2009 |
Mefford, Heather C |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Novel Genomic Rearrangement in Developmental Pediatric Disorders @ University of Washington
DESCRIPTION (provided by applicant): Genomic disorders are conditions that result from DNA rearrangements due to regional genomic architecture as a result of non-allelic homologous recombination (NAHR) between segmental duplications. These rearrangements result in microdeletion or microduplication, and cause the loss, gain, or disruption of dosage-sensitive genes. One hundred and thirty rearrangement "hotspots" of the genome have been identified with features that are common to all known genomic disorders - 50kb-5Mb of sequence flanked by large (>10kb) segmental duplications with >95% sequence identity. Although these genomic features suggest a predisposition to recurrent de novo rearrangement, many of the hotspot regions show no variation in a large series of normal controls or in 290 individuals with idiopathic mental retardation. The candidate hypothesizes that many of these "silent" regions contain genes that are essential for normal development but are involved in pathways other than those critical for normal cognition, and that de novo deletions or duplications will be seen in individuals with congenital anomalies. She proposes a targeted approach to detect novel rearrangements associated (i) with congenital heart disease, and (ii) with pediatric renal abnormalities. By targeting "hotspot" regions, the candidate will detect rearrangements that are likely to be recurrent. In the process, she will identify genes that are critical for developmental pathways and important for pediatric disease. In addition, she will investigate structural and copy number variation within hotspot regions to determine whether these features play a role in an individual's risk for de novo rearrangement during meiosis. PUBLIC HEALTH RELEVANCE: A main goal of this project is to identify new genetic causes of birth defects, with a focus on heart defects and kidney abnormalities. The results of this study will provide new insight into the basis of both normal and abnormal development. The identification of new syndromes will allow more accurate diagnosis of patients and better genetic counseling for families.
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0.958 |
2010 — 2019 |
Mefford, Heather C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
A Genomic Approach to Epilepsy @ University of Washington
DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological disorders in humans. The etiology of epilepsy is complex, with the contribution of both environmental and genetic factors. Linkage analysis and candidate gene studies have enabled the discovery of several epilepsy genes, mutations in which cause rare, autosomal dominant or sporadic forms of epilepsy. Despite these advances, for the vast majority of individuals with epilepsy, the genetic cause is unknown. Recent advances in technology now permit genome-wide analyses for both copy number and sequence changes. Unlike genome-wide studies in many neurodevelopmental disorders, there are no published genome-wide studies in epilepsy to date. The overall goal of this study is to use genomic approaches, including array comparative genomic hybridization and whole exome sequencing, to identify novel candidate genes for epilepsy. We will perform genome-wide array CGH analysis for copy number changes in a cohort of 2000 individuals with epilepsy. We will also use next- generation sequencing technology to perform exome sequencing to identify mutations in a subset of individuals with severe childhood-onset encephalopathy. Each of these whole-genome technologies offers an unbiased approach for identifying novel candidate genes and pathways for epilepsy. We will then use the results of these studies to inform selection of candidate genes for resequencing in 500 affected individuals. The discovery of novel genes and pathways in epilepsy using the genomic approaches within this proposal will further our understanding of brain development and epileptogenesis and allow better prognosis and recurrence risk counseling for families. PUBLIC HEALTH RELEVANCE: Epilepsy is one of the most common neurological disorders in humans, affecting up to 3% of the population. Although it is clear that there is a strong genetic component for epilepsy, there are still only a few genes known. This research will identify new genes and genetic pathways in epilepsy and will directly benefit individuals with epilepsy and their families through improved diagnostic, prognostic and recurrence risk information. Greater understanding of the genes involved in normal development and function of the brain will facilitate improved therapies for this common disorder and benefit society as a whole.
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0.958 |
2011 |
Eichler, Evan E. (co-PI) [⬀] Goldstein, David B. [⬀] Heinzen Cox, Erin L Mefford, Heather C Shianna, Kevin |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
3 of 7 Epi4k: Sequencing, Biostatistics &Bioinformatics Core
DESCRIPTION (provided by applicant): The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The specific goals of this core (3 of 7 - Sequencing, Biostatistics, and Bioinformatics Core) are to 1) sequence and annotate 4,000 genomes, 2) develop computational procedures for calling CNVs in whole exome data, 3) identify and prioritize variants of interest for all three projects, 4) conduct follow up genotypin analyses in a cohort of additional cases and controls, and 5) quickly and efficiently share data among the Epi4K consortium. PUBLIC HEALTH RELEVANCE: Epilepsy is one of the most common human neurological disorders, affecting 3% of the population. Although it is clear that there is a strong genetic component for epilepsy, there are still only a few genes known. The Epi4K project will identify new genes and genetic pathways in epilepsy and will directly benefit individuals with epilepsy and their families through improved diagnostic, prognostic and recurrence risk information. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.
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0.928 |
2011 — 2013 |
Eichler, Evan [⬀] Mefford, Heather C |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
7 of 7 Epi 4k: Copy Number Variants Project @ University of Washington
DESCRIPTION (provided by applicant): The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The specific goals of this project (7 of 7 - CNV Detection) are to discover copy number variants (CNVs) from exome and whole genome sequence data; to describe the CNV landscape in epilepsy patients compared to controls; and to evaluate the broader impact of a subset of CNVs in a large case-control comparison study. Dr. Evan Eichler of Genome Sciences and Dr. Heather Mefford of Pediatrics & Genetic Medicine will co-direct this project. The discovery of novel, disease-related CNVs in the Epi4K cohorts will further our understanding of epilepsy genetics and lead to the identification of new epilepsy genes and pathways.
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0.958 |
2012 — 2018 |
Eichler, Evan (co-PI) [⬀] Goldstein, David B. [⬀] Heinzen Cox, Erin L Mefford, Heather C |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
3 of 7 Epi4k: Sequencing, Biostatistics & Bioinformatics Core
DESCRIPTION (provided by applicant): The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The specific goals of this core (3 of 7 - Sequencing, Biostatistics, and Bioinformatics Core) are to 1) sequence and annotate 4,000 genomes, 2) develop computational procedures for calling CNVs in whole exome data, 3) identify and prioritize variants of interest for all three projects, 4) conduct follow up genotypin analyses in a cohort of additional cases and controls, and 5) quickly and efficiently share data among the Epi4K consortium.
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0.928 |
2014 |
Eichler, Evan (co-PI) [⬀] Goldstein, David B. [⬀] Heinzen Cox, Erin L Mefford, Heather C |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
3 of 7 Epi4k: Gene Discovery in 4,000 Epilepsy Genomes
DESCRIPTION (provided by applicant): The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The specific goals of this core (3 of 7 - Sequencing, Biostatistics, and Bioinformatics Core) are to 1) sequence and annotate 4,000 genomes, 2) develop computational procedures for calling CNVs in whole exome data, 3) identify and prioritize variants of interest for all three projects, 4) conduct follow up genotypin analyses in a cohort of additional cases and controls, and 5) quickly and efficiently share data among the Epi4K consortium.
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0.928 |