Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Hadalin, Vlasta; Šuštar, Maja; Volk, Marija; Maver, Aleš; Sajovic, Jana; Jarc-Vidmar, Martina; Peterlin, Borut; Hawlina, Marko; Fakin, Ana

doi:10.3390/genes12040499

Cited by 9 publications

(11 citation statements)

References 94 publications

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“…The hypoautofluorescence within the ring in DRAM2 corresponded to the RPE atrophy, which presumably followed photoreceptor loss, as has been observed in other CRD patients [30]. FAF images from follow-up visits showed the enlargement of the hyperautofluorescent rings, a clinical feature that suggests disease progression over time and that has also been reported in patients with other CRD [31,[33][34][35]. The enlarging of central hypoautofluorescence is consistent with expanding macular atrophy, and the expansion of the hyperautofluorescent ring probably reflects the disorganization of the photoreceptors during the progress of the disease [31,33].…”

Section: Fafsupporting

confidence: 65%

“…and a missense variant (p.Leu246Pro). The other six patients with relatively late disease onset (30)(31)(32)(33)(34)(35)(36)(37)(38)(39) ). We presume that certain alleles, such as p.Leu246Pro, retain some residual function of DRAM2 protein; however, a larger cohort of patients with the same genotypes and/or in vitro studies are needed to confirm this.…”

Section: Disease Onsetmentioning

confidence: 99%

“…Among these, 42% (8/19) Macular photoreceptor loss, normal peripheral retina (29). Maculopathy, mid-peripheral degenerations (35). Central macular atrophy, surrounding granular appearance, mid-peripheral bone-spicule pigmentation (47).…”

Section: Genetic Findingsmentioning

confidence: 99%

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The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

Krašovec

Volk

Habjan

et al. 2022

IJMS

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Pathogenic variants in DNA-damage regulated autophagy modulator 2 gene (DRAM2) cause a rare autosomal recessive retinal dystrophy and its disease course is not well understood. We present two Slovenian patients harboring a novel DRAM2 variant and a detailed review of all 23 other patients described to date. Whole exome and whole genome sequencing were performed in the two patients, and both underwent ophthalmological examination with a 2-year follow-up. PubMed was searched for papers with clinical descriptions of DRAM2 retinopathy. Patient 1 was homozygous for a novel variant, p.Met1?, and presented with the acute onset of photopsia and retina-wide retinopathy at the age of 35 years. The patient was first thought to have an autoimmune retinopathy and was treated with mycophenolate mofetil, which provided some symptomatic relief. Patient 2 was compound heterozygous for p.Met1? and p.Leu246Pro and presented with late-onset maculopathy at the age of 59 years. On review, patients with DRAM2 retinopathy usually present in the third decade with central visual loss, outer retinal layer loss on optical coherence tomography and a hyperautofluorescent ring on fundus autofluorescence. Either cone–rod or rod–cone dystrophy phenotype is observed on electroretinography, reflecting the importance of DRAM2 in both photoreceptor types. Non-null variants can result in milder disease.

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Section: Fafsupporting

confidence: 65%

Section: Disease Onsetmentioning

confidence: 99%

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The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

Krašovec

Volk

Habjan

et al. 2022

IJMS

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“…Inactivation of the X chromosome is believed to contribute to more severe phenotype [18], however, presence of other modifying genetic factors has also been discussed [19]. According to literature, RPGR carriers are most likely to present symptoms that might be grouped in four main patterns of fundus appearance: normal or near normal pattern, a tapetal reflex, focal or patchy pigmentary retinopathy limited to a quadrant or hemisphere, and three or more quadrants of bone spicule pigmentation or atrophy [20]. Most patients complain of myopia, with 50% -72% having a refractive error of greater than −6 diopters [21].…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Nonsense <i>RPGR</i> Variant Causing Mild X-Linked Cone-Rod Dystrophy and Myopia

Kamenarova¹,

Cherninkova²,

Mihova³

et al. 2022

CRCM

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Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders characterized by the primary degeneration of cone photoreceptors often followed by progressive loss of rod photoreceptors in the peripheral visual field. Purpose: The aim of this study was to describe the milder CRD phenotype associated with a novel pathogenic variant c.1905 + 223C > T (p.Q710X) found in RPGR which results in shortening of the photoreceptor specific isoform RPGR ORF15 . Method: An 11-year-old boy with symptoms of CRD and two female relatives were referred for detailed ophthalmic examinations. Genetic testing was performed by next-generation sequencing of clinical exome followed by Sanger sequencing for segregation analysis. Results: Genetic analysis identified a novel variant in ORF15 of the RPGR gene (c.1905 + 223C > T, p.Q710X) in the proband considered as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) standards. Segregation study identified the mutation in a heterozygous state in the mother and her sister. Detailed ophthalmological examination revealed slightly reduced color vision and scattered grayish point-like deposits in the posterior pole of the fundus in the male patient. All mutation carriers were myopic. Conclusion: We report a novel pathogenic RPGR variant in a Bulgarian patient with clinical features compatible with the CRD diagnosis.

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“…Indeed, Ttll5 −/− and Rpgr −/− mice share common features (early cone involvement and overall long-term disease progression) because both phenotypes are due to a nonfunctional RPGR ORF15 . In humans, RPGR ORF15 gene defects are observed in both CORD and RCD patients [35][36][37]. Sun et al suggested a selection bias for CORD involvement.…”

Section: Phenotype Characteristicsmentioning

confidence: 99%

Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

Smirnov

Grunewald

Muller

et al. 2021

IJMS

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Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

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Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Cited by 9 publications

References 94 publications

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

Identification of Novel Nonsense <i>RPGR</i> Variant Causing Mild X-Linked Cone-Rod Dystrophy and Myopia

Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

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Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Cited by 9 publications

References 94 publications

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

The Clinical Spectrum and Disease Course of DRAM2 Retinopathy

Identification of Novel Nonsense &lt;i&gt;RPGR&lt;/i&gt; Variant Causing Mild X-Linked Cone-Rod Dystrophy and Myopia

Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

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Identification of Novel Nonsense <i>RPGR</i> Variant Causing Mild X-Linked Cone-Rod Dystrophy and Myopia