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

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.

Multilobar unilateral hypoplasia with emphasis on the posterior quadrant and severe epilepsy in children with FCD ILAE Type 1A

“…This patient is seizure-free after invasive recording with subdural grids and strips and a resection, which included the entire temporal lobe and posteriortemporal-, parietal-, and occipital junction areas unsupervised dimensionality reduction and hierarchical cluster analysis. In addition to previously described FCD and TLE-specific methylation classes, 14,15 we confirmed and extended these data showing that FCD1A forms a separate and novel cluster in the UMAP dimensionality reduction (Figure 3A). No confounding correlation with any other variable of our data was detected, that is, sex, age, and lobe.…”

“…Eighty-seven samples were analyzed using Illumina Infinium Methylation EPIC (850K) BeadChip arrays as described elsewhere. 14 DNA methylation data were generated at the Dept. of Neuropathology, Universitätsklinikum Heidelberg, Germany.…”

Somatic mutation involving diverse genes leads to a spectrum of focal cortical malformations

“…Only one high-quality somatic CNV was identified in the FCDI + cohort, a chromosome 1q duplication (Supplementary Figure 2). Chromosome 1q duplications have been reported in individuals with hemimegalencephaly, (Poduri et al, 2012) and unilateral PMG with dysmorphic neurons (Kobow et al, 2020). This individual was diagnosed with FCDNOS with heterotopic white matter neurons and pancortical eosinophilic astrocytic inclusions, a pattern described in detail [see case 2) in (Fischer et al, 2020)].…”

Methylation classifiers: Brain tumors, sarcomas, and what's next

“…These include the “infant type hemispheric glioma” previously diagnosed as glioblastoma in most instances or the “diffuse glioneuronal tumor with oligodendroglioma‐like features and nuclear clusters (DGONC),” 69 Novel tumors not yet included are the “PLAGL1‐fused neuroepithelial tumor” 70 reminiscent of ependymoma or the “Primary mismatch repair deficient IDH‐mutant astrocytoma (PMMRDIA).” 71 Characterization of several other novel tumor types can be expected within short time. Recently, methylation analysis has been employed to characterize hamartous malformations and cortical dysplasias, both constituting challenging differential diagnoses to low glioneuronal tumors 72,73 …”

“…"71 Characterization of several other novel tumor types can be expected within short time. Recently, methylation analysis has been employed to characterize hamartous malformations and cortical dysplasias, both constituting challenging differential diagnoses to low glioneuronal tumors 72,73.…”