title: Detection and Quantification of Mosaic Mutations in Disease Genes by Next-Generation Sequencing.
abstract: The identification of mosaicism is important in establishing a disease diagnosis, assessing recurrence risk, and genetic counseling. Next-generation sequencing (NGS) with deep sequence coverage enhances sensitivity and allows for accurate quantification of the level of mosaicism. NGS identifies low-level mosaicism that would be undetectable by conventional Sanger sequencing. A customized DNA probe library was used for capturing targeted genes, followed by deep NGS analysis. The mean coverage depth per base was approximately 800×. The NGS sequence data were analyzed for single-nucleotide variants and copy number variations. Mosaic mutations in 10 cases/families were detected and confirmed by NGS analysis. Mosaicism was identified for autosomal dominant (JAG1, COL3A1), autosomal recessive (PYGM), and X-linked (PHKA2, PDHA1, OTC, and SLC6A8) disorders. The mosaicism was identified either in one or more tissues from the probands or in a parent of an affected child. When analyzing data from patients with unusual testing results or inheritance patterns, it is important to further evaluate the possibility of mosaicism. Deep NGS analysis not only provides insights into the spectrum of mosaic mutations but also underlines the importance of the detection of mosaicism as an integral part of clinical molecular diagnosis and genetic counseling.
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas.
authors.forename: Lan
authors.initials: L
authors.lastname: Qin
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas.
authors.forename: Cavatina
authors.initials: C
authors.lastname: Truong
authors.affiliation: Division of Pediatric Endocrinology, Montreal Children's Hospital, Montreal, Quebec, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mitchell
authors.affiliation: Department of Pediatrics, Section of Genetics, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.
authors.forename: Klaas J
authors.initials: KJ
authors.lastname: Wierenga
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Victor Wei
authors.initials: VW
authors.lastname: Zhang
authors.affiliation: Baylor Miraca Genetics Laboratories, Houston, Texas; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. Electronic address: ljwong@bcm.edu.
authors.forename: Lee-Jun C
authors.initials: LC
authors.lastname: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D050172:Genes, X-Linked; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000235:genetics; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D009030:Mosaicism; D009154:Mutation; D055815:Young Adult