Somatic variants in diverse genes leads to a spectrum of focal cortical malformations

Abstract

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signaling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n=16), focal cortical dysplasia type I and related phenotypes (n=48), focal cortical dysplasia type II (n=44), or focal cortical dysplasia type III (n=15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel, and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1, and NIPBL, genes associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that FCD types I, II, and III, are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

“…Notably, the PTPN11 (c.1507G>A and c.1508G>T), KRAS (c.35G>A and c.35G>T), and BRAF (c.1797A>G and c.1799T>A) variants are all located in mutational hot spots for cancer and neurodevelopmental disorders. [19][20][21] However, except for KRAS c.35G>T and BRAF c.1799T>A, which have been reported in FCDs 22,23 and LEATs, 24 to our knowledge, none of the other somatic variants have been previously described in focal epilepsies. Both patients with NF1 somatic variants carried a diagnosis of neurofibromatosis type 1 and had known germline variants in the NF1 gene (c.499_502del and c.6904C>T) based on clinical testing.…”

Glioma genetic profiles associated with electrophysiologic hyperexcitability

“…[36][37][38][39] Somatic mutations in genes overlapping with some of the hyperexcitable variants identified in this study (PIK3CA, KRAS, PTEN, NF1, TSC2) have been reported in association with focal cortical dysplasia and drug-resistant epilepsy. 40 Indeed, the hyperexcitable gene set here demonstrated phenotypic enrichment of multiple brain malformations, suggesting the potential for similar epileptogenic mechanisms mediated by somatic mutations in gliomas. However, whether these genetic alterations contribute to epileptogenicity by the same mechanisms in different cell types is uncertain.…”

Genetic Testing for Malformations of Cortical Development

“…In addition, pathogenic or likely pathogenic variants in CASK , KRAS , NF1 , and NIPBL were detected in patients with FCD type I. 35 In our center, we began to introduce somatic testing in diagnostic workup in 2019, and the numbers of patients examined continue to increase. In addition, somatic sequencing of brain tissue samples obtained in epilepsy surgery involves certain technical caveats.…”