Epileptic encephalopathy (EE) is an umbrella-term for a class of severe epilepsies characterized by debilitating seizures. Epileptic activity often begins in early adolescence, contributing to developmental, cognitive, and behavioral abnormalities. Identification of genetic mutations in EE-patients has implicated >50 genes, with clinical diagnostic labs reporting a molecular diagnosis in 24-40% of cases. Current EE gene discovery focuses primarily on identifying de novo mutations in genomic coding regions, which alter the amino acid sequence of the resulting protein, disrupting the protein’s function and leading to neural abnormalities. A de novo mutation is not inherited from either unaffected parent; it first occurs in an affected individual, suggesting a genetic cause for the phenotype. My research focuses on identifying novel noncoding mutations in a cohort of 167 patients with EE of unknown cause. The proportion of rare diseases caused by noncoding mutations is unknown and relatively few examples of functional noncoding causative mutations exist. My goal is to identify de novo variants in intronic and untranslated genomic regions, and also to identify synonymous variants in which the resulting amino acid is unaltered. Initially, the 167-patient cohort was screened for variants in 44 established EE genes using targeted next-generation DNA sequencing. I have filtered this data for high-quality noncoding variants, which are unreported in a healthy population. I am currently screening patients’ parents for these noncoding variants to determine the mode of inheritance. Confirmed de novo variants will be followed-up with functional studies to test their molecular consequences (via mRNA, splicing, gene expression). Determining genetic causes of EE unveils molecular mechanisms behind phenotypes, allowing for precise diagnoses, and leading to treatment of severe epilepsies based on their causes. I hope to identify causative noncoding variants in epilepsy genes to expand epigenetic analysis of EE, and contribute to a better understanding of EE genotype-phenotype relationship.

Epileptic encephalopathies (EEs) are devastating childhood epilepsies characterized by multiple seizure types that are usually refractory to medication. Next-generation sequencing has revealed the prominent role of de novo mutations in causing EEs with clinical diagnostic labs reporting a molecular diagnosis in as many as 24-40% of cases. Despite this significant progress, the majority of cases are unexplained. Exome sequencing, a next-generation sequencing technique, allows one to look at all the protein coding regions of an individual’s genome, offering an affordable and unbiased approach to gene discovery. Using exome sequence data for 50 trios (proband and unaffected parents), in which the child had seizure onset in the first 2 years of life, we identified 76 candidate genes, of which 37 are confirmed de novo variants through Sanger sequencing. Notably, 2 affected individuals were identified to have a de novo variant in the guanine nucleotide-binding protein (G-protein) beta1 subunit, GNB1. This was a statistically significant finding (p=0.005), and in collaboration with colleagues we have now identified 13 patients with neurodevelopmental delays with and without seizures. This previously unrecognized genetic condition is characterized by global developmental delays (13/13), hypotonia (11/13), seizures (10/13), ocular manifestations (8/13) and growth delay (6/13). These genetic findings will have immediate impact to clinicians and families when discussing diagnosis and prognosis, and hopefully guide future studies of finding effective therapies for these patients. Future work will screen for genetic variants in the candidate genes identified by exome sequencing using a targeted sequencing approach in a cohort of 600 patients with EE of unknown etiology.

This project focused on redesigning the application and related sites for mPOWEr, a research project building a mobile post-operative wound evaluator to reduce surgical site infections. The redesign of the application’s overall aesthetic focused on improving usability and creating a more cohesive look. One of the major tasks in redesign was reimagining the patient-facing site. After brainstorming and interacting with the initial patient site, I realized the necessity of a distinct, categorized system for the website instead of a primarily single-document layout. I created basic wireframes, which turned into higher-fidelity prototypes, and eventually culminated in coding the live site. Through group critique, feedback, and continued iterations, the patient-site went through the steps of creative problem-solving to construct a cohesive identity for mPOWEr and provide compelling visuals that match the group’s purposes. After creating a new identity for the patient-facing site, similar design can be applied to the application itself, as well as other of marketing materials, to build cohesive aesthetic and distinctive design across all elements of the project.

Epileptic encephalopathies (EE) are severe forms of childhood epilepsies. Recent studies have shown that some cases of pediatric EE are caused by copy number variants (CNV), which are chromosomal deletions, duplications, or insertions of DNA. CNVs may contain genes that are important for neural health, causing disease when there is a copy number change. I am investigating rare CNVs in EE patients where the genetic cause is not known. I will screen EE patients for CNVs using a technique called array comparative genomic hybridization (aCGH) to identify rare CNVs that may be disease-causing. If a CNV is found, I will conduct aCGH on parents to determine if the CNV is de novo (arising for the first time in that individual and not inherited from either parent). We also expect that in cases with multiple affected family members, patients may inherit rare mutations from an affected parent. Preliminary results show that out of 69 patients screened thus far, 15 rare CNVs that range in size and number of genes affected have been identified in 13 patients. Of these, 3 de novo CNVs were identified that include a single exon deletion of the gene SLC2A1, a partial deletion of the gene NRXN1, and a 2.4 mb deletion in chromosomal region 7q11.23, affecting 40 genes. In addition, 2 patients each have a 1.4-1.5 mb deletion encompassing the region 16p13.11, which has been reported to be associated with epilepsy and developmental delay. Parental and segregation testing is ongoing for many patients. Rare CNVs can highlight genes implicated for proper neural function and development. This will help advance our understanding of the pathology and genetic basis of epilepsy. Furthermore, identification of particular pathogenic genes will be useful in the clinical setting for genetic counseling of affected patients and families.

Depressive disorders are a significant public health concern, affecting 11.4% of youth, and are associated with a loss of interest in activities and anxiety, psychosocial problems such as academic difficulties, and psychosocial impairment in adulthood including increased risk for substance abuse and suicide. By providing adequate mental health treatment, adverse effects of depressive disorders in youth and adolescence may be mitigated. Although mental health services for youth are currently inaccessible for 70% of the youth population who would benefit from these services, healthcare is experiencing a trend towards increased access to mental health services both through the Affordable Care Act and the expansion of Medicaid. My study’s goal is to look at ways to provide these quality mental health services to youth. In order to provide quality health mental health care for youth with depressive disorder, a collaborative care model may be used. Collaborative care uses a multidisciplinary team of primary care providers, mental health specialists, and community support to deliver a multifaceted approach to patients with mental health issues through cognitive-behavioral therapy (CBT), pharmacotherapy, or both delivered by primary care providers in community health settings. To date, 3 RCTs have evaluated the effectiveness of collaborative care against usual care for youth depression. One mainstay treatment for youth depression has been CBT. While collaborative care is an emerging model of treatment for youth depression, it has not been compared to stand-alone CBT. In this investigation, benchmarking is used to find an applied effectiveness for both collaborative care and cognitive behavioral therapy. I searched through peer-reviewed journals using search engines such as Medline and PsychInfo to gather published studies. Using these results and data, I then used statistical analyses and benchmarking to compare the effectiveness of both CBT and collaborative care.