A Novel FLVCR1 Variant Implicated in Retinitis Pigmentosa

Dockery, Adrian; Carrigan, Matthew; Wynne, Niamh; Stephenson, Kirk; Keegan, David; Kenna, Paul F.; Farrar, G. Jane

doi:10.1007/978-3-030-27378-1_33

Cited by 7 publications

(10 citation statements)

References 18 publications

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“…It is notable the c.1022A>G (p.Tyr341Cys) variant is only the second disease-associated variant to be found in FLVCR1 associated with RP without posterior column degeneration [43]. Moreover, it is the first protein coding variant found in this gene to be affiliated with non-syndromic RP [45]. There were no extraocular features associated with this variant (Figure 10).…”

Section: Discussionmentioning

confidence: 99%

“…Typically, variants in FLVCR1 have been associated with a neurological syndrome, posterior column ataxia with retinitis pigmentosa (PCARP; MIM: 609033) [39][40][41], and more recently a specific splice variant (c.1092 + 5G>A) has been reported multiple times to be associated with non-syndromic RP [42][43][44]. Through Target 5000, substantial evidence has been obtained that suggests the first incidence of a protein coding FLVCR1 variant c.1022A>G (p.Tyr341Cys) implicated in non-syndromic RP [45]. RP is the most common clinical diagnosis for participants in the Target 5000 study, where the clinical diagnosis of RP accounts for nearly 40% (379/1004) of total pedigrees enrolled to date (Figure 1).…”

Section: Flvcr1mentioning

confidence: 99%

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

Whelan

Dockery

Wynne

et al. 2020

Genes

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Flvcr1mentioning

confidence: 99%

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

Whelan

Dockery

Wynne

et al. 2020

Genes

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“…Our team has previously reported a pedigree in which five affected members of the family were broadly categorised as RP phenotypes. After genetic investigation it was revealed that four of these individuals were homozygous for a FLVCR1 variant, while the remaining affected patient was compound heterozygous for pathogenic variants in NR2E3 [ 84 ]. Similarly, in a US study, involving three IRD pedigrees, each given an initial diagnosis of RP, one with a dominant RP and the other two with a dominant, incompletely penetrant RP, it was found that multiple IRD genes were responsible for various affected individuals in each of the three families: both USH2A and RP1 was segregating in one family; PRPH2 and CRX in a second family and PRPH2 , PRPH8 and USH2A in the third family [ 85 ].…”

Section: Irds—target Panels and Whole Exome Studiesmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Dockery

Whelan

Humphries

et al. 2021

IJMS

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Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.

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“…Of note, nine reported cases with isolated RP carry the c.1092+5G>A splice site variant on at least one allele (Glöckle et al, 2014;Tiwari et al, 2016;Yusuf et al, 2018). The c.1022A>G variant was reported in a homozygous state in seven patients with isolated RP (Dockery et al, 2019). It has also been noted by Kuehlewein et al.…”

Section: Discussionmentioning

confidence: 68%

Extending the phenotype of posterior column ataxia with retinitis pigmentosa caused by variants in FLVCR1

Vaughan

Costello

2021

American J of Med Genetics Pt A

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Posterior column ataxia with retinitis pigmentosa (PCARP) is a rare autosomal recessive condition due to variants in the Feline Leukemia Virus Subgroup C Cellular Receptor 1 (FLVCR1) gene which was first described in 1997. In this article, we describe a young female patient with a childhood diagnosis of retinitis pigmentosa and learning disability, presenting with progressive ataxia from her late teens. Examination revealed spastic lower limbs with absent reflexes, and reduced vibration and joint position sensation. Magnetic resonance imaging showed normal cerebellar volume and linear signal abnormality within the posterior columns of her spinal cord.Trio exome analysis confirmed two variants in FLVCR1. Our case extends the phenotype of PCARP to include learning disability and developmental delay, and highlights the importance of considering this rare condition in young adults or children with visual impairment and ataxia.

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A Novel FLVCR1 Variant Implicated in Retinitis Pigmentosa

Cited by 7 publications

References 18 publications

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

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

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Extending the phenotype of posterior column ataxia with retinitis pigmentosa caused by variants in FLVCR1

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