Recurrent mosaic MTOR c.5930C > T (p.Thr1977Ile) variant causing megalencephaly, asymmetric polymicrogyria, and cutaneous pigmentary mosaicism: Case report and review of the literature

Am J Med Genet A. 2019 Mar;179(3):475-479. doi: 10.1002/ajmg.a.61007. Epub 2018 Dec 19.


Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling result in brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri-color of the Blaschko-linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C > T (p.Thr1977Ile) MTOR variant. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings. We report a fourth case of a 3-year-old female presenting with megalencephaly, obstructive hydrocephalus due to cerebral aqueductal stenosis, asymmetric polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism. Oligonucleotide and SNP chromosomal microarray (CMA), karyotype, and trio whole exome sequencing (WES) in the peripheral blood, as well as a targeted gene variant panel from fibroblasts derived from hyperpigmented and non-hyperpigmented skin did not detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes. Unlike the previously reported cases, the de novo c.5930C > T (p.Thr1977Ile) MTOR variant was detected at 32% mosaicism in our patient only after WES was performed on fibroblast-derived DNA from the hyperpigmented skin. This case demonstrates the tissue variability in mosaic expression of the recurrent p.Thr1977Ile MTOR variant, emphasizes the need for skin biopsies in the genetic evaluation of patients with skin pigmentary mosaicism, and expands the clinical phenotype associated with this pathogenic MTOR variant.

Keywords: MTOR gene; cutaneous pigmentary mosaicism; megalencephaly; polymicrogyria; somatic mosaicism.

Publication types

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

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Child, Preschool
  • Female
  • Genotype
  • Humans
  • Magnetic Resonance Imaging
  • Malformations of Cortical Development / diagnosis*
  • Malformations of Cortical Development / genetics*
  • Megalencephaly / diagnosis*
  • Megalencephaly / genetics*
  • Mosaicism
  • Mutation*
  • Phenotype
  • Pigmentation Disorders / diagnosis*
  • Pigmentation Disorders / genetics*
  • Polymorphism, Single Nucleotide
  • TOR Serine-Threonine Kinases / genetics*


  • MTOR protein, human
  • TOR Serine-Threonine Kinases

Supplementary concepts

  • Polymicrogyria, Asymmetric