title: Variable levels of tissue mosaicism can confound the interpretation of chromosomal microarray results from peripheral blood.
abstract: Chromosomal microarray analysis (CMA) has significantly increased the ability to diagnose medical conditions caused by copy-number variation in the human genome. Given that the regions involved in copy-number abnormalities often encompass multiple genes, it has been common practice in recent years to compare the phenotypes of individuals with specific copy-number alterations identified by CMA, with the goal of identifying the critical regions for particular elements of a disease phenotype. It is rarely mentioned that this practice relies heavily on the assumption that the absence of mosaicism on CMA from a peripheral blood sample (the most common source of DNA in current clinical practice) reflects the absence of mosaicism in other tissues. We report here a case that violates that assumption. A 28-year-old male with Charcot-Marie-Tooth disease was found by CMA to have a duplication of 17p12 along with two other abnormalities: A duplication of 12p13.33 translocated to the long arm of chromosome 3 and an interstitial duplication of 12p11.23. The patient did not have any clinical features suggestive of 12p duplication syndrome. Chromosomal microarray analysis on skin fibroblasts revealed the duplications at 17p12 and 12p11.23, but not the terminal duplication of 12p13.33. FISH analysis on skin fibroblasts confirmed the presence of very low levels of mosaicism for the terminal 12p duplication. The case illustrates how the absence of mosaicism in blood is not always indicative of the absence of mosaicism in other tissues. Even in an era of high-throughput, highly accurate DNA-based tests, it is important to remember the limitations of testing before drawing conclusions about the relationship between a test results and a clinical phenotype.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Chandni V
authors.initials: CV
authors.lastname: Pal
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Eble
authors.affiliation: Laboratory Corporation of America, Center for Molecular Biology and Pathology, 1904 Alexander Dr., Research Triangle Park, NC 27709, USA.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Burnside
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address: lfranco@bcm.edu.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Franco
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology; D058674:Chromosome Duplication; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D055028:Comparative Genomic Hybridization / Q000379:methods; D056915:DNA Copy Number Variations; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D046228:Microarray Analysis / Q000379:methods*; D009030:Mosaicism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012867:Skin / Q000473:pathology
keywords: Array comparative genomic hybridization; Charcot–Marie–Tooth disease; Chromosomal abnormalities; Duplication 12p; Mosaicism