate variant detection rate of approximately 70% (495/710). Where an autosomal recessive inheritance pattern is observed, an additional 9% (64/710) of probands have tested positive for a single candidate variant. Many novel variants have also been detected as part of this endeavor. The target capture approach is an economic and effective means of screening patients with inherited retinal disorders. Despite the advances in sequencing technology and the ever-decreasing associated processing costs, target capture remains an attractive option as the data produced is easily processed, analyzed, and stored compared to more comprehensive methods. However, with decreasing costs of whole genome and whole exome sequencing, the focus will likely move towards these methods for more comprehensive data generation.

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

Purpose A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). Methods Two hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. Results The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). Conclusion Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.