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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.

SUBMITTER: Kobow K

PROVIDER: S-EPMC7666281 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Kobow Katja K Jabari Samir S Pieper Tom T Kudernatsch Manfred M Polster Tilman T Woermann Friedrich G FG Kalbhenn Thilo T Hamer Hajo H Rössler Karl K Mühlebner Angelika A Spliet Wim G M WGM Feucht Martha M Hou Yanghao Y Stichel Damian D Korshunov Andrey A Sahm Felix F Coras Roland R Blümcke Ingmar I von Deimling Andreas A

Acta neuropathologica 20200926 6

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 ...[more]

PMID: 32979071

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Project description:ObjectiveWe sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.MethodsWe enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA.ResultsAcross the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus.SignificanceThis study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.

Project description:We aimed to investigate the working memory (WM) and language separate contributions to verbal learning and memory in patients with unilateral drug-resistant temporal lobe epilepsy (drTLE); additionally, we explored the mediating role of WM on the relationship between the number of antiepileptic drugs (AEDs) and short-term verbal memory. We retrospectively enrolled 70 patients with left (LTLE; n = 44) and right (RTLE; n = 26) drTLE. About 40 similar (age and education) healthy controls were used to determine impairments of groups at WM, language (naming and verbal fluency), and verbal learning and memory (five trials list-learning, story memory-immediate recall). To disentangle the effect of learning from the short-term memory, we separately analyzed performances at the first trial, last trial, and delayed-recall list-learning measures, in addition to the total learning capacity (the sum of the five trials). Correlation and regression analyses were used to assess the contribution of potential predictors while controlling for main clinical and demographic variables, and ascertain the mediating role of WM. All patients were impaired at WM and story memory, whereas only LTLE showed language and verbal learning deficits. In RTLE, language was the unique predictor for the most verbal learning performances, whereas WM predicted the results at story memory. In LTLE, WM was the sole predictor for short-term verbal learning (list-learning capacity; trial 1) and mediated the interaction between AED number and the performance at these measures, whereas language predicted the delayed-recall. Finally, WM confounded the performance at short-term memory in both groups, although at different measures. WM is impaired in drTLE and contributes to verbal memory and learning deficits in addition to language, mediating the relationship between AED number and short-term verbal memory in LTLE. Clinicians should consider this overlap when interpreting poor performance at verbal learning and memory in drTLE.

Dataset Information

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

Publications

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

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