Interpretation of BRCA2 Splicing Variants: A Case Series of Challenging Variant Interpretations and the Importance of Functional RNA Analysis.
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SUBMITTER: Nix P
PROVIDER: S-EPMC8799590 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:SpliceAI is an open-source deep learning splicing prediction algorithm that has demonstrated in the past few years its high ability to predict splicing defects caused by DNA variations. However, its outputs present several drawbacks: (1) although the numerical values are very convenient for batch filtering, their precise interpretation can be difficult, (2) the outputs are delta scores which can sometimes mask a severe consequence, and (3) complex delins are most often not handled. We present here SpliceAI-visual, a free online tool based on the SpliceAI algorithm, and show how it complements the traditional SpliceAI analysis. First, SpliceAI-visual manipulates raw scores and not delta scores, as the latter can be misleading in certain circumstances. Second, the outcome of SpliceAI-visual is user-friendly thanks to the graphical presentation. Third, SpliceAI-visual is currently one of the only SpliceAI-derived implementations able to annotate complex variants (e.g., complex delins). We report here the benefits of using SpliceAI-visual and demonstrate its relevance in the assessment/modulation of the PVS1 classification criteria. We also show how SpliceAI-visual can elucidate several complex splicing defects taken from the literature but also from unpublished cases. SpliceAI-visual is available as a Google Colab notebook and has also been fully integrated in a free online variant interpretation tool, MobiDetails ( https://mobidetails.iurc.montp.inserm.fr/MD ).
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Project description:BackgroundAlport syndrome is a hereditary kidney disease characterized by hematuria and proteinuria. Although there have been reports of autosomal dominant COL4A4 variants, this is likely an underdiagnosed condition. Improved access to affordable genetic testing has increased the diagnosis of Alport syndrome. As genetic testing becomes ubiquitous, it is imperative that clinical nephrologists understand the benefits and challenges associated with clinical genetic testing.Case presentationWe present a family of Mexican descent with a heterozygous COL4A4 variant (c.5007delC, ClinVar accession numbers: SCV001580980.2, SCV001993731.1) not previously discussed in detail in the literature. The proband received a biopsy diagnosis suggestive of Fabry disease 18 years after she first developed hematuria and progressed to chronic kidney disease stage III. One year later, the proband was provisionally diagnosed with Alport syndrome after a variant of uncertain significance in the COL4A4 gene was identified following targeted family variant testing of her daughter. Upon review of the medical histories of the proband's children and niece, all but one had the same variant. Of the four with the variant, three display clinical symptoms of hematuria, and/or proteinuria. The youngest of the four, only months old, has yet to exhibit clinical symptoms. Despite these findings there was a considerable delay in synthesizing this data, as patients were tested in different commercial genetic testing laboratories. Subsequently, understanding this family's inheritance pattern, family history, and clinical symptoms, as well as the location of the COL4A4 variant resulted in the upgrade of the variant's classification. Although the classification of this variant varied among different clinical genetic testing laboratories, the consensus was that this variant is likely pathogenic.ConclusionsThis COL4A4 variant (c.5007delC) not yet discussed in detail in the literature is associated with Alport syndrome. The inheritance pattern is suggestive of autosomal dominant inheritance. This report highlights the intricacies of variant interpretation and classification, the siloed nature of commercial genetic testing laboratories, and the importance of a thorough family history for proper variant interpretation. Additionally, the cases demonstrate the varied clinical presentations of Alport syndrome and suggest the utility of early screening, diagnosis, monitoring, and treatment.
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Project description:BackgroundExtracorporeal membrane oxygenation (ECMO) use in patients with active bleedings or traumatic injuries may be challenging because of the risk of refractory haemorrhage related to systemic anticoagulation (SA). Technological advancements, especially heparin coated circuits, allowed ECMO application with a mild or no anticoagulation regimen in some circumstances. We herein report a limited case-series of ECMO application without anticoagulation.MethodsECMO without SA was established in 6 patients. Four of them received veno-arterial mode. Full heparin antagonization with protamine was provided in 3 post-cardiotomy cases. Tip-to-tip heparin-coated ECMO circuit was used in 4 patients, whereas heparin-coated tubing and no heparin-coated cannulas were applied for the remaining subjects.ResultsMean duration of support and pump flow were 10±4 hours and 3.0±0.7 litres respectively. No ECMO related complication or oxygenator failure occurred, nor was clotting of the circuit observed at inspection. All patients were weaned from ECMO and half of them survived and were discharged.ConclusionsShort ECMO duration without anticoagulation was feasible and provided effective cardiopulmonary support in patients with active bleeding or high hemorrhagic risk. Further investigations are needed to evaluate its benefits or limitations for a protracted time, in a wider range of clinical conditions and in larger patient populations.
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