Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies

Tiwari, Anjali; Bahr, Angela; Bähr, Luzy; Fleischhauer, Johannes; Zinkernagel, Martin S.; Winkler, Niklas; Barthelmes, Daniel; Berger, Lieselotte Erika; Gerth‐Kahlert, Christina; Neidhardt, John; Berger, Wolfgang

doi:10.1038/srep28755

Cited by 67 publications

(67 citation statements)

References 30 publications

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“…Here, we demonstrated homozygosity for the previously identified p.Pro221Ser FLVCR1 variation in a sporadic case of an Italian woman with a mixed phenotype of HSAN, PCARP, and acute lymphocytic leukemia. To date, FLVCR1 mutations were linked to PCARP (Ishiura et al, ; Rajadhyaksha et al, ; Shaibani et al, ), isolated retinitis pigmentosa (Glöckle et al, ; Tiwari et al, ), and HSAN (Chiabrando et al, ) (Table ). In the present patient, the term HSAN was justified by the combination of congenital insensitivity to pain, sensory loss to all modalities and multiple autonomic dysregulations.…”

Section: Discussionmentioning

confidence: 99%

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Posterior column ataxia with retinitis pigmentosa coexisting with sensory‐autonomic neuropathy and leukemia due to the homozygous p.Pro221Ser FLVCR1 mutation

Castori

Morlino

Ungelenk

et al. 2017

American J of Med Genetics Pt B

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FLVCR1 encodes for a ubiquitous heme exporter, whose recessive mutations cause posterior column ataxia with retinitis pigmentosa (PCARP). Recently, FLVCR1 recessive mutations were also found in two sporadic children with hereditary sensory-autonomic neuropathy (HSAN). We report the unique case of a 33-year-old Italian woman with a combination of typical PCARP, sensory-autonomic neuropathy with sensory loss to all modalities and multiple autonomic dysfuctions, and acute lymphocytic leukemia. Molecular analysis demonstrated homozygosity for the previously identified FLVCR1 p.Pro221Ser variation. The same variation, in combination with a frameshift mutation, was previously identified in an Italian child with HSAN. Functional studies carried out on patient-derived lymphoblastoid cell lines showed decreased FLVCR1a transcript, increased reactive oxygen species, excessive intracellular heme accumulation, and increased number of Annexin V positive cells. This indicates that the homozygous p.Pro221Ser FLVCR1 variation compromises the ability of FLVCR1a to export heme leading to enhanced susceptibility to programmed cell death. Our study demonstrates the existence of a phenotypic continuum among the discrete disorders previously linked to FLVCR1 mutations, and suggests that the related alteration of heme metabolism may lead to the degeneration of specific neuronal cell populations.

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Section: Discussionmentioning

confidence: 99%

“…The identified mutations were demonstrated to affect the expression, localization and folding of FLVCR1, and the regulation of heme efflux (Yanatori et al, ). FLVCR1 recessive mutations are also a rare cause of isolated retinitis pigmentosa (Glöckle et al, ; Tiwari et al, ).…”

Section: Introductionmentioning

confidence: 99%

Posterior column ataxia with retinitis pigmentosa coexisting with sensory‐autonomic neuropathy and leukemia due to the homozygous p.Pro221Ser FLVCR1 mutation

Castori

Morlino

Ungelenk

et al. 2017

American J of Med Genetics Pt B

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“…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].…”

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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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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“…To date, a molecular diagnosis can be identified by whole exome sequencing (WES) in approximately 60%–70% of RP and LCA patients (Haer‐Wigman et al., ; Kumaran et al., ; Tiwari et al., ; Zhao et al., ). In the remaining cases, the causative variants could be located in a gene that has not yet been associated with early‐onset retinal dystrophies.…”

Section: Introductionmentioning

confidence: 99%

The identification of a RNA splice variant in TULP1 in two siblings with early‐onset photoreceptor dystrophy

Verbakel

Fadaie

Klevering

et al. 2019

Molec Gen & Gen Med

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Background Early‐onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30%–40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease. Methods Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit‐lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay. Results Clinical assessment showed a typical early‐onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift. Conclusion Here, we report the first near‐exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early‐onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.

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Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies

Cited by 67 publications

References 30 publications

Posterior column ataxia with retinitis pigmentosa coexisting with sensory‐autonomic neuropathy and leukemia due to the homozygous p.Pro221Ser FLVCR1 mutation

Posterior column ataxia with retinitis pigmentosa coexisting with sensory‐autonomic neuropathy and leukemia due to the homozygous p.Pro221Ser FLVCR1 mutation

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

The identification of a RNA splice variant in TULP1 in two siblings with early‐onset photoreceptor dystrophy

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