Browsing by Author "Schnur, Rhonda E."

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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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    Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia
    (Elsevier, 2021-05) Muir, Alison M.; Gardner, Jennifer F.; van Jaarsveld, Richard H.; de Lange, Iris M.; van der Smagt, Jasper J.; Wilson, Golder N.; Dubbs, Holly; Goldberg, Ethan M.; Zitano, Lia; Bupp, Caleb; Martinez, Jose; Srour, Myriam; Accogli, Andrea; Alhakeem, Afnan; Meltzer, Meira; Gropman, Andrea; Brewer, Carole; Caswell, Richard C.; Montgomery, Tara; McKenna, Caoimhe; McKee, Shane; Powell, Corinna; Vasudevan, Pradeep C.; Brady, Angela F.; Joss, Shelagh; Tysoe, Carolyn; Noh, Grace; Tarnopolsky, Mark; Brady, Lauren; Zafar, Muhammad; Schrier Vergano, Samantha A.; Murray, Brianna; Sawyer, Lindsey; Hainline, Bryan E.; Sapp, Katherine; DeMarzo, Danielle; Huismann, Darcy J.; Wentzensen, Ingrid M.; Schnur, Rhonda E.; Monaghan, Kristin G.; Juusola, Jane; Rhodes, Lindsay; Dobyns, William B.; Lecoquierre, Francois; Goldenberg, Alice; Polster, Tilman; Axer-Schaefer, Susanne; Platzer, Konrad; Klöckner, Chiara; Hoffman, Trevor L.; MacArthur, Daniel G.; O'Leary, Melanie C.; VanNoy, Grace E.; England, Eleina; Varghese, Vinod C.; Mefford, Heather C.; Medical and Molecular Genetics, School of Medicine
    Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.