De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Genet Med. 2020 Mar;22(3):538-546. doi: 10.1038/s41436-019-0693-9. Epub 2019 Nov 14.

Abstract

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Keywords: ZNF292; autism spectrum disorders; exome sequencing; intellectual disability; next-generation sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autism Spectrum Disorder / diagnosis
  • Autism Spectrum Disorder / diagnostic imaging
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / pathology
  • Carrier Proteins / genetics*
  • Child
  • Child, Preschool
  • Female
  • Genetic Predisposition to Disease*
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Male
  • Nerve Tissue Proteins / genetics*
  • Neurodevelopmental Disorders / diagnosis
  • Neurodevelopmental Disorders / diagnostic imaging
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / pathology
  • Neuroimaging / methods
  • Whole Exome Sequencing / methods

Substances

  • Carrier Proteins
  • Nerve Tissue Proteins
  • ZNF292 protein, human