@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 {697, title = {De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Aug 01}, pages = {403-412}, abstract = {

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.06.007}, author = {Snijders Blok, Lot and Kleefstra, Tjitske and Venselaar, Hanka and Maas, Saskia and Kroes, Hester Y and Lachmeijer, Augusta M A and van Gassen, Koen L I and Firth, Helen V and Tomkins, Susan and Bodek, Simon and {\~O}unap, Katrin and Wojcik, Monica H and Cunniff, Christopher and Bergstrom, Katherine and Powis, Z{\"o}e and Tang, Sha and Shinde, Deepali N and Au, Catherine and Iglesias, Alejandro D and Izumi, Kosuke and Leonard, Jacqueline and Abou Tayoun, Ahmad and Baker, Samuel W and Tartaglia, Marco and Niceta, Marcello and Dentici, Maria Lisa and Okamoto, Nobuhiko and Miyake, Noriko and Matsumoto, Naomichi and Vitobello, Antonio and Faivre, Laurence and Philippe, Christophe and Gilissen, Christian and Wiel, Laurens and Pfundt, Rolph and Deriziotis, Pelagia and Brunner, Han G and Fisher, Simon E} } @article {130, title = {Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Sep 03}, pages = {457-64}, abstract = {

Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, ATPases Associated with Diverse Cellular Activities, Base Sequence, Exome, Female, Gene Frequency, Genes, Recessive, Hearing Loss, Homeodomain Proteins, Humans, Intellectual Disability, Male, Microcephaly, Molecular Sequence Data, Mutation, Seizures, Sequence Alignment, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.07.014}, author = {Tanaka, Akemi J and Cho, Megan T and Millan, Francisca and Juusola, Jane and Retterer, Kyle and Joshi, Charuta and Niyazov, Dmitriy and Garnica, Adolfo and Gratz, Edward and Deardorff, Matthew and Wilkins, Alisha and Ortiz-Gonzalez, Xilma and Mathews, Katherine and Panzer, Karin and Brilstra, Eva and van Gassen, Koen L I and Volker-Touw, Catharina M L and van Binsbergen, Ellen and Sobreira, Nara and Hamosh, Ada and McKnight, Dianalee and Monaghan, Kristin G and Chung, Wendy K} }