Biallelic loss of EEF1D function links heat shock response pathway to autosomal recessive intellectual disability

J Hum Genet. 2019 May;64(5):421-426. doi: 10.1038/s10038-019-0570-z. Epub 2019 Feb 21.

Abstract

Intellectual disability (ID) is a genetically heterogeneous neurodevelopmental disorder characterised by significantly impaired intellectual and adaptive functioning. ID is commonly syndromic and associated with developmental, metabolic and/or neurological findings. Autosomal recessive ID (ARID) is a significant component of ID especially in the presence of parental consanguinity. Several ultra rare ARID associated variants in numerous genes specific almost to single families have been identified by unbiased next generation sequencing technologies. However, most of these new candidate ARID genes have not been replicated in new families due to the rarity of associated alleles in this highly heterogeneous condition. To determine the genetic component of ARID in a consanguineous family from Turkey, we have performed SNP-based linkage analysis in the family along with whole exome sequencing (WES) in an affected sibling. Eventually, we have identified a novel pathogenic variant in EEF1D, which has recently been recognised as a novel candidate gene for ARID in a single family. EEF1D encodes a ubiquitously expressed translational elongation factor functioning in the cytoplasm. Herein, we suggest that the loss of function variants exclusively targeting the long EEF1D isoform may explicate the ARID phenotype through the heat shock response pathway, rather than interfering with the canonical translational elongation.

MeSH terms

  • Family
  • Female
  • Genes, Recessive*
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / metabolism
  • Genetic Linkage
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism
  • Loss of Function Mutation*
  • Male
  • Peptide Elongation Factor 1 / genetics*
  • Peptide Elongation Factor 1 / metabolism
  • Polymorphism, Single Nucleotide*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism

Substances

  • EEF1D protein, human
  • Peptide Elongation Factor 1
  • Protein Isoforms