Detection of brain somatic variation in epilepsy‐associated developmental lesions

Bedrosian, Tracy A.; Miller, Katherine E.; Grischow, Olivia; Schieffer, Kathleen M.; LaHaye, Stephanie; Yoon, Hyojung; Miller, Anthony R.; Navarro, Jason B.; Westfall, Jesse; Leraas, Kristen; Choi, Samantha; Williamson, Rachel K; Fitch, James; Kelly, Benjamin J.; White, Peter; Lee, Kristy; McGrath, Sean; Cottrell, Catherine E.; Magrini, Vincent; Leonard, Jeffrey R.; Pindrik, Jonathan; Shaikhouni, Ammar; Boué, Daniel R.; Thomas, Diana; Pierson, Christopher R.; Wilson, Richard K.; Ostendorf, Adam P.; Mardis, Elaine R.; Koboldt, Daniel C.

doi:10.1111/epi.17323

Cited by 36 publications

(40 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have additionally supported the idea that somatic mosaicism in the diseased brain may be a mechanism for neurodevelopmental and neurodegeneration disorders [132][133][134]. Furthermore, clinical (neurodevelopmental) cohorts repeatedly demonstrate high rates of somatic mosaicism [135][136][137], which may be seen as a mechanism for the disease or a target for therapeutic interventions [23,138].…”

Section: What Is Now and What Is Next?mentioning

confidence: 90%

Somatic mosaicism in the diseased brain

et al. 2022

View full text Add to dashboard Cite

It is hard to believe that all the cells of a human brain share identical genomes. Indeed, single cell genetic studies have demonstrated intercellular genomic variability in the normal and diseased brain. Moreover, there is a growing amount of evidence on the contribution of somatic mosaicism (the presence of genetically different cell populations in the same individual/tissue) to the etiology of brain diseases. However, brain-specific genomic variations are generally overlooked during the research of genetic defects associated with a brain disease. Accordingly, a review of brain-specific somatic mosaicism in disease context seems to be required. Here, we overview gene mutations, copy number variations and chromosome abnormalities (aneuploidy, deletions, duplications and supernumerary rearranged chromosomes) detected in the neural/neuronal cells of the diseased brain. Additionally, chromosome instability in non-cancerous brain diseases is addressed. Finally, theoretical analysis of possible mechanisms for neurodevelopmental and neurodegenerative disorders indicates that a genetic background for formation of somatic (chromosomal) mosaicism in the brain is likely to exist. In total, somatic mosaicism affecting the central nervous system seems to be a mechanism of brain diseases.

show abstract

Section: What Is Now and What Is Next?mentioning

confidence: 90%

Somatic mosaicism in the diseased brain

et al. 2022

View full text Add to dashboard Cite

show abstract

“…PTPN11 was previously identified as a novel epilepsy gene (Lopez-Rivera et al, 2022, Bedrosian et al, 2022). However, it was never described before in brain somatic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Protein Tyrosine Phosphatase Non-receptor Type 11 ( PTPN11 ) has been recently discovered as a new candidate gene in brain tissue obtained from drug-resistant structural epilepsies (Lopez-Rivera et al, 2022, Bedrosian et al, 2022). The PTPN11 gene encodes for an early non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2) of the RAS-/MAP-Kinase pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Protein Tyrosine Phosphatase Non-receptor Type 11 ( PTPN11 ) has been recently discovered as a new candidate gene in brain tissue obtained from drug-resistant structural epilepsies [2, 21] The PTPN11 gene encodes for an early non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2) of the RAS-/MAP-Kinase pathway. Germline variants in PTPN11 , i.e., missense variants or copy number variations (CNV), or other RAS-/MAP -Kinase signaling pathway genes including SHOC2, CBL, KRAS , are known to cause an autosomal dominant multisystem disorder – the Noonan syndrome – or Noonan syndrome-associated disorders [10, 25, 28, 29].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Alterations inPTPN11and other RAS-/MAP-Kinase pathway genes define ganglioglioma with adverse clinical outcome and atypic histopathological features

Hoffmann

Coras

Kobow

et al. 2022

Preprint

View full text Add to dashboard Cite

The PTPN11 gene was recently described as a novel lesional epilepsy gene by extensive exome-wide sequencing studies. However, germline mutations of PTPN11 and other RAS-/MAP-Kinase signaling pathway genes cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11 gene compared to GG with other common MAP-Kinase signaling pathway alterations. Seventy-two GG were submitted to whole exome sequencing and genotyping and 86 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. Clinical data were retrieved from hospital files including postsurgical disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in FGFR4, RHEB, NF1, KRAS as well as BRAFV600E alterations. Histopathology revealed an atypical and complex glio-neuronal phenotype with subpial tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11 alterations were free of disabling-seizures two years after surgery (38% Engel I). This was remarkably different from our series of GG with BRAFV600E mutations (85% Engel I). Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by PTPN11 and other Noonan syndrome-related alterations of the RAS-/MAP-Kinase signaling pathway. These findings need prospective validation in clinical practice as they argue for an adapted WHO grading system in developmental, glio-neuronal tumors associated with early-onset focal epilepsy. These findings also open avenues for targeted medical treatment.

show abstract

“…As noted before, somatic mosaicism for gene mutations is common in epilepsy and seems to play a specific role in the pathogenesis of epileptic disorders, especially when affecting brain tissues/brain foci. Genomic analyses of postoperative samples of the brain in patients suffering from epilepsy have become a common research practice [ 19 , 20 , 105 , 106 ]. Currently, several monogenic neurodevelopmental disorders exhibiting epilepsy have been reported to demonstrate brain-specific mosaicism for gene mutations: focal cortical dysplasia— MTOR (1p36.22), TSC1 (9q34.13), TSC2 (16p13.3), DEPDC5 (22q12.2q12.3) [ 107 – 110 ]; hemimegalencephaly— MTOR (1p36.22), AKT3 (1q43q44), PIK3CA (3q26.32), RPS6 (9p22.1), AKT1 (14q32.33) [ 107 , 108 , 111 , 112 ]; hypothalamic hamartoma— GLI3 (7p14.1), OFD1 (Xp22.2) [ 113 , 114 ]; nonlesional focal epilepsy— SLC35A2 (Xp11.23) [ 115 ]; Sturge-Weber syndrome (leptomeningeal angiomatosis)— GNAQ (9q21.2) [ 116 ]; tuberous sclerosis 16p13.3—( TSC2 ) [ 117 ].…”

Section: Introductionmentioning

confidence: 99%

Cytogenomic epileptology

et al. 2023

View full text Add to dashboard Cite

Molecular cytogenetic and cytogenomic studies have made a contribution to genetics of epilepsy. However, current genomic research of this devastative condition is generally focused on the molecular genetic aspects (i.e. gene hunting, detecting mutations in known epilepsy-associated genes, searching monogenic causes of epilepsy). Nonetheless, chromosomal abnormalities and copy number variants (CNVs) represent an important part of genetic defects causing epilepsy. Moreover, somatic chromosomal mosaicism and genome/chromosome instability seem to be a possible mechanism for a wide spectrum of epileptic conditions. This idea becomes even more attracting taking into account the potential of molecular neurocytogenetic (neurocytogenomic) studies of the epileptic brain. Unfortunately, analyses of chromosome numbers and structure in the affected brain or epileptogenic brain foci are rarely performed. Therefore, one may conclude that cytogenomic area of genomic epileptology is poorly researched. Accordingly, molecular cytogenetic and cytogenomic studies of the clinical cohorts and molecular neurocytogenetic analyses of the epileptic brain appear to be required. Here, we have performed a theoretical analysis to define the targets of the aforementioned studies and to highlight future directions for molecular cytogenetic and cytogenomic research of epileptic disorders in the widest sense. To succeed, we have formed a consortium, which is planned to perform at least a part of suggested research. Taking into account the nature of the communication, “cytogenomic epileptology” has been introduced to cover the research efforts in this field of medical genomics and epileptology. Additionally, initial results of studying cytogenomic variations in the Russian neurodevelopmental cohort are reviewed with special attention to epilepsy. In total, we have concluded that (i) epilepsy-associated cytogenomic variations require more profound research; (ii) ontological analyses of epilepsy genes affected by chromosomal rearrangements and/or CNVs with unraveling pathways implicating epilepsy-associated genes are beneficial for epileptology; (iii) molecular neurocytogenetic (neurocytogenomic) analysis of postoperative samples are warranted in patients suffering from epileptic disorders.

show abstract

Detection of brain somatic variation in epilepsy‐associated developmental lesions

Cited by 36 publications

References 50 publications

Somatic mosaicism in the diseased brain

Somatic mosaicism in the diseased brain

Alterations inPTPN11and other RAS-/MAP-Kinase pathway genes define ganglioglioma with adverse clinical outcome and atypic histopathological features

Cytogenomic epileptology

Contact Info

Product

Resources

About