Monogenic causes of pigmentary mosaicism

Hum Genet. 2022 Nov;141(11):1771-1784. doi: 10.1007/s00439-022-02437-w. Epub 2022 May 3.


Pigmentary mosaicism of the Ito type, also known as hypomelanosis of Ito, is a neurocutaneous syndrome considered to be predominantly caused by somatic chromosomal mosaicism. However, a few monogenic causes of pigmentary mosaicism have been recently reported. Eleven unrelated individuals with pigmentary mosaicism (mostly hypopigmented skin) were recruited for this study. Skin punch biopsies of the probands and trio-based blood samples (from probands and both biological parents) were collected, and genomic DNA was extracted and analyzed by exome sequencing. In all patients, plausible monogenic causes were detected with somatic and germline variants identified in five and six patients, respectively. Among the somatic variants, four patients had MTOR variant (36%) and another had an RHOA variant. De novo germline variants in USP9X, TFE3, and KCNQ5 were detected in two, one, and one patients, respectively. A maternally inherited PHF6 variant was detected in one patient with hyperpigmented skin. Compound heterozygous GTF3C5 variants were highlighted as strong candidates in the remaining patient. Exome sequencing, using patients' blood and skin samples is highly recommended as the first choice for detecting causative genetic variants of pigmentary mosaicism.

MeSH terms

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Humans
  • Hypopigmentation* / genetics
  • Mosaicism*
  • TOR Serine-Threonine Kinases / genetics
  • Ubiquitin Thiolesterase / genetics


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • USP9X protein, human
  • TOR Serine-Threonine Kinases
  • Ubiquitin Thiolesterase