1. Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing
- Author
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Grace J. Noh, Marjon van Slegtenhorst, Ingrid M.B.H. van de Laar, Lisa Ohden, Joshua L. Deignan, Jane Juusola, Naghmeh Dorrani, Katherine Agre, Anne Gregor, Vidya Krishnamurthy, Arif B. Ekici, Julian A. Martinez-Agosto, Vimla Aggarwal, T. Niroshi Senaratne, Seema R. Lalani, Antje Wiesener, Stella A. de Man, Mahshid S. Azamian, Marina S. Dutra-Clarke, Jill A. Rosenfeld, Ahna M. Neustadt, Daryl A. Scott, Brent L. Fogel, Stanley F. Nelson, Ghayda M. Mirzaa, Irma van de Beek, Kirsty McWalter, Wayne W. Grody, Rachel Straussberg, Ralitza H. Gavrilova, Hane Lee, Anna Fliedner, Quinten Waisfisz, Mieke M. van Haelst, Jessica Kianmahd, Fabiola Quintero-Rivera, Marina Dutra-Clarke, Rony Cohen, Laura Davis-Keppen, Anna Alkelai, Christiane Zweier, Fan Xia, Brooke Horist, Philipp Kirchner, Sung-Hae Kang, Franceska L. Hinkamp, Natalie Lippa, Valerie A. Arboleda, Human Genetics, Clinical Genetics, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
- Subjects
Male ,Heterozygote ,RNA polymerase II ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,Transcription (biology) ,Report ,Exome Sequencing ,Genetics ,medicine ,Animals ,Humans ,RNA, Messenger ,RNA Processing, Post-Transcriptional ,Child ,Gene ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,seizures ,0303 health sciences ,Gene knockdown ,Serine-Arginine Splicing Factors ,Genetic Variation ,SCAF4 ,medicine.disease ,Phenotype ,neurodevelopmental disorder ,Drosophila melanogaster ,Neurodevelopmental Disorders ,intellectual disability ,Gene Knockdown Techniques ,RNA splicing ,Mutation ,biology.protein ,epilepsy ,Female ,RNA Polymerase II ,mRNA processing ,030217 neurology & neurosurgery ,Locomotion - Abstract
RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.
- Published
- 2020
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