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A Synonymous DLG4 Variant (c.771G>A) Causes Exon 9 Skipping via Paternal Germline Mosaicism in DLG4-Related

Jing Chen1,2, Qinfei Zhao1, Xinyue Zhang3

  • 1Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.

Molecular Genetics & Genomic Medicine
|July 22, 2026
PubMed
Abstract

Insights

This study confirms a synonymous DLG4 variant causes neurodevelopmental delay by disrupting splicing. It provides the first molecular evidence of paternal germline mosaicism in DLG4-related synaptopathy.

Area of Science:

  • Genetics
  • Molecular Biology
  • Neuroscience

Background:

  • Synonymous variants in DLG4 have conflicting pathogenicity.
  • The molecular mechanism of DLG4 variants is often uncharacterized.
  • Paternal germline mosaicism in DLG4-related synaptopathy is suspected but unconfirmed.

Purpose of the Study:

  • To functionally validate the pathogenicity of the synonymous DLG4 variant c.771G>A.
  • To elucidate the inheritance mechanism of this variant in a neurodevelopmental delay case.
  • To provide molecular confirmation of paternal germline mosaicism.

Main Methods:

  • Trio-whole-exome sequencing identified the variant.
  • Bioinformatic predictors, Sanger sequencing, RNA sequencing, and RT-PCR assessed pathogenicity.
  • High-depth amplicon sequencing of paternal sperm investigated inheritance.

Main Results:

  • The DLG4 c.771G>A variant caused exon 9 skipping, frameshift, and premature termination.
  • The variant was absent in gnomAD, indicating rarity.
  • Paternal germline mosaicism was confirmed with 3.83% variant allele frequency in sperm.

Conclusions:

  • The DLG4 c.771G>A variant is pathogenic due to splice disruption.
  • This is the first molecular confirmation of paternal germline mosaicism in DLG4-related synaptopathy.
  • Functional analysis of synonymous variants and mosaicism detection are crucial for genetic counseling.
Keywords:
DLG4RNA splicingexon skippingpaternal germline mosaicismsynaptopathysynonymous variant

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