Browsing by Author "Belbin, Gillian M."

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    Boricua Founder Variant in FRRS1L Causes Epileptic Encephalopathy With Hyperkinetic Movements
    (Sage, 2021) Abdelmoumen, Imane; Jimenez, Sandra; Valencia, Ignacio; Melvin, Joseph; Legido, Agustin; Diaz-Diaz, Mayela M.; Griffith, Christopher; Massingham, Lauren J.; Yelton, Melissa; Rodríguez-Hernández, Janice; Schnur, Rhonda E.; Walsh, Laurence E.; Cristancho, Ana G.; Bergqvist, Christina A.; McWalter, Kirsty; Mathieson, Iain; Belbin, Gillian M.; Kenny, Eimear E.; Ortiz-Gonzalez, Xilma R.; Schneider, Michael C.; Neurology, School of Medicine
    Objective: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. Background: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. Methods: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. Results: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). Conclusions: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.
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    Correction to: Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
    (BioMed Central, 2019-11-05) Glicksberg, Benjamin S.; Amadori, Letizia; Akers, Nicholas K.; Sukhavasi, Katyayani; Franzén, Oscar; Li, Li; Belbin, Gillian M.; Ayers, Kristin L.; Shameer, Khader; Badgeley, Marcus A.; Johnson, Kipp W.; Readhead, Ben; Darrow, Bruce J.; Kenny, Eimear E.; Betsholtz, Christer; Ermel, Raili; Skogsberg, Josefin; Ruusalepp, Arno; Schadt, Eric E.; Dudley, Joel T.; Ren, Hongxia; Kovacic, Jason C.; Giannarelli, Chiara; Li, Shuyu D.; Björkegren, Johan L. M.; Chen, Rong; Pediatrics, School of Medicine
    Erratum for Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. [BMC Med Genomics. 2019]
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    Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
    (Biomed Central, 2019-07-25) Glicksberg, Benjamin S.; Amadori, Letizia; Akers, Nicholas K.; Sukhavasi, Katyayani; Franzén, Oscar; Li, Li; Belbin, Gillian M.; Akers, Kristin L.; Shameer, Khader; Badgeley, Marcus A.; Johnson, Kipp W.; Readhead, Ben; Darrow, Bruce J.; Kenny, Eimear E.; Betsholtz, Christer; Ermel, Raili; Skogsberg, Josefin; Ruusalepp, Arno; Schadt, Eric E.; Dudley, Joel T.; Ren, Hongxia; Kovacic, Jason C.; Giannarelli, Chiara; Li, Shuyu D.; Björkegren, Johan L. M.; Chen, Rong; Pediatrics, IU School of Medicine
    BACKGROUND: Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. RESULTS: We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. CONCLUSION: In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.