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

Weisschuh, Nicole; Mazzola, Pascale; Heinrich, T.; Haack, Tobias B.; Wissinger, Bernd; Tonagel, Felix; Kelbsch, Carina

doi:10.1186/s12881-020-01166-z

Cited by 18 publications

(20 citation statements)

References 29 publications

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“…Screening for large-scale rearrangements was performed using multiplex ligation-dependent probe amplification (MLPA) [ 60 ]. Since 2012, patients’ DNAs were subjected to next-generation sequencing (NGS), either using a panel-based approach or whole genome sequencing [ 62 , 77 ].…”

Section: Methodsmentioning

confidence: 99%

“…Accordingly, the majority of disease-causing variants are predicted to give rise to truncated OPA1 polypeptides, either due to nonsense, frameshift or splice variants, the latter including deep intronic variants causing the inclusion of pseudoexons into the transcript [ 58 , 59 ]. In addition, structural variants such as copy number variants (CNVs) and inversions are part of the mutation spectrum of OPA1 [ 60 – 62 ]. Disease-causing variants are spread over the entire coding sequence, however, very few have been reported for the alternatively spliced exons [ 63 ].…”

Section: Introductionmentioning

confidence: 99%

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Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants

et al. 2021

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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 probands with a diagnosis of bilateral optic atrophy were referred to our laboratory for molecular genetic investigation. Genetic testing of the OPA1 gene was initially performed by a combined analysis using either single-strand conformation polymorphism or denaturing high performance liquid chromatography followed by Sanger sequencing to validate aberrant bands or melting profiles. The presence of copy number variations was assessed using multiplex ligation-dependent probe amplification. Since 2012, genetic testing was based on next-generation sequencing platforms. Genetic screening of the OPA1 gene revealed putatively pathogenic variants in 278 unrelated probands which represent 36.8% of the entire cohort. A total of 156 unique variants were identified, 78% of which can be considered null alleles. Variant c.2708_2711del/p.(V903Gfs*3) was found to constitute 14% of all disease-causing alleles. Special emphasis was placed on the validation of splice variants either by analyzing cDNA derived from patients´ blood samples or by heterologous splice assays using minigenes. Splicing analysis revealed different aberrant splicing events, including exon skipping, activation of exonic or intronic cryptic splice sites, and the inclusion of pseudoexons. Forty-eight variants that we identified were novel. Nine of them were classified as pathogenic, 34 as likely pathogenic and five as variant of uncertain significance. Our study adds a significant number of novel variants to the mutation spectrum of the OPA1 gene and will thereby facilitate genetic diagnostics of patients with suspected dominant optic atrophy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants

et al. 2021

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“…All three patients in this study underwent diagnostic genetic testing by whole genome sequencing. Methodological details have already been published [13]. Briefly, sequencing (2 × 150 bp paired-end reads) was performed on an Illumina platform (NovaSeq6000).…”

Section: Validation Of Variantsmentioning

confidence: 99%

“…Genetic diagnostic testing was performed by whole genome sequencing. Methodological details have already been published [13].…”

Section: Genetic Diagnostic Testingmentioning

confidence: 99%

Clinical Characteristics of POC1B-Associated Retinopathy and Assignment of Pathogenicity to Novel Deep Intronic and Non-Canonical Splice Site Variants

Weisschuh

Mazzola

Bertrand

et al. 2021

IJMS

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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 photophobia. Whole genome sequencing revealed a novel homozygous frameshift variant in one patient. Another patient was shown to harbor a novel deep intronic variant in compound heterozygous state with a previously reported canonical splice site variant. The third patient showed a novel nonsense variant and a novel non-canonical splice site variant. We aimed to validate the effect of the deep intronic variant and the non-canonical splice site variant by means of in vitro splice assays. In addition, direct RNA analysis was performed in one patient. Splicing analysis revealed that the non-canonical splice site variant c.561-3T>C leads to exon skipping while the novel deep intronic variant c.1033-327T>A causes pseudoexon activation. Our data expand the genetic landscape of POC1B mutations and confirm the benefit of genome sequencing in combination with downstream functional validation using minigene assays for the analysis of putative splice variants. In addition, we provide clinical multimodal phenotyping of the affected individuals.

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“…Thus, there is a possibility that the copy-neutral rearrangements, such as inversions or insertions, contribute to disease occurrence. However, they cannot be detected through microarray (Figure 4), as evidenced in the literature [47][48][49]. Hence, with the usage of whole-genome analysis and the availability of appropriate algorithms or analysis software that can efficiently detect inversions and insertions without copy number changes, the diagnostic yields of the disease-causing genomic backgrounds will increase.…”

Section: Novel Developments Expected In Whole Genome Analysis For the Detection Of Chromosomal Aberrationsmentioning

confidence: 99%

Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders

Yamamoto

2021

Cells

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Genomic studies are increasingly revealing that neurodevelopmental disorders are caused by underlying genomic alterations. Chromosomal microarray testing has been used to reliably detect minute changes in genomic copy numbers. The genes located in the aberrated regions identified in patients with neurodevelopmental disorders may be associated with the phenotypic features. In such cases, haploinsufficiency is considered to be the mechanism, when the deletion of a gene is related to neurodevelopmental delay. The loss-of-function mutation in such genes may be evaluated using next-generation sequencing. On the other hand, the patients with increased copy numbers of the genes may exhibit different clinical symptoms compared to those with loss-of-function mutation in the genes. In such cases, the additional copies of the genes are considered to have a dominant negative effect, inducing cell stress. In other cases, not the copy number changes, but mutations of the genes are responsible for causing the clinical symptoms. This can be explained by the dominant negative effects of the gene mutations. Currently, the diagnostic yield of genomic alterations using comprehensive analysis is less than 50%, indicating the existence of more subtle alterations or genomic changes in the untranslated regions. Copy-neutral inversions and insertions may be related. Hence, better analytical algorithms specialized for the detection of such alterations are required for higher diagnostic yields.

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

Cited by 18 publications

References 29 publications

Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants

Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants

Clinical Characteristics of POC1B-Associated Retinopathy and Assignment of Pathogenicity to Novel Deep Intronic and Non-Canonical Splice Site Variants

Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders

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