A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

Eur J Hum Genet. 2016 Mar;24(3):455-8. doi: 10.1038/ejhg.2015.140. Epub 2015 Jul 8.


Megalencephaly is a congenital condition characterized by severe overdeveloped brain size. This phenotype is often caused by mutations affecting the RTK/PI3K/mTOR (receptor tyrosine kinase-phosphatidylinositol-3-kinase-AKT) signaling and its downstream pathway of mammalian target of rapamycin (mTOR). Here, using a whole-exome sequencing in a Moroccan consanguineous family, we show that a novel autosomal-recessive neurological condition characterized by megalencephaly, thick corpus callosum and severe intellectual disability is caused by a homozygous nonsense variant in the HERC1 gene. Assessment of the primary skin fibroblast from the proband revealed complete absence of the HERC1 protein. HERC1 is an ubiquitin ligase that interacts with tuberous sclerosis complex 2, an upstream negative regulator of the mTOR pathway. Our data further emphasize the role of the mTOR pathway in the regulation of brain development and the power of next-generation sequencing technique in elucidating the genetic etiology of autosomal-recessive disorders and suggest that HERC1 defect might be a novel cause of autosomal-recessive syndromic megalencephaly.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Atrophy
  • Base Sequence
  • Cerebellum / pathology*
  • Child
  • Child, Preschool
  • Codon, Nonsense / genetics*
  • Corpus Callosum / pathology*
  • Female
  • Genetic Predisposition to Disease*
  • Guanine Nucleotide Exchange Factors / genetics*
  • Humans
  • Infant, Newborn
  • Intellectual Disability / complications
  • Intellectual Disability / genetics*
  • Male
  • Megalencephaly / complications
  • Megalencephaly / genetics*
  • Molecular Sequence Data
  • Pedigree
  • Ubiquitin-Protein Ligases


  • Codon, Nonsense
  • Guanine Nucleotide Exchange Factors
  • HERC1 protein, human
  • Ubiquitin-Protein Ligases