Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal
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ORIGINAL PAPER
Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early‑onset focal epilepsy, and severe developmental delay Katja Kobow1 · Samir Jabari1 · Tom Pieper2 · Manfred Kudernatsch3,4 · Tilman Polster5 · Friedrich G. Woermann5 · Thilo Kalbhenn6 · Hajo Hamer7 · Karl Rössler8,9 · Angelika Mühlebner10 · Wim G. M. Spliet11 · Martha Feucht12 · Yanghao Hou13 · Damian Stichel13 · Andrey Korshunov13 · Felix Sahm13 · Roland Coras1 · Ingmar Blümcke1 · Andreas von Deimling13 Received: 16 July 2020 / Revised: 16 September 2020 / Accepted: 16 September 2020 © The Author(s) 2020
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 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 normalappearing 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. Keywords Chromosome 1 · Copy number variation · Brain development · Cortical malformation · ID · Seizures
Introduction
Katja Kobow, Samir Jabari, Ingmar Blümcke, and Andreas von Deimling have contributed equally Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02228-5) contains supplementary material, which is available to authorized users. * Katja Kobow katja.kobow@uk‑erlangen.de Extended author information available on the last pag
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