Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing

Am J Hum Genet. 2020 Sep 3;107(3):544-554. doi: 10.1016/j.ajhg.2020.06.019. Epub 2020 Jul 29.

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.

Keywords: SCAF4; epilepsy; intellectual disability; mRNA processing; neurodevelopmental disorder; seizures.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Child
  • Drosophila melanogaster / genetics
  • Female
  • Gene Knockdown Techniques
  • Genetic Variation / genetics
  • Heterozygote
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Locomotion / genetics
  • Male
  • Mutation / genetics
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / physiopathology
  • RNA Polymerase II / genetics
  • RNA Processing, Post-Transcriptional / genetics
  • RNA, Messenger / genetics
  • Seizures / genetics*
  • Seizures / physiopathology
  • Serine-Arginine Splicing Factors / genetics*
  • Whole Exome Sequencing

Substances

  • RNA, Messenger
  • SCAF4 protein, human
  • Serine-Arginine Splicing Factors
  • RNA Polymerase II