Further delineation of the phenotype caused by biallelic variants in the WDR4 gene

Clin Genet. 2018 Feb;93(2):374-377. doi: 10.1111/cge.13074. Epub 2017 Sep 29.


Microcephalic primordial dwarfisms are a group of rare Mendelian disorders characterized by severe growth retardation and microcephaly. The molecular basis is heterogeneous, with disease-causing genes implicated in different cellular functions. Recently, 2 patients were reported with the same homozygous variant in the WDR4 gene, coding for an enzyme responsible for the m7 G46 post transcriptional modification of tRNA. We report here 2 sisters harboring compound heterozygous variants of WDR4. Their phenotype differs from that of the first 2 described patients: they both have a severe microcephaly but only one of the 2 sisters had a head circumference at birth below -2 SD, their intellectual deficiency is less severe, and they have a growth hormone deficiency and a partial hypogonadotropic hypogonadotropism. One of the 2 variants is a frameshift mutation, and the other one is a missense occurring in the same nucleotide affected by the first reported pathogenic variant, which could therefore be a mutational hot spot. The description of these 2 sisters allow us to confirm that biallelic variants in the WDR4 gene can lead to a specific phenotype, characterized by severe growth retardation and microcephaly.

Keywords: WDR4; exome sequencing; growth retardation; microcephaly.

MeSH terms

  • Adolescent
  • Child
  • Dwarfism / genetics*
  • Dwarfism / physiopathology
  • Exome / genetics
  • Facies
  • Female
  • Frameshift Mutation
  • GTP-Binding Proteins / genetics*
  • Genetic Predisposition to Disease*
  • Heterozygote
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Microcephaly / genetics*
  • Microcephaly / physiopathology
  • Pedigree
  • Phenotype
  • Siblings


  • WDR4 protein, human
  • GTP-Binding Proteins

Supplementary concepts

  • Seckel syndrome 1