Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia Academic Article uri icon

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abstract

  • 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.

authors

  • 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

publication date

  • May 2021