Novel de novo ZNF148 truncating variant causing autism spectrum disorder, attention deficit hyperactivity disorder, and intellectual disability.

Researchers found a child with autism, ADHD, and intellectual disability who has a genetic change in the ZNF148 gene. This gene was previously linked to intellectual disability but not autism or ADHD. The genetic change affects how the gene works and may contribute to the child's conditions. This discovery suggests the ZNF148 gene might be important in autism development.

This case report describes a patient with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual disability who has a novel truncating variant in the ZNF148 gene. ZNF148 is a transcription factor previously associated with intellectual disability syndrome, but not with ASD or ADHD. The patient carries a heterozygous variant c.1818dupC that produces a truncated protein lacking the C-terminal activation domain, potentially affecting transcriptional function. Unlike previously reported ZNF148 cases, this patient showed normal brain development on MRI.

The findings expand the known phenotypic spectrum of ZNF148 variants to include ASD and suggest ZNF148 as a potential target gene for autism spectrum disorders.

This case expands the phenotypic spectrum of ZNF148 variants to include ASD and ADHD. Clinicians should consider ZNF148 testing in patients with co-occurring ASD, ADHD, and intellectual disability, even with normal brain imaging. Further research is needed to establish causality and prevalence.

Single case report limits generalizability. No functional studies of the variant provided. Lack of family history or segregation analysis. No comparison with other ZNF148 cases with similar variants.

ZNF148 gene is a Krüppel-type transcription factor that has transcriptional regulatory function. Heterozygous variant in ZNF148 gene causes an intellectual disability syndrome characterized by global developmental delay, absence, or hypoplasia of corpus callosum, wide intracerebral ventricles, and dysmorphic facial features, while its associations with ASD and ADHD have not been reported. We report a new patient with intellectual disability, autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). The patient had a novel heterozygous truncating variant c.1818dupC (p.Lys607Glnfs*11) in the ZNF148 gene.

This variation produces a ZNF148 truncated protein with a deletion of the C-terminal activation domain and may destabilize the protein by affecting the transcriptional activation function. Brain MRI shows normal brain development. Here, we identify a novel ZNF148 heterozygous truncating variant in a patient with distinct phenotypes of ASD and ADHD, which expands the genotype-phenotype spectrum of ZNF148, and indicates ZNF148 is also a potential target gene for ASD.