A deep intronic DLG4 variant resulting in DLG4-related synaptopathy

Amanda M. Levy, Mythily Ganapathi, Wendy K. Chung, Zeynep Tümer*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

2 Citations (Scopus)
13 Downloads (Pure)

Abstract

The rare autosomal dominant brain disorder DLG4-related synaptopathy is caused by de novo variants in DLG4 (encoding PSD-95), the majority of which are predicted to be protein-truncating. In addition to splice site variants, a number of synonymous and missense DLG4 variants are predicted to exert their effect through altered RNA splicing, although the pathogenicity of these variants is uncertain without functional RNA studies. Here, we describe a young boy with a deep intronic DLG4 variant (c.2105+235C>T) identified using whole genome sequencing. By using reverse-transcription PCR on RNA derived from peripheral blood, we demonstrate that DLG4 mRNA expression is detectable in blood and the deep intronic variant gives rise to two alternative DLG4 transcripts, one of which includes a pseudoexon. Both alternative transcripts are out-of-frame and predicted to result in protein-truncation, thereby establishing the genetic diagnosis for the proband. This adds to the evidence concerning the pathogenic potential of deep intronic variants and underlines the importance of functional studies, even in cases where reported tissue-specific gene expression might suggest otherwise.

Original languageEnglish
JournalClinical Genetics
Volume105
Issue number1
Pages (from-to)77-80
Number of pages4
ISSN0009-9163
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

Keywords

  • alternative splicing
  • deep intronic variant
  • DLG4
  • DLG4-related synaptopathy
  • epilepsy
  • intellectual disability
  • neurodevelopmental disorder
  • PSD-95
  • pseudoexon

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