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A comparative analysis of RAS variants in patients with disorders of somatic mosaicism

Ying-Chen Claire Hou1, Michael J Evenson1, Meagan M Corliss1

  • 1Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|December 26, 2022
PubMed
Abstract

Insights

Mosaic RAS variants are common in somatic mosaicism disorders, with hotspots linked to diverse phenotypes and in-frame duplications/insertions primarily associated with vascular malformations.

Area of Science:

  • Genetics
  • Molecular Biology
  • Clinical Medicine

Background:

  • RAS genes (HRAS, KRAS, NRAS) are frequently mutated in cancers.
  • Activating RAS variants are also implicated in disorders of somatic mosaicism (DoSM).
  • The mutational spectrum of RAS variants in DoSM has not been previously surveyed.

Purpose of the Study:

  • To investigate the mutational spectrum of RAS variants in individuals with suspected DoSM.
  • To explore genotype-phenotype associations of mosaic RAS variants.
  • To provide insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.

Main Methods:

  • High-sensitivity clinical next-generation sequencing was performed on 938 individuals with suspected DoSM.
  • Analysis focused on identifying and characterizing mosaic RAS variants.
  • Genotype-phenotype correlations were examined.

Main Results:

  • Classic RAS hotspots (Gly12, Gly13, Gln61) were the most common variants.
  • Twelve individuals presented with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain.
  • In-frame dup/ins variants (18.3% of cases) were mainly associated with vascular malformations.
  • Hotspot variants were linked to a broad spectrum of phenotypes including vascular tumors, nevoid proliferations, overgrowth, and digital anomalies.
  • Individuals with in-frame dup/ins variants had a higher median age at testing and lower variant allelic fraction compared to those with hotspot variants.

Conclusions:

  • This study characterizes the mutational landscape of RAS variants in DoSM.
  • Mosaic RAS variants exhibit significant allelic and clinical heterogeneity.
  • Findings contribute to understanding the genetic basis and clinical manifestations of DoSM.
Keywords:
Disorders of somatic mosaicismHRASIn-frame insertionsKRASRAS

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