Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay
Kobow, Katja; Jabari, Samir; Pieper, Tom; Kudernatsch, Manfred; Polster, Tilman; Woermann, Friedrich G; Kalbhenn, Thilo; Hamer, Hajo; Rössler, Karl; Mühlebner, Angelika; Spliet, Wim G M; Feucht, Martha; Hou, Yanghao; Stichel, Damian; Korshunov, Andrey; Sahm, Felix; Coras, Roland; Blümcke, Ingmar; von Deimling, Andreas
(2020) Acta Neuropathologica, volume 140, issue 6, pp. 881 - 891
(Article)
Abstract
Polymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also
... read more
been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here, we analyzed 26 PMG patients employing array-based DNA methylation profiling on formalin-fixed paraffin-embedded material. A series of 62 well-characterized non-PMG cortical malformations (focal cortical dysplasia type 2a/b and hemimegalencephaly), temporal lobe epilepsy, and non-epilepsy autopsy controls was used as reference cohort. Unsupervised dimensionality reduction and hierarchical cluster analysis of DNA methylation profiles showed that PMG formed a distinct DNA methylation class. Copy number profiling from DNA methylation data identified a uniform duplication spanning the entire long arm of chromosome 1 in 7 out of 26 PMG patients, which was verified by additional fluorescence in situ hybridization analysis. In respective cases, about 50% of nuclei in the center of the PMG lesion were 1q triploid. No chromosomal imbalance was seen in adjacent, architecturally normal-appearing tissue indicating mosaicism. Clinically, PMG 1q patients presented with a unilateral frontal or hemispheric PMG without hemimegalencephaly, a severe form of intractable epilepsy with seizure onset in the first months of life, and severe developmental delay. Our results show that PMG can be classified among other structural brain lesions according to their DNA methylation profile. One subset of PMG with distinct clinical features exhibits a duplication of chromosomal arm 1q.
show less
Download/Full Text
Keywords: Brain development, Chromosome 1, Copy number variation, Cortical malformation, ID, Seizures, Clinical Neurology, Cellular and Molecular Neuroscience, Pathology and Forensic Medicine, Journal Article
ISSN: 0001-6322
Publisher: Springer
Note: Funding Information: We kindly thank B. Rings for her expert technical assistance. Our work was supported by the European Union's Seventh Framework Program (DESIRE project, Grant agreement 602531) and European Reference Network EpiCare (Grant agreement 769501). A. Korshunov is supported by the German Helmholtz Association Research Grant (project number HRSF-0005). A. M?hlebner is supported by the Dutch Epilepsy Foundation (project number 20-02). Funding Information: We kindly thank B. Rings for her expert technical assistance. Our work was supported by the European Union's Seventh Framework Program (DESIRE project, Grant agreement 602531) and European Reference Network EpiCare (Grant agreement 769501). A. Korshunov is supported by the German Helmholtz Association Research Grant (project number HRSF-0005). A. Mühlebner is supported by the Dutch Epilepsy Foundation (project number 20-02). Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
(Peer reviewed)