TY  - JOUR
AB  - 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.
AU  - Spieler, D.
AU  - Velayos-Baeza, A.*
AU  - Mühlbäck, A.*
AU  - Castrop, F.*
AU  - Maegerlein, C.*
AU  - Slotta-Huspenina, J.*
AU  - Bader, B.*
AU  - Haslinger, B.*
AU  - Danek, A.*
C1  - 59010
C2  - 48446
TI  - Identification of two compound heterozygous VPS13A large deletions in chorea-acanthocytosis only by protein and quantitative DNA analysis.
JO  - Mol. Genet. Genomic Med.
VL  - 8
IS  - 9
PY  - 2020
SN  - 2324-9269
ER  - 

TY  - JOUR
AB  - Background: Genes encoding cardiac ion channels or regulating proteins have been associated with the inherited form of long QT syndrome (LQTS). Complex pathophysiology and missing functional studies, however, often bedevil variant interpretation and classification. We aimed to evaluate the rate of change in variant classification based on current interpretation standards and dependent on clinical findings. Methods: Medical charts of children with a molecular genetic diagnosis of LQTS presenting at our centers were retrospectively reviewed. Reinterpretation of originally reported variants in genes associated with LQTS was performed based on current knowledge (March 2019) and according to the “Standards and Guidelines for the Interpretation of Sequence Variants” by the ACMG 2015. Results: About 84 distinct (likely) pathogenic variants identified in 127 patients were reinterpreted. In 12 variants (12/84, 14.3%), classification changed from (likely) pathogenic to variant of unknown significance (VUS). One of these variants was a hypomorphic allele escaping the standard variant classification. Individuals with variants that downgraded to VUS after reevaluation showed significantly lower Schwartz scores and QTc intervals compared to individuals with unchanged variant characterization. Conclusion: This finding confirms genetic variant interpretation as a dynamic process and underlines the importance of ongoing genetic counseling, especially in LQTS patients with minor clinical criteria.
AU  - Westphal, D.S.
AU  - Burkard, T.*
AU  - Moscu-Gregor, A.*
AU  - Gebauer, R.*
AU  - Hessling, G.*
AU  - Wolf, C.M.*
C1  - 59067
C2  - 48553
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Reclassification of genetic variants in children with long QT syndrome.
JO  - Mol. Genet. Genomic Med.
VL  - 8
IS  - 9
PB  - Wiley
PY  - 2020
SN  - 2324-9269
ER  -