Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea

Abstract

Neurodevelopmental delay accompanied unexplained dyspnea is a highly lethal disease in clinic. This study is to investigate the performance characteristics of trio whole exome sequencing (Trio-WES) in a pediatric setting by presenting our patient cohort and displaying the diagnostic yield. A total of 31 pediatric patients showing neurodevelopmental delay accompanied unexplained dyspnea were admitted to our hospital and referred for molecular genetic testing using Trio-WES. Eight genes namely MMACHC, G6PC, G6PT, ETFDH, OTC, NDUFAF5, SLC22A5, and MAGEL2 were suspected to be responsible for the onset of the clinical symptoms and 6 variants were novel. Standard interpretation according to ACMG guideline showed that the variants were pathogenic. Finally, diagnosis of methylmalonic aciduria and homocystinuria, glycogen storage disease, ornithine transcarbamylase deficiency, glutaric acidemia II, mitochondrial complex 1 deficiency, carnitine deficiency, and Schaaf-Yang syndrome was made in 12 out of the 31 patients. Trio-WES is an effective means for molecular diagnosis of infantile neurodevelopmental delay accompanied unexplained dyspnea. As for molecular etiology identification, when routine potential monogenetic inheritance patterns including de novo, autosomal recessive, autosomal dominant, and X-linked recessive inheritance analysis is negative, physicians should take into account imprinted genes.

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

“…Therefore, we highly recommended WES in 2018, and more patients underwent WES than Panel (172 vs 34). The positive rate of WES in this study was 36.6% (63/172), which is consistent with our previous study (38.7%, 12/31)29 and a large cohort study that included 1059 patients by Bergant et al (42.2%) 32. Notebaly, 248 pediatric patients underwent NGS during the incorporation time, and 28 patients were excluded.…”

“…Sun et al showed that the lower coverage of WES/WGS did not result in a significantly reduced diagnosis rate. 28 Our clinical practice shows that the average depth of WES is approximately100×, 29 which is sufficient for variant identification.…”

“…The process for WES was described previously. 17 Briefly, peripheral blood was harvested from the patients and family members. Genomic DNA was extracted from leukocytes after blood cell isolation using a Blood Genomic DNA Mini Kit (Cwbiotech, Beijing, China).…”

MAGEL2‐related disorders: A study and case series

“…Literature review yielded 23 articles and 1 Letter to the Editor pertaining to these syndromes, which are summarized in the Preferred Reporting Items for Systematic Reviews (PRISMA) diagram (Figure ) . We include a simplified summary of the patients' symptoms (Table ) and further summaries of all CHS and SYS patients to date (Table S1 in Appendix S1).…”

“…Literature review yielded 23 articles and 1 Letter to the Editor pertaining to these syndromes, which are summarized in the Preferred Reporting Items for Systematic Reviews (PRISMA) diagram ( Figure 2). 4,[7][8][9]14,15,[17][18][19][20][21][22][29][30][31][32][33][34][35][36][37][38] We include a simplified summary of the patients' symptoms (Table 1) and further summaries of all CHS and SYS patients to date (Table S1 in Appendix S1). In addition, tissue-specific symptomatic breakdowns for CHS, SYS and PWS are also included (Table S2 in Appendix S1).…”