The Value of Parental Testing by Next-Generation Sequencing Includes the Detection of Germline Mosaicism
| Autor: | Joseph Fierro, Casey J Brewer, Hanlin Gao, Hai-Yun Yen, Jie Mickey Li, William A Scaringe, Che-Yu Lee, Samuel P. Strom, Meghan Gillespie |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Proband Male Heterozygote Genotype Inheritance Patterns Germline mosaicism Computational biology Biology DNA sequencing Pathology and Forensic Medicine Recurrence risk 03 medical and health sciences symbols.namesake 0302 clinical medicine Humans Allele Gene Alleles Sanger sequencing Mosaicism Inheritance (genetic algorithm) Computational Biology Genetic Variation High-Throughput Nucleotide Sequencing Sequence Analysis DNA Pedigree 030104 developmental biology Germ Cells 030220 oncology & carcinogenesis Mutation symbols Molecular Medicine Female |
| Zdroj: | The Journal of molecular diagnostics : JMD. 22(5) |
| ISSN: | 1943-7811 |
| Popis: | When a potential disease-causing variant is detected in a proband, parental testing is used to determine the mode of inheritance. This study demonstrates that next-generation sequencing (NGS) is uniquely well suited for parental testing, in particular because of its ability to detect clinically relevant germline mosaicism. Parental variant testing by NGS was performed in a clinical laboratory for 1 year. The detection of mosaicism by NGS was compared with its detection by Sanger sequencing. Eight cases of previously unrevealed mosaicism were detected by NGS across eight different genes. Mosaic variants were differentiated from sequencing noise using custom bioinformatics analyses in combination with familial inheritance data and complementary Sanger sequencing. Sanger sequencing detected mosaic variants with allele fractions ≥8% by NGS, but could not detect mosaic variants below that level. Detection of germline mosaicism by NGS is invaluable to parents, providing a more accurate recurrence risk that can alter decisions on family planning and pregnancy management. Because NGS can also confirm parentage and increase scalability, it simultaneously streamlines and strengthens the variant curation process. These features make NGS the ideal method for parental testing, superior even to Sanger sequencing for most genomic loci. |
| Databáze: | OpenAIRE |
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