First submicroscopic inversion of the OPA1 gene identified in dominant optic atrophy - a case report

Published on Nov 26, 2020in BMC Medical Genetics1.585
· DOI :10.1186/S12881-020-01166-Z
Nicole Weisschuh27
Estimated H-index: 27
(University of Tübingen),
Pascale Mazzola1
Estimated H-index: 1
(University of Tübingen)
+ 4 AuthorsCarina Kelbsch7
Estimated H-index: 7
(University of Tübingen)
Dominant optic atrophy (DOA) is an inherited optic neuropathy that mainly affects visual acuity, central visual fields and color vision due to a progressive loss of retinal ganglion cells and their axons that form the optic nerve. Approximately 45–90% of affected individuals with DOA harbor pathogenic variants in the OPA1 gene. The mutation spectrum of OPA1 comprises nonsense, canonical and non-canonical splice site, frameshift and missense as well as copy number variants, but intragenic inversions have not been reported so far. We report a 33-year-old male with characteristic clinical features of DOA. Whole-genome sequencing identified a structural variant of 2.4 kb comprising an inversion of 937 bp at the OPA1 locus. Fine mapping of the breakpoints to single nucleotide level revealed that the structural variation was an inversion flanked by two deletions. As this rearrangement inverts the entire first exon of OPA1, it was classified as likely pathogenic. We report the first DOA case harboring an inversion in the OPA1 gene. Our study demonstrates that copy-neutral genomic rearrangements have to be considered as a possible cause of disease in DOA cases.
#1Nicole Weisschuh (University of Tübingen)H-Index: 27
#2Marc Sturm (University of Tübingen)H-Index: 20
Last. Susanne Kohl (University of Tübingen)H-Index: 41
view all 25 authors...
: Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic ...
12 CitationsSource
#1Bastien Le RouxH-Index: 1
#2Guy Lenaers (University of Angers)H-Index: 40
Last. Marc Ferré (University of Angers)H-Index: 21
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Background The dysfunction of OPA1, a dynamin GTPase involved in mitochondrial fusion, is responsible for a large spectrum of neurological disorders, each of which includes optic neuropathy. The database dedicated to OPA1 ( ), created in 2005, has now evolved towards a centralized and more reliable database using the Global Variome shared Leiden Open-source Variation Database (LOVD) installation.
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#2Ashley D. SandersH-Index: 15
Last. Charles Lee (Ewha Womans University)H-Index: 88
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The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per ge...
354 CitationsSource
#1Stacy L. PinelesH-Index: 1
#1Stacy L. PinelesH-Index: 22
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Abstract The diagnosis of optic neuropathy is usually considered under two circumstances: (1) when visual loss is associated with an anomalous, swollen, or pale optic disc or (2) when the fundus examination is normal but deficits in acuity, color, and visual field are accompanied by an afferent pupillary defect. In each of these situations the examiner must rely upon historical information, examination findings, and diagnostic testing first to confirm the presence of optic nerve dysfunction, the...
3 CitationsSource
#1Fritz J. Sedlazeck (BCM: Baylor College of Medicine)H-Index: 29
#2Philipp Rescheneder (Medical University of Vienna)H-Index: 14
Last. Michael C. Schatz (Johns Hopkins University)H-Index: 71
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Structural variations are the greatest source of genetic variation, but they remain poorly understood because of technological limitations. Single-molecule long-read sequencing has the potential to dramatically advance the field, although high error rates are a challenge with existing methods. Addressing this need, we introduce open-source methods for long-read alignment (NGMLR; ) and structural variant identification (Sniffles;
546 CitationsSource
#1Ramona Bolognini (University of Bern)H-Index: 3
#2Christina Gerth-Kahlert (UZH: University of Zurich)H-Index: 9
Last. André Schaller (University of Bern)H-Index: 18
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Background We report two novel splice region mutations in OPA1 in two unrelated families presenting with autosomal-dominant optic atrophy type 1 (ADOA1) (ADOA or Kjer type optic atrophy). Mutations in OPA1 encoding a mitochondrial inner membrane protein are a major cause of ADOA.
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Summary: We describe Manta, a method to discover structural variants and indels from next generation sequencing data. Manta is optimized for rapid germline and somatic analysis, calling structural variants, medium-sized indels and large insertions on standard compute hardware in less than a tenth of the time that comparable methods require to identify only subsets of these variant types: for example NA12878 at 50× genomic coverage is analyzed in less than 20 min. Manta can discover and score var...
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#1Tatiana Varanita (UNIPD: University of Padua)H-Index: 9
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Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects m...
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Polymorphic inversions are a type of structural variants that are difficult to analyze owing to their balanced nature and the location of breakpoints within complex repeated regions. So far, only a handful of inversions have been studied in detail in humans and current knowledge about their possible functional effects is still limited. However, inversions have been related to phenotypic changes and adaptation in multiple species. In this review, we summarize the evidences of the functional impac...
64 CitationsSource
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Last. Matthis Synofzik (University of Tübingen)H-Index: 53
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The genetic diagnosis in inherited optic neuropathies often remains challenging, and the emergence of complex neurological phenotypes that involve optic neuropathy is puzzling. Here we unravel two novel principles of genetic mechanisms in optic neuropathies: deep intronic OPA1 mutations, which explain the disease in several so far unsolved cases; and an intralocus OPA1 modifier, which explains the emergence of syndromic ‘optic atrophy plus’ phenotypes in several families. First, we unravelled a ...
50 CitationsSource
Cited By4
#1Nicole Weisschuh (University of Tübingen)H-Index: 27
#2Simone Schimpf-Linzenbold (University of Tübingen)H-Index: 4
Last. Helmut Wilhelm (University of Tübingen)H-Index: 28
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Autosomal dominant optic atrophy is one of the most common inherited optic neuropathies. This disease is genetically heterogeneous, but most cases are due to pathogenic variants in the OPA1 gene: depending on the population studied, 32-90% of cases harbor pathogenic variants in this gene. The aim of this study was to provide a comprehensive overview of the entire spectrum of likely pathogenic variants in the OPA1 gene in a large cohort of patients. Over a period of 20 years, 755 unrelated proban...
#1Guy Lenaers (French Institute of Health and Medical Research)H-Index: 40
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Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions. Twent...
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#1Nicole Weisschuh (University of Tübingen)H-Index: 27
#2Pascale Mazzola (University of Tübingen)H-Index: 1
Last. Katarina Stingl (University of Tübingen)H-Index: 18
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Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy or cone-rod dystrophy) with normal funduscopy but disrupted outer retinal layers on optical coherence tomography and variable age of onset. Other symptoms were decreased visual acuity and ...
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We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-ons...