Targeted next generation sequencing and family survey enable correct genetic diagnosis in CRX associated macular dystrophy – a case report

Al‐Khuzaei, Saoud; Hudspith, Karl A. Z.; Broadgate, Suzanne; Shanks, Morag; Clouston, Penny; Németh, Andrea H.; Halford, Stephanie; Downes, Susan M.

doi:10.1186/s12886-021-01919-1

Cited by 3 publications

(3 citation statements)

References 18 publications

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“…CRX, a cone-rod homeobox-containing gene (OMIM: 602225), encodes a homeodomain transcription factor crucial for the development and survival of photoreceptors [85,86]. CRX-retinopathy encompasses severe AR-LCA, AR-RP, AD-CORD, AD-COD, and AD-MD; AD-MD shows a mild phenotype [39,[87][88][89][90][91][92][93][94][95][96][97][98][99][100][101]. The relatively mild phenotype of patients with CRX-OMD is consistent with the previous AD-CRX cases [87], although there are no reported CRX cases with the identical variant.…”

Section: Discussionmentioning

confidence: 99%

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5

Fujinami-Yokokawa,

Yang,

Joo

et al. 2023

Genes

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Occult macular dystrophy (OMD) is the most prevalent form of macular dystrophy in East Asia. Beyond RP1L1, causative genes and mechanisms remain largely uncharacterised. This study aimed to delineate the clinical and genetic characteristics of OMD syndrome (OMDS). Patients clinically diagnosed with OMDS in Japan, South Korea, and China were enrolled. The inclusion criteria were as follows: (1) macular dysfunction and (2) normal fundus appearance. Comprehensive clinical evaluation and genetic assessment were performed to identify the disease-causing variants. Clinical parameters were compared among the genotype groups. Seventy-two patients with OMDS from fifty families were included. The causative genes were RP1L1 in forty-seven patients from thirty families (30/50, 60.0%), CRX in two patients from one family (1/50, 2.0%), GUCY2D in two patients from two families (2/50, 4.0%), and no genes were identified in twenty-one patients from seventeen families (17/50, 34.0%). Different severities were observed in terms of disease onset and the prognosis of visual acuity reduction. This multicentre large cohort study furthers our understanding of the phenotypic and genotypic spectra of patients with macular dystrophy and normal fundus. Evidently, OMDS encompasses multiple Mendelian retinal disorders, each representing unique pathologies that dictate their respective severity and prognostic patterns.

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Section: Discussionmentioning

confidence: 99%

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5

Fujinami-Yokokawa,

Yang,

Joo

et al. 2023

Genes

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“…This is further complicated by the existence of phenocopies, which must be considered especially when only one variant is identified or in families with a pseudo-dominant inheritance pattern. This is because the IRD could be due to variants in other genes, such as PRPH2 [70] and CRX [72], which are associated with an autosomal dominant inheritance pattern, and have variable penetrance. There may be other clinical features in these other disorders that could help distinguish them [30].…”

Section: Discussionmentioning

confidence: 99%

“…Occasionally, the peripapillary region can be spared, as in STGD1 [78]. Heterozygous variants in CRX can result in a phenotype that mimics STGD1 and is associated with late-onset disease with a bull's eye maculopathy (BEM) [72], and cone and rod dysfunction detected on electrodiagnostic testing [73]. In a recent study, Wolock et al found that CRX and PRPH2 variants accounted for~10% of their "STGD1" patients not found to carry ABCA4 variants.…”

Section: Clinical Phenotypes and Phenocopies In Abca4 Retinopathies (Abca4r)mentioning

confidence: 99%

An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

Al‐Khuzaei

Broadgate

Foster

et al. 2021

Genes

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Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. Diagnosing ABCA4R is complex due to its phenotypic variability and the presence of other inherited retinal dystrophy phenocopies. ABCA4 is a large gene, comprising 50 exons; to date >2000 variants have been described. These include missense, nonsense, splicing, structural, and deep intronic variants. Missense variants account for the majority of variants in ABCA4. However, in a significant proportion of patients with an ABCA4R phenotype, a second variant in ABCA4 is not identified. This could be due to the presence of yet unknown variants, or hypomorphic alleles being incorrectly classified as benign, or the possibility that the disease is caused by a variant in another gene. This underlines the importance of accurate genetic testing. The pathogenicity of novel variants can be predicted using in silico programs, but these rely on databases that are not ethnically diverse, thus highlighting the need for studies in differing populations. Functional studies in vitro are useful towards assessing protein function but do not directly measure the flippase activity. Obtaining an accurate molecular diagnosis is becoming increasingly more important as targeted therapeutic options become available; these include pharmacological, gene-based, and cell replacement-based therapies. The aim of this review is to provide an update on the current status of genotyping in ABCA4 and the status of the therapeutic approaches being investigated.

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The utility of genomic testing in the ophthalmology clinic: A review

Burdon

2021

Clinical Exper Ophthalmology

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Genomic testing assesses many genes in one test. It is often used in the diagnosis of heterogeneous single gene disorders where pathogenic variation in one of many genes are known to cause similar phenotypes, or where a clinical diagnosis is difficult to reach. In the ophthalmic setting, genomic testing can be used to diagnose several groups of diseases, including inherited retinal dystrophies, paediatric cataract, glaucoma and anterior segment dysgenesis and other syndromic developmental disorders with eye involvement. The testing can encompass several modalities ranging from whole genome sequencing to exome sequencing or targeted gene panels. The advantages to the patient of receiving a molecular diagnosis include an end to the diagnostic odyssey, determination of prognosis and clarification of treatment, access to accurate genetic counselling, and confirming eligibility for clinical trials or genetic specific therapies. Genomic testing is a powerful addition to the diagnosis and management of inherited eye disease.

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Targeted next generation sequencing and family survey enable correct genetic diagnosis in CRX associated macular dystrophy – a case report

Cited by 3 publications

References 18 publications

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5

An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

The utility of genomic testing in the ophthalmology clinic: A review

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