TY - JOUR

T1 - A deep intronic DLG4 variant resulting in DLG4-related synaptopathy

AU - Levy, Amanda M.

AU - Ganapathi, Mythily

AU - Chung, Wendy K.

AU - Tümer, Zeynep

N1 - Publisher Copyright: © 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - alternative splicing

KW - deep intronic variant

KW - DLG4

KW - DLG4-related synaptopathy

KW - epilepsy

KW - intellectual disability

KW - neurodevelopmental disorder

KW - PSD-95

KW - pseudoexon

U2 - 10.1111/cge.14411

DO - 10.1111/cge.14411

M3 - Journal article

C2 - 37525972

AN - SCOPUS:85166516484

VL - 105

SP - 77

EP - 80

JO - Clinical Genetics

JF - Clinical Genetics

SN - 0009-9163

IS - 1

ER -