Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

Katja Kobow,Karl Rössler,Felix Sahm,Tilman Polster,Tom Pieper,Yanghao Hou,Friedrich G Woermann,Manfred Kudernatsch,Damian Stichel,Wim G M Spliet,Roland Coras,Hajo Hamer,Andreas Von Deimling,Martha Feucht,Ingmar Blümcke,Thilo Kalbhenn,Angelika Mühlebner,Andrey Korshunov,Samir Jabari

doi:10.1007/s00401-020-02228-5

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 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.

Highlights

PMG is a malformation of cortical development (MCD) characterized by an excessive number of abnormally small and partly fused, and so-called frustrane gyration together with abnormal cortical lamination [8]
We reviewed clinical, imaging and histological data of individuals who underwent surgery for the treatment of their focal pharmacoresistent epilepsy and were diagnosed with unilateral PMG (n = 26; mean age at surgery ± SEM = 12.5 ± 3.5 years; Table 1), hemimegalencephaly (HME, n = 6; mean age ± SEM = 1.3 ± 0.2 years), focal cortical dysplasia (FCD) type 2 (n = 36; mean age ± SEM = 15.8 ± 2.2 years), or temporal lobe epilepsy (TLE, n = 15; mean age ± SEM = 37.0 ± 4.0 years; All TLE patients had a histopathological diagnosis of hippocampal sclerosis, but only apparently normal temporal neocortex was used in the present analysis.)
Whether DNA methylation signatures can be used to classify structurally related MCD molecularly, we used the methylation data from surgical brain samples obtained from 26 pharmacoresistant epilepsy patients with a histopathological diagnosis of PMG (Table 1) and 62 MCD and no-MCD reference cases (i.e., FCD type 2a, FCD type 2b, HME, TLE) as well as from no-seizure autopsy controls (CTRL, microdissected white matter and neocortex; Supplement Table 1, online resource)

Summary

Introduction

PMG is a malformation of cortical development (MCD) characterized by an excessive number of abnormally small and partly fused, and so-called frustrane gyration together with abnormal cortical lamination [8]. Clinical signs and symptoms are heterogeneous depending on how many and which brain regions are affected. They may range from mild intellectual disability, mobility and language problems to severe encephalopathy with intractable epilepsy. PMG is genetically heterogeneous with about 40 associated genes [34, 55, 65]. Small copy number variants (CNVs) have been associated with PMG, but only deletions in 1p36.3 and 22q11.2 are common; otherwise, CNVs are rare [23, 57]. Among non-genetic causes of PMG hypoxia-ischemia, trauma or congenital infections mainly from cytomegalovirus have been reported [9, 39]

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