A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability

Neurogenetics. 2023 Oct;24(4):251-262. doi: 10.1007/s10048-023-00727-7. Epub 2023 Jul 31.


Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired adaptive behavior and cognitive capacity. High throughput sequencing approaches have revealed the genetic etiologies for 25-50% of ID patients, while inherited genetic mutations were detected in <5% cases. Here, we investigated the genetic cause for non-syndromic ID in a Han Chinese family. Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children, and their asymptomatic parents. Data was filtered for rare variants, and in silico prediction tools were used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. In silico modeling was used to evaluate the mutation's effects on the protein encoded by a candidate coding gene. A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts zinc binding within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. This is the first report of an inherited ZBTB18 mutation for ID. This study further validates WGS for the accurate molecular diagnosis of ID.

Keywords: Intellectual disability; Whole genome sequencing (WGS); ZBTB18; c.1323C>G.

MeSH terms

  • Child
  • Family
  • Humans
  • Intellectual Disability* / genetics
  • Intellectual Disability* / pathology
  • Mutation
  • Mutation, Missense*
  • Pedigree
  • Proteins / genetics


  • Proteins
  • ZBTB18 protein, human