Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis
Abstract Background Chorea‐acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely...
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| Format: | Article |
| Language: | English |
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Wiley
2020-09-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1179 |
| _version_ | 1827345743830056960 |
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| author | Derek Spieler Antonio Velayos‐Baeza Alžbeta Mühlbäck Florian Castrop Christian Maegerlein Julia Slotta‐Huspenina Benedikt Bader Bernhard Haslinger Adrian Danek |
| author_facet | Derek Spieler Antonio Velayos‐Baeza Alžbeta Mühlbäck Florian Castrop Christian Maegerlein Julia Slotta‐Huspenina Benedikt Bader Bernhard Haslinger Adrian Danek |
| author_sort | Derek Spieler |
| collection | DOAJ |
| description | Abstract Background Chorea‐acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. Methods Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. Results We report a 33‐year‐old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. Conclusion Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT‐PCR analysis, necessary to avoid false negative results. |
| first_indexed | 2024-03-07T23:17:04Z |
| format | Article |
| id | doaj.art-87d6d31fc1f649f3ae452680d792cfdc |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:17:04Z |
| publishDate | 2020-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-87d6d31fc1f649f3ae452680d792cfdc2024-02-21T10:24:50ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-09-0189n/an/a10.1002/mgg3.1179Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysisDerek Spieler0Antonio Velayos‐Baeza1Alžbeta Mühlbäck2Florian Castrop3Christian Maegerlein4Julia Slotta‐Huspenina5Benedikt Bader6Bernhard Haslinger7Adrian Danek8Department of Psychosomatic Medicine and Psychotherapy Center for Mental Health Faculty of Medicine Albert‐Ludwigs‐Universität Freiburg Freiburg GermanyWellcome Centre for Human Genetics University of Oxford Oxford United Kingdomkbo‐Isar‐Amper‐Klinikum Taufkirchen (Vils) Taufkirchen (Vils) GermanyDepartment of Neurology Klinikum rechts der Isar Technische Universität München Munich GermanyDepartment of Neuroradiology Klinikum rechts der Isar Technische Universität München Munich GermanyInstitut für Allgemeine Pathologie und Pathologische Anatomie der Technischen Universität München Klinikum rechts der Isar Technische Universität München Munich GermanyNeurologische Klinik und Poliklinik Ludwigs‐Maximilians Universität München Munich GermanyDepartment of Neurology Klinikum rechts der Isar Technische Universität München Munich GermanyNeurologische Klinik und Poliklinik Ludwigs‐Maximilians Universität München Munich GermanyAbstract Background Chorea‐acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. Methods Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. Results We report a 33‐year‐old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. Conclusion Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT‐PCR analysis, necessary to avoid false negative results.https://doi.org/10.1002/mgg3.1179chorea‐acanthocytosischoreincompound heterozygositydeletionVPS13A |
| spellingShingle | Derek Spieler Antonio Velayos‐Baeza Alžbeta Mühlbäck Florian Castrop Christian Maegerlein Julia Slotta‐Huspenina Benedikt Bader Bernhard Haslinger Adrian Danek Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis Molecular Genetics & Genomic Medicine chorea‐acanthocytosis chorein compound heterozygosity deletion VPS13A |
| title | Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis |
| title_full | Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis |
| title_fullStr | Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis |
| title_full_unstemmed | Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis |
| title_short | Identification of two compound heterozygous VPS13A large deletions in chorea‐acanthocytosis only by protein and quantitative DNA analysis |
| title_sort | identification of two compound heterozygous vps13a large deletions in chorea acanthocytosis only by protein and quantitative dna analysis |
| topic | chorea‐acanthocytosis chorein compound heterozygosity deletion VPS13A |
| url | https://doi.org/10.1002/mgg3.1179 |
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