ABSTRACT
PURPOSE: Congenital stationary night blindness (CSNB) is a heterogeneous group of Mendelian retinal disorders that present in childhood. Biallelic variants altering the protein-coding region of the TRPM1 gene are one of the commonest causes of CSNB. Here, we report the clinical and genetic findings in 10 unrelated individuals with TRPM1-retinopathy. METHODS: Study subjects were recruited through a tertiary clinical ophthalmic genetic service at Manchester, UK. All participants underwent visual electrodiagnostic testing and panel-based genetic analysis. RESULTS: Study subjects had a median age of 8 years (range: 3-20 years). All probands were myopic and had electroretinographic findings in keeping with complete CSNB. Notably, three probands reported no night vision problems. Fourteen different disease-associated TRPM1 variants were detected. One individual was homozygous for the NM_001252024.2 (TRPM1):c.965 + 29G>A variant and a mini-gene assay highlighted that this change results in mis-splicing and premature protein termination. Additionally, two unrelated probands who had CSNB and mild neurodevelopmental abnormalities were found to carry a 15q13.3 microdeletion. This copy number variant encompasses seven genes, including TRPM1, and was encountered in the heterozygous state and in trans with a missense TRPM1 variant in each case. CONCLUSION: Our findings highlight the importance of comprehensive genomic analysis, beyond the exons and protein-coding regions of genes, for individuals with CSNB. When this characteristic retinal phenotype is accompanied by extraocular findings (including learning and/or behavioural difficulties), a 15q13.3 microdeletion should be suspected. Focused analysis (e.g. microarray testing) is recommended to look for large-scale deletions encompassing TRPM1 in patients with CSNB and neurodevelopmental abnormalities.
Subject(s)
Eye Diseases, Hereditary , Genetic Diseases, X-Linked , Night Blindness , TRPM Cation Channels , Chromosome Deletion , Chromosome Disorders , Chromosomes, Human, Pair 15 , Electroretinography , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/genetics , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Humans , Intellectual Disability , Mutation , Myopia , Night Blindness/congenital , Night Blindness/diagnosis , Night Blindness/genetics , Pedigree , Seizures , TRPM Cation Channels/genetics , TRPM Cation Channels/metabolismABSTRACT
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.
Subject(s)
Cataract , Eye Abnormalities , Genetic Testing , Retinal Diseases , Cataract/diagnosis , Cataract/genetics , Child, Preschool , Eye , Eye Abnormalities/genetics , Humans , Infant , Infant, Newborn , Retinal Diseases/diagnosis , Retinal Diseases/geneticsABSTRACT
PURPOSE: Broadening access to genomic testing and counseling will be necessary to realize the benefits of personalized health care. This study aimed to assess the feasibility of delivering a standardized genomic care model for inherited retinal dystrophy (IRD) and of using selected measures to quantify its impact on patients. METHODS: A pre-/post- prospective cohort study recruited 98 patients affected by IRD to receive standardized multidisciplinary care. A checklist was used to assess the fidelity of the care process. Three patient-reported outcome measures-the Genetic Counselling Outcome Scale (GCOS-24), the ICEpop CAPability measure for Adults (ICECAP-A), and the EuroQol 5-dimension questionnaire (EQ-5D)-and a resource-use questionnaire were administered to investigate rates of missingness, ceiling effects, and changes over time. RESULTS: The care model was delivered consistently. Higher rates of missingness were found for the genetic-specific measure (GCOS-24). Considerable ceiling effects were observed for the generic measure (EQ-5D). The ICECAP-A yielded less missing data without significant ceiling effects. It was feasible to use telephone interviews for follow-up data collection. CONCLUSION: The study highlighted challenges and solutions associated with efforts to standardize genomic care for IRD. The study identified appropriate methods for a future definitive study to assess the clinical effectiveness and cost-effectiveness of the care model.Genet Med advance online publication 02 March 2017.
