Molecular diagnosis of somatic overgrowth conditions: A single‐center experience
| Autor: | Keith Rafferty, Tapan Ganguly, Richard Grant, Arupa Ganguly, Jennifer M. Kalish, Jennifer Marie Rosado, Erik Toorens, Emilie Lalonde, Jennifer Richards-Yutz, Jessica Ebrahimzadeh, Matthew A. Deardorff, Erica Schindewolf |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Lineage (genetic) Somatic cell Class I Phosphatidylinositol 3-Kinases Vascular Malformations 030105 genetics & heredity Biology somatic overgrowth Single Center DNA sequencing Proteus Syndrome 03 medical and health sciences Unknown Significance Sturge-Weber Syndrome Genetics medicine Humans Diagnostic laboratory Genetic Testing Molecular Biology Nevus Genetics (clinical) Original Articles Sequence Analysis DNA medicine.disease Phenotype PIK3CA‐related overgrowth spectrum Proteus syndrome Musculoskeletal Abnormalities 030104 developmental biology mosaicism Mutation Original Article Lipoma |
| Zdroj: | Molecular Genetics & Genomic Medicine |
| ISSN: | 2324-9269 |
| Popis: | Background Somatic overgrowth conditions, including Proteus syndrome, Sturge–Weber syndrome, and PIK3CA‐related overgrowth spectrum, are caused by post‐zygotic pathogenic variants, result in segmental mosaicism, and give rise to neural, cutaneous and/or lipomatous overgrowth. These variants occur in growth‐promoting pathways leading to cellular proliferation and expansion of tissues that arise from the affected cellular lineage. Methods We report on 80 serial patients evaluated for somatic overgrowth conditions in a diagnostic laboratory setting, including three prenatal patients. In total, 166 tissues from these 80 patients were subjected to targeted sequencing of an 8‐gene panel capturing 10.2 kb of sequence containing known pathogenic variants associated with somatic overgrowth conditions. Deep next‐generation sequencing was performed with the IonTorrent PGM platform at an average depth typically >5,000×. Results Likely pathogenic or pathogenic variants were identified in 36 individuals and variants of unknown significance in four. The overall molecular diagnostic yield was 45% but was highly influenced by both submitted tissue type and phenotype. In the prenatal setting, two patients had pathogenic variants identified in cultured amniocytes but in a third patient, the pathogenic variant was only present in post‐natal tissues. Finally, expanding the test to include full gene sequencing of PIK3CA in contrast to targeted sequencing identified likely pathogenic variants in 3 of 7 patients that tested negative on the original panel. Conclusion Next‐generation sequencing has enabled sensitive detection of somatic pathogenic variants associated with overgrowth conditions. However, as the pathogenic variant allele frequency varies by tissue type within an individual, submission of affected tissue(s) greatly increases the chances of a molecular diagnosis. |
| Databáze: | OpenAIRE |
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