The combination of whole‐exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders

Abstract

This retrospective study aims to investigate the diagnostic yields of multiple strategies of next-generation sequencing (NGS) for children with rare neurological disorders (NDs). A total of 220 pediatric patients with NDs who visited our hospital between Jan 2017 and Dec 2018 and had undergone NGS were included. Most patients were 5 years old or younger, and the number of patients visiting the hospital decreased with age. Seizures were the most common symptom in this cohort. The positive rates for targeted NGS panels (Panel), whole-exome sequencing (WES), and copy number variation sequencing (CNVseq) were 26.5% (9/34), 36.6% (63/172), and 16.7% (22/132), respectively. The positive rate for patients undergoing a combination of WES and CNVseq (WES + CNVseq) was 47.8% (54/113), which was significantly better than the positive rate for patients who underwent WES alone (32.7%, 37/113). A total of 83 variants were found in 42 genes, and SCN1A was the most frequently mutanted gene. Twenty-four CNVs were identified in 22 patients: two CNVs were inherited from the mother; 12 CNVs were de novo; and the CNV origins could not be determined in 10 patients. WES + CNVseq may potentially be the mostly effective NGS approach for diagnosis of rare NDs in pediatric patients. K E Y W O R D Scopy number variation sequencing, diagnostic yield, neurological disorders, targeted nextgeneration sequencing panels, whole-exome sequencing

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders

“…In this study, we performed trio-WES and low-coverage WGS (0.3×) simultaneously and uncovered pathological causes in over half of the patients. The rate of patients with neurological features was 67% (14/21), which was higher than previous reports (Gao et al, 2019;Jiao et al, 2019). However, it was notable that our sample size was relatively small, and more researches were needed to better the clinical efficacy.…”

“…The resolution of CNV-seq can be adjusted by increasing or decreasing the sequencing data volume of raw data. For pediatric diagnosis, the resolution was usually >100 Kb (Gao et al, 2019;Jiao et al, 2019). By comparing differences of aligned reads number between case and control samples, losses or gains of chromosomal regions can be identified and quantitated.…”

“…On the other hand, low-coverage WGS or CNV-seq were widely used in spontaneous miscarriage and prenatal cases, but only a few pediatric CNV-seq testing studies were reported. Most of the studies focused only on neurological disorders (Gao et al, 2019;Jiao et al, 2019). In our study, we performed parallel tests of trio-WES and CNV-seq for 60 children from different clinical departments.…”

Targeted gene panel sequencing for the rapid diagnosis of acutely ill infants

“…ARUP Laboratories is currently in the process of rigorous validation of a new in‐house developed algorithm to accurately identify multi‐exon CNVs, and the process will be implemented as soon as all the requirements for clinical testing in CLIA and ISO 15189‐certified lab are fulfilled. Based on the published data, detection of CNVs may increase the overall detection yield of exome/medical exome sequencing cases by an additional 1.67%–16.7% (Jiao et al, ; Marchuk et al, ). Therefore, most patients underwent CMA analysis postnatally, either prior to or concurrently with RapSeq testing.…”

Assessing utility of clinical exome sequencing in diagnosis of rare idiopathic neurodevelopmental disorders in Indian population

“…Whilst microarray has been the mainstay for detection of CNVs, exome sequencing based large CNV detection (>400 kb) are increasingly becoming prominent in diagnosing neurological disorders [32].…”