Abbreviations:indel (insertion/deletion), LP (linear porokeratosis), NGS (next-generation sequencing), PPK (phacomatosis pigmentokeratotica), PS (Proteus syndrome), SNV (single-nucleotide variant), VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), WES (whole-exome sequencing), WGS (whole-genome sequencing)
- •Mosaicism refers to genetically different populations of cells in individuals due to postzygotic alterations and can have clinical consequences depending on cell lineage, tissue distribution, variant type, variant timing, and gene function.
- •Sequence variants that would otherwise be embryonic lethal may present in isolated regions of the epidermis through somatic mosaicism, as seen in the case of the Proteus syndrome.
- •Identifying causal variants can change the paradigm for understanding diseases, as seen with the reclassification of phacomatosis pigmentokeratotica as a mosaic RASopathy.
- •Genotype-driven, phenotype-neutral strategies are modern approaches to the discovery of pathogenic variants for previously unrecognized clinical phenotype groupings, as seen with the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome.
- •There are numerous technologies that can profile disorders of cutaneous mosaicism at the molecular level, including Sanger sequencing, multiplex mutation assays, whole-exome sequencing, and whole-genome sequencing.
- •Exome sequencing has emerged as a particularly powerful and cost-effective tool for unbiased discovery of pathogenic variants.
- •Identifying causal variants can serve as the starting point for understanding the biology underlying the complex phenotypes of mosaic disorders.
- •Recent developments in single-cell and CRISPR gene perturbation technologies have the potential for higher resolution analysis of affected cells and studying the pathogenesis of the mutant alleles.
- •Each of the molecular profiling and sequencing technologies has limitations regarding coverage, resolution, and cost.
- •Technical challenges with capturing high-quality data from DNA molecules in individual cells have limited the potential of single-cell variant or genotype-based studies.
- •Although these methods are powerful for identifying disease-associated variants, further studies are warranted to determine the mechanisms by which the alterations lead to such complex phenotypes.
Whole-exome sequencing for Proteus syndrome
Targeted molecular assays for phakomatosis pigmentokeratotica
Second-hit loss of heterozygosity in linear porokeratosis
Genotype-driven approaches for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome
Novel biology revealed by study of cutaneous diseases
Study design for cutaneous mosaicism disorders
Advantages and limitations of molecular techniques
Single-cell genomics, genomic perturbations, and future directions
Conflict of Interest
- Teaching Slides
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