A somatic mutation in MEN1 gene detected in periventricular nodular heterotopia tissue obtained from depth electrodes

Abstract

Periventricular nodular heterotopia (PNH) is a common structural malformation of cortical development. Mutations in the filamin A gene are frequent in familial cases with X‐linked PNH. However, many cases with sporadic PNH remain genetically unexplained. Although medically refractory epilepsy often brings attention to the underlying PNH, patients are often not candidates for surgical resection. This limits access to neuronal tissue harboring causal mutations. We evaluated a patient with PNH and medically refractory focal epilepsy who underwent a presurgical evaluation with stereotactically placed electroencephalographic (SEEG) depth electrodes. Following SEEG explantation, we collected trace tissue adherent to the electrodes and extracted the DNA. Whole‐exome sequencing performed in a Clinical Laboratory Improvement Amendments–approved genetic diagnostic laboratory uncovered a de novo heterozygous pathogenic variant in novel candidate PNH gene MEN1 (multiple endocrine neoplasia type 1; c.1546dupC, p.R516PfsX15). The variant was absent in an earlier exome profiling of the venous blood–derived DNA. The MEN1 gene encodes the ubiquitously expressed, nuclear scaffold protein menin, a known tumor suppressor gene with an established role in the regulation of transcription, proliferation, differentiation, and genomic integrity. Our study contributes a novel candidate gene in PNH generation and a novel practical approach that integrates electrophysiological and genetic explorations of epilepsy.

Roots of the Malformations of Cortical Development in the Cell Biology of Neural Progenitor Cells

“…The timing of mutation is often associated with the severity of phenotype ( Sarnat, 1987 ; Sarnat and Flores-Sarnat, 2014 ). In this context, somatic mutations have recently been found to exert and important contribution to MCDs with focal insult, such as in focal heterotopia, focal cortical dysplasia and hemimegalencephaly ( Jamuar et al, 2014 ; Jansen et al, 2015 ; Gonzalez-Moron et al, 2017 ; Montier et al, 2019 ). Somatic mutations can be of type 1 or type 2, which cause a new heterozygous mutation or lead to a loss of heterozygosity, respectively ( Qin et al, 2010 ; Jansen et al, 2015 ; Juric-Sekhar and Hevner, 2019 ).…”

Genetic causes underlying grey matter heterotopia

“…Rarely, agyria/pachygria and SBH can be identified in the same patient. In a large lissencephaly study genetic analysis revealed a causal mutation in 123/155 SBH cases, the majority of which were DCX mutations, and several LIS1 mutations (34). So in total, only 2 genes explained 80% of cases (34).…”

“…In a large lissencephaly study genetic analysis revealed a causal mutation in 123/155 SBH cases, the majority of which were DCX mutations, and several LIS1 mutations (34). So in total, only 2 genes explained 80% of cases (34). DCX mutations in females cause a thick or thin SBH, with either a diffuse localization or anterior to posterior gradient (Figure 2B) (5).Recently, a novel lissencephaly gene, CEP85L has been discovered, mutations cause a posterior predominant agyria/pachygyria or SBH (35,36).…”

“…DCX mutations in females cause a thick or thin SBH, with either a diffuse localization or anterior to posterior gradient (Figure 2B) (5).Recently, a novel lissencephaly gene, CEP85L has been discovered, mutations cause a posterior predominant agyria/pachygyria or SBH (35,36). Except for females with diffuse SBH caused by DCX mutations, there is evidence supporting a role for mosaic mutations in other forms of SBH (34,37). There is no compelling evidence to date of non-genetic causes of SBH (34).…”

“…Except for females with diffuse SBH caused by DCX mutations, there is evidence supporting a role for mosaic mutations in other forms of SBH (34,37). There is no compelling evidence to date of non-genetic causes of SBH (34). Due to the limited amount of genes, and several key features in either imaging or dysmorphology, a differential diagnosis can be created for an individual patient, followed by targeted single gene/ gene panel analysis.…”