# Identification and molecular characterization of somatic mutations in MCD

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $636,227

## Abstract

PROJECT SUMMARY
Genetic mutations causing disease may be inherited, newly acquired in parental gametes and present in the
zygote, or acquired as somatic events at some point in development after fertilization (post-zygotic). The
burden and localization of any acquired mutation depends on when the mutation arises. As is the case for
inherited genetic variation, there is accumulating evidence that somatic mutations can lead to severe tissue-
specific disease. Malformations of cortical development (MCD) represent a group of disorders characterized by
a range of morphological and structural abnormalities of the cerebral cortex reflecting errors in embryonic
cortical development. MCD are associated with intellectual disability, as well as refractory epilepsy, and may
require the surgical removal of the affected tissue. Inherited gene mutations involved in neuronal development
explain only a fraction of MCD cases. These observations have led to the hypothesis that some MCD result
from somatic mutations occurring in neuroglial progenitor cells give rise to abnormal cortical development. In
fact, we and others have shown that in hemimegalencephaly, a severe hemispheric MCD subtype, ~30% of
patients have somatic mutations in the PI3K-AKT-mTOR signaling pathway, detectable only by directly
studying abnormal cortical tissue. Thus, in this project we will evaluate the hypothesis that somatic mutations
disrupt embryonic cortical development and are responsible for a substantial fraction of MCD. We, with a
network of collaborators, have access to a large number of resected epilepsy surgical tissue specimens. Using
high-coverage next-generation sequencing of protein-coding regions in DNA extracted from abnormal brain
tissue and unaffected tissue (leukocytes) from patients with three forms of MCD, we will identify somatic
mutations within each patient with MCD (Aim 1). Somatic mutations confirmed to be selectively present in
affected tissue will be assessed for their likelihood of being responsible for the cortical abnormality using
comparisons of patterns of somatic mutations between cases and controls, phenotypic comparisons between
individuals with somatic candidates in the same gene, patterns of mutations in pathologically abnormal and
normal cell populations, and evaluations of the effects of the candidate mutation on cerebral cortical
development in vivo (Aim 2). Finally, initial characterization of the effects and presentation of the disease-
causing mutation in the cortex will be studied using in vitro assays to evaluate the effects of the mutation on
key cortical developmental processes, and mutation lineage tracing to identify cell populations carrying the
mutation (Aim 3). Our project brings together clinical, genetic, and neurobiological expertise and builds on the
activities of the Epilepsy Phenome/Genome Project (EPGP), Epi4K, and multiple NINDS-funded initiatives in
somatic genetics. These studies will: (i) provide the first detailed assessment of...

## Key facts

- **NIH application ID:** 9970548
- **Project number:** 5R01NS094596-06
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Peter B Crino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $636,227
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970548

## Citation

> US National Institutes of Health, RePORTER application 9970548, Identification and molecular characterization of somatic mutations in MCD (5R01NS094596-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9970548. Licensed CC0.

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