@article {918, title = {De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 04}, pages = {653-660}, abstract = {

PURPOSE: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

METHODS: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

RESULTS: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

CONCLUSION: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."

}, keywords = {Brain Diseases, Child, Preschool, Epilepsy, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, Synaptosomal-Associated Protein 25}, issn = {1530-0366}, doi = {10.1038/s41436-020-01020-w}, author = {Kl{\"o}ckner, Chiara and Sticht, Heinrich and Zacher, Pia and Popp, Bernt and Babcock, Holly E and Bakker, Dewi P and Barwick, Katy and Bonfert, Michaela V and B{\"o}nnemann, Carsten G and Brilstra, Eva H and Chung, Wendy K and Clarke, Angus J and Devine, Patrick and Donkervoort, Sandra and Fraser, Jamie L and Friedman, Jennifer and Gates, Alyssa and Ghoumid, Jamal and Hobson, Emma and Horvath, Gabriella and Keller-Ramey, Jennifer and Keren, Boris and Kurian, Manju A and Lee, Virgina and Leppig, Kathleen A and Lundgren, Johan and McDonald, Marie T and McLaughlin, Heather M and McTague, Amy and Mefford, Heather C and Mignot, Cyril and Mikati, Mohamad A and Nava, Caroline and Raymond, F Lucy and Sampson, Julian R and Sanchis-Juan, Alba and Shashi, Vandana and Shieh, Joseph T C and Shinawi, Marwan and Slavotinek, Anne and St{\"o}dberg, Tommy and Stong, Nicholas and Sullivan, Jennifer A and Taylor, Ashley C and Toler, Tomi L and van den Boogaard, Marie-Jos{\'e} and van der Crabben, Saskia N and van Gassen, Koen L I and van Jaarsveld, Richard H and Van Ziffle, Jessica and Wadley, Alexandrea F and Wagner, Matias and Wigby, Kristen and Wortmann, Saskia B and Zarate, Yuri A and M{\o}ller, Rikke S and Lemke, Johannes R and Platzer, Konrad} } @article {974, title = {Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 05}, pages = {881-887}, 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.

}, keywords = {Child, Developmental Disabilities, Humans, Intellectual Disability, Muscle Hypotonia, Neurodevelopmental Disorders, Seizures, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-01076-8}, author = {Muir, Alison M and Gardner, Jennifer F and van Jaarsveld, Richard H and de Lange, Iris M and van der Smagt, Jasper J and Wilson, Golder N and Dubbs, Holly and Goldberg, Ethan M and Zitano, Lia and Bupp, Caleb and Martinez, Jose and Srour, Myriam and Accogli, Andrea and Alhakeem, Afnan and Meltzer, Meira and Gropman, Andrea and Brewer, Carole and Caswell, Richard C and Montgomery, Tara and McKenna, Caoimhe and McKee, Shane and Powell, Corinna and Vasudevan, Pradeep C and Brady, Angela F and Joss, Shelagh and Tysoe, Carolyn and Noh, Grace and Tarnopolsky, Mark and Brady, Lauren and Zafar, Muhammad and Schrier Vergano, Samantha A and Murray, Brianna and Sawyer, Lindsey and Hainline, Bryan E and Sapp, Katherine and DeMarzo, Danielle and Huismann, Darcy J and Wentzensen, Ingrid M and Schnur, Rhonda E and Monaghan, Kristin G and Juusola, Jane and Rhodes, Lindsay and Dobyns, William B and Lecoquierre, Francois and Goldenberg, Alice and Polster, Tilman and Axer-Schaefer, Susanne and Platzer, Konrad and Kl{\"o}ckner, Chiara and Hoffman, Trevor L and MacArthur, Daniel G and O{\textquoteright}Leary, Melanie C and VanNoy, Grace E and England, Eleina and Varghese, Vinod C and Mefford, Heather C} }