Date of Award
Doctor of Philosophy (PhD)
Dr. Jane M. DeLuca
Dr. Sara M. Sarasua
Dr. Luigi Boccuto
Dr. Steven A. Skinner
Dr. Christopher W. Cowan
Hannah Warren Moore, MS, CGC
MEF2C-related disorders are characterized by intellectual disability, developmental delay, lack of speech, seizures, stereotypic movements, hypotonia, and brain abnormalities and are caused by pathogenic alterations involving the MEF2C gene. Despite published cases, MEF2C-related disorders are difficult to recognize clinically. These studies sought to further characterize MEF2C-related disorders by investigating the genotypes, phenotypes, and gene functions (or dysfunctions) associated with the disorder.
Tremors have been reported in some patients with MEF2C-related disorders, but the concept of tremors has been complicated by vague definitions and numerous categorization methods. We performed a concept analysis following the Walker and Avant method to clarify the concept and develop an operational definition of tremors. We concluded that tremors are a movement disorder characterized by shaking motions that are involuntary, oscillatory, rhythmic, non-painful, always present although vary in severity, and can be repressed by changing posture or going into a rest position.
We then performed a systematic literature review to record the genotypes and comprehensive phenotype of MEF2C-related disorders reported in the literature. Forty-three articles characterizing 117 patients met the inclusion criteria. Common features included intellectual disability, developmental delay, seizures, hypotonia, absent speech, inability to walk, stereotypic movements, and MRI abnormalities. Nonclassical findings included question mark ear, jugular pit, and a unique neuroendocrine finding.
Next, we developed a survey based on validated instruments to gather developmental and clinical information from the parents of children with MEF2C-related disorders. Seventy-three parents completed the survey. Limited speech, seizures, bruxism, repetitive movements, and high pain tolerance were some of the prominent features identified from the survey data. Statistical analyses showed that patients with MEF2C variants were similarly affected as patients with deletions and females showed higher verbal abilities. This natural history study details phenotypic and developmental information of the largest single cohort reported to date.
Lastly, we discussed current techniques used to investigate the mouse Mef2c gene expression and regulation in the brain. Previous unbiased RNA sequencing of whole cortex from Mef2c global heterozygous mice showed hundreds of dysregulated genes, particularly autism risk genes and microglial genes. The Cowan lab is currently performing single nuclei RNA sequencing (snRNAseq) to better understand the role of Mef2c in neurons and microglia. Techniques used include nuclei dissociation, fluorescence-activated cell sorting, library preparation and sequencing, and bioinformatic analysis of the snRNAseq data. Additional research techniques include perfusion fixation, brain extraction and slicing, and immunohistochemistry.
These studies characterize the phenotype and document the severity of the disorder. The information reported will help providers diagnose and care for patients with MEF2C-related disorders. Additionally, the systematic review and survey data can be useful for further genotype-phenotype correlations, as baseline data for treatment trials, and to develop future studies.
Cooley Coleman, Jessica Ann, "Characterization of MEF2C-Related Disorders: Genotype, Phenotype, and Gene Pathway Dysregulation" (2022). All Dissertations. 3029.
Author ORCID Identifier