mTOR pathway somatic variants and the molecular pathogenesis of hemimegalencephaly

Abstract

Objectives Recently, defects in the protein kinase mTOR (mammalian target of rapamycin) and its associated pathway have been correlated with hemimegalencephaly (HME). mTOR acts as a central regulator of important physiological cellular functions such as growth and proliferation, metabolism, autophagy, death, and survival. This study was aimed at identifying specific variants in mTOR signaling pathway genes in patients diagnosed with HME. Methods Using amplicon and whole exome sequencing (WES) of resected brain and paired blood samples from five HME patients, we were able to identify pathogenic mosaic variants in the mTOR pathway genes MTOR, PIK3CA, and DEPDC5. Results These results strengthen the hypothesis that somatic variants in PI3K‐Akt‐mTOR pathway genes contribute to HME. We also describe one patient presenting with a pathogenic variant on DEPDC5 gene, which reinforces the role of DEPDC5 on cortical structural changes due to mTORC1 hyperactivation. These findings also provide insights into when in brain development these variants occurred. An early developmental variant is expected to affect a larger number of cells and to result in a larger malformation, whereas the same variant occurring later in development would cause a minor malformation. Significance In the future, numerous somatic variants in known or new genes will undoubtedly be revealed in resected brain samples, making it possible to draw correlations between genotypes and phenotypes and allow for a genetic clinical diagnosis that may help to predict a given patient's outcome.

The Role of KRAS Mutations in Cortical Malformation and Epilepsy Surgery: A Novel Report of Nevus Sebaceous Syndrome and Review of the Literature

“…Indeed, several FCD cohort studies have shown the proportion of cells showing mutant allele in the resected brain tissue to vary from 1% to 14% [ 70 , 71 ]. In comparison, HME specimens from HME patients, in whom a more extensive area of the brain is abnormal, the mutant allelic proportions tend to be higher, ranging between 2.5% and 44% [ 72 , 73 , 74 ]. Hypothetically, these findings could be suggestive of a “gene dosage effect” in which greater mutant allele proportion is associated with more extensive and often more severe cortical malformations [ 74 ].…”

Comprehensive multiomic profiling of somatic mutations in malformations of cortical development

“…From Phases 1 to 3, 1181 candidate somatic SNVs were identified. Of these, 628 were excluded based on gnomAD allele frequencies, dinucleotide repeats, homopolymers, and additional BSMN established criteria (Methods) 15,16 . This yielded 554 candidate somatic SNV that were further assessed by TASeq, yielding 108 validated somatic SNV calls (19.4% validation rate, Fig.…”

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

“…Incidentally, the role of signals that regulate hamartin and tuberin activity as well as the mTORC1 substrates responsible for specific developmental events are only now being determined. Perhaps most striking is the fact that somatic mutations that cause mTORC1 pathway activation have been identified as a cause of a plethora of neurological diseases (Lee et al, 2012 ; Poduri et al, 2012 ; Parker et al, 2013 ; Lal et al, 2014 ; Baek et al, 2015 ; Baulac et al, 2015 ; Crino, 2015 ; D’Gama et al, 2015 , 2017 ; Leventer et al, 2015 ; Lim et al, 2015 ; Baulac, 2016 ; Korenke et al, 2016 ; Møller et al, 2016 ; Hanai et al, 2017 ; Park et al, 2018 ; Iffland and Crino, 2019 ; Kim et al, 2019 ; Pelorosso et al, 2019 ; Salinas et al, 2019 ; Zhao et al, 2019 ; Garcia et al, 2020 ). Thus, what has been learned by studying the TSC pathway may now be applied to an expanding number of patients.…”