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.

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Neurology Klinikum rechts der Isar Technische Universität München Munich Germany

Department of Neuroradiology Klinikum rechts der Isar Technische Universität München Munich Germany

Department of Psychosomatic Medicine and Psychotherapy Center for Mental Health Faculty of Medicine Albert Ludwigs Universität Freiburg Freiburg Germany

Institut für Allgemeine Pathologie und Pathologische Anatomie der Technischen Universität München Klinikum rechts der Isar Technische Universität München Munich Germany

Institute of Epidemiology Mental Health Research Unit Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

kbo Isar Amper Klinikum Taufkirchen Germany

Neurologische Klinik und Poliklinik Ludwigs Maximilians Universität München Munich Germany

Wellcome Centre for Human Genetics University of Oxford Oxford United Kingdom

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