Browsing by Author "Cope, Heidi"

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    Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.
    (BMC medical genomics, 2014-06) Markunas, Christina A; Lock, Eric; Soldano, Karen; Cope, Heidi; Ding, Chien-Kuang C; Enterline, David S; Grant, Gerald; Fuchs, Herbert; Ashley-Koch, Allison E; Gregory, Simon G

    Background

    Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.

    Methods

    A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.

    Results

    All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.

    Conclusions

    Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.
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    Joint eQTL assessment of whole blood and dura mater tissue from individuals with Chiari type I malformation.
    (BMC Genomics, 2015-01-22) Lock, Eric F; Soldano, Karen L; Garrett, Melanie E; Cope, Heidi; Markunas, Christina A; Fuchs, Herbert; Grant, Gerald; Dunson, David B; Gregory, Simon G; Ashley-Koch, Allison E
    BACKGROUND: Expression quantitative trait loci (eQTL) play an important role in the regulation of gene expression. Gene expression levels and eQTLs are expected to vary from tissue to tissue, and therefore multi-tissue analyses are necessary to fully understand complex genetic conditions in humans. Dura mater tissue likely interacts with cranial bone growth and thus may play a role in the etiology of Chiari Type I Malformation (CMI) and related conditions, but it is often inaccessible and its gene expression has not been well studied. A genetic basis to CMI has been established; however, the specific genetic risk factors are not well characterized. RESULTS: We present an assessment of eQTLs for whole blood and dura mater tissue from individuals with CMI. A joint-tissue analysis identified 239 eQTLs in either dura or blood, with 79% of these eQTLs shared by both tissues. Several identified eQTLs were novel and these implicate genes involved in bone development (IPO8, XYLT1, and PRKAR1A), and ribosomal pathways related to marrow and bone dysfunction, as potential candidates in the development of CMI. CONCLUSIONS: Despite strong overall heterogeneity in expression levels between blood and dura, the majority of cis-eQTLs are shared by both tissues. The power to detect shared eQTLs was improved by using an integrative statistical approach. The identified tissue-specific and shared eQTLs provide new insight into the genetic basis for CMI and related conditions.
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    Novel approaches to quantify CNS involvement in children with Pompe disease.
    (Neurology, 2020-06-09) Korlimarla, Aditi; Spiridigliozzi, Gail A; Crisp, Kelly; Herbert, Mrudu; Chen, Steven; Malinzak, Michael; Stefanescu, Mihaela; Austin, Stephanie L; Cope, Heidi; Zimmerman, Kanecia; Jones, Harrison; Provenzale, James M; Kishnani, Priya S
    OBJECTIVE:To characterize the extent of central nervous system involvement in children with Pompe disease using brain magnetic resonance imaging (MRI) and developmental assessments. METHODS:The study included fourteen children (ages 6-18 years) with infantile Pompe disease (IPD) (n=12) or late onset Pompe disease (LOPD) (n=2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach; the individual FS scores from ten anatomical areas were summed to yield a total FS score (range: absent-0 to severe-30) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period. RESULTS:Mild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age-10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in Processing Speed, Fluid Reasoning, Visual Perception, and receptive vocabulary. The two children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments. CONCLUSION:This study systematically characterized WM hyperintense foci in children with IPD; which could serve as a benchmark for longitudinal follow up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children.
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    Participant-Partners in Genetic Research: An Exome Study with Families of Children with Unexplained Medical Conditions
    (Journal of Participatory Medicine, 2018) Katsanis, Sara Huston; Minear, Mollie A; Sadeghpour, Azita; Cope, Heidi; Perilla, Yezmin; Cook-Deegan, Robert; Duke Task Force For Neonatal Genomics; Katsanis, Nicholas; Davis, Erica E; Angrist, Misha
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    Stratified whole genome linkage analysis of Chiari type I malformation implicates known Klippel-Feil syndrome genes as putative disease candidates.
    (PloS one, 2013-01) Markunas, Christina A; Soldano, Karen; Dunlap, Kaitlyn; Cope, Heidi; Asiimwe, Edgar; Stajich, Jeffrey; Enterline, David; Grant, Gerald; Fuchs, Herbert; Gregory, Simon G; Ashley-Koch, Allison E
    Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of "CTD-negative" families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3-5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.