title: Challenges in detecting genomic copy number aberrations using next-generation sequencing data and the eXome Hidden Markov Model: a clinical exome-first diagnostic approach.
abstract: Next-generation sequencing (NGS) is widely used for the detection of disease-causing nucleotide variants. The challenges associated with detecting copy number variants (CNVs) using NGS analysis have been reported previously. Disease-related exome panels such as Illumina TruSight One are more cost-effective than whole-exome sequencing (WES) because of their selective target regions (~21% of the WES). In this study, CNVs were analyzed using data extracted through a disease-related exome panel analysis and the eXome Hidden Markov Model (XHMM). Samples from 61 patients with undiagnosed developmental delays and 52 healthy parents were included in this study. In the preliminary study to validate the constructed XHMM system (microarray-first approach), 34 patients who had previously been analyzed by chromosomal microarray testing were used. Among the five CNVs larger than 200 kb that were considered as non-pathogenic CNVs and were used as positive controls, four CNVs was successfully detected. The system was subsequently used to analyze different samples from 27 patients (NGS-first approach); 2 of these patients were successfully diagnosed as having pathogenic CNVs (an unbalanced translocation der(5)t(5;14) and a 16p11.2 duplication). These diagnoses were re-confirmed by chromosomal microarray testing and/or fluorescence in situ hybridization. The NGS-first approach generated no false-negative or false-positive results for pathogenic CNVs, indicating its high sensitivity and specificity in detecting pathogenic CNVs. The results of this study show the possible clinical utility of pathogenic CNV screening using disease-related exome panel analysis and XHMM.
authors: Tokyo Women's Medical University Institute for Integrated Medical Sciences , Tokyo, Japan.
authors: Toshiyuki
authors: 0000-0002-9484-3505
authors: T
authors: Yamamoto
authors: Tokyo Women's Medical University Institute for Integrated Medical Sciences , Tokyo, Japan.
authors: Keiko
authors: K
authors: Shimojima
authors: Tokyo Women's Medical University Institute for Integrated Medical Sciences , Tokyo, Japan.
authors: Yumiko
authors: Y
authors: Ondo
authors: National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders , Shizuoka, Japan.
authors: Katsumi
authors: K
authors: Imai
authors: Department of Pediatric Neurology, Fukuoka Children's Hospital , Fukuoka, Japan.
authors: Pin Fee
authors: PF
authors: Chong
authors: Department of Pediatric Neurology, Fukuoka Children's Hospital , Fukuoka, Japan.
authors: Ryutaro
authors: R
authors: Kira
authors: Division of Biomedical Informatics, StaGen Co., Ltd. , Tokyo, Japan.
authors: Mitsuhiro
authors: M
authors: Amemiya
authors: Division of Biomedical Informatics, StaGen Co., Ltd. , Tokyo, Japan.
authors: Akira
authors: A
authors: Saito
authors: Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health , Osaka, Japan.
authors: Nobuhiko
authors: N
authors: Okamoto