Clinical Implications of Mosaicism and Low-Level Mosaicism in Neurocutaneous Disorders
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COUNSELING AND TESTING (C WALTON AND C REISER, SECTION EDITORS)
Clinical Implications of Mosaicism and Low-Level Mosaicism in Neurocutaneous Disorders Heather B. Radtke 1,2
&
Leah E. Lalor 3 & Donald G. Basel 1 & Dawn H. Siegel 3
Accepted: 20 October 2020 / Published online: 18 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review Advances in genetic testing technologies allow for deep sequencing with improved ability to diagnose neurocutaneous and other genetic disorders with higher sensitivity. These newer molecular technologies have also increased the ability to detect low levels of mosaicism. This has impacted the understanding of the natural history of neurocutaneous disorders, contributed to phenotypic expansion of many genes, and created new challenges to both clinical interpretation and medical management recommendations. Recent Findings With improved testing, more individuals with neurocutaneous disorders are being diagnosed with mosaicism and low-level mosaicism in well-known genes, as well as newer genes associated through pathway and functional studies. Summary As more individuals are diagnosed with mosaicism and low-level mosaicism by newer techniques, clinicians are likely to encounter some uncertainty about management and counseling of these individuals. This paper provides a practical approach to patients suspected to have and identified with mosaic neurocutaneous disorders. Keywords Low-level mosaicism . Mosaicism . Segmental . Next generation sequencing . Neurocutaneous disorders . Phakomatoses
Introduction Genomic mosaicism is the presence of two or more genetically distinct cell lines originating in one zygote resulting from a post-zygotic mutation [1]. Factors influencing the phenotypic consequence of mosaicism include the cell type, gene function, pattern of gene expression, type of pathogenic variant, timing of genetic alteration, and the presence of germline variants [2••]. There are several ways to classify genomic mosaicism, most broadly, as somatic only, gonadal (or germline) only, or gonosomal (affecting both somatic cells and the germline). This article is part of the Topical Collection on Counseling and Testing * Heather B. Radtke [email protected]; [email protected] 1
Department of Pediatrics, Division of Genetics, Medical College of Wisconsin, Milwaukee, WI, USA
2
Children’s Tumor Foundation, New York, NY, USA
3
Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI, USA
Next-generation sequencing (NGS) with deep sequence coverage has revolutionized the field of genetics, allowing for a rapid and cost-effective diagnostic approach with improved detection of genetic variants [3]. High throughput NGS and digital PCR (dPCR), another recent technique, are better able to identify mosaicism, including low levels of mosaicism (LLM), often measured as variant allele frequency (VAF) [4]. These technologies were first used in the oncology setting, but have now been integrated into many diagnostic testing approaches o
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