Expanding the genotypes and phenotypes for 19 rare diseases by exome sequencing performed in pediatric intensive care unit

Abstract

Phenotypes of some rare genetic diseases are atypical and it is a challenge for pediatric intensive care units (PICUs) to diagnose and manage such patients in an emergency. In this study, we investigated 58 PICU patients (39 deceased and 19 surviving) in critical ill status or died shortly without a clear etiology. Whole exome sequencing was performed of 103 DNA samples from their families. Disease-causing single-nucleotide variants (SNVs) and copy number variants (CNVs) were identified to do genotype-phenotypes analysis. In total, 27 (46.6%) patients received a genetic diagnosis. We identified 34 pathogenic or likely pathogenic SNVs from 26 genes, which are related to at least 19 rare diseases. Each rare disease involved an isolated patient except two patients caused by the same gene ACAT1. The genotypic spectrum was expanded by 23 novel SNVs from gene MARS1, PRRT2, TBCK, TOR1A, ECE1, ARX, ZEB2, ACAT1, CPS1, VWF, NBAS, COG4, and INVS. We also identified two novel pathogenic CNVs. Phenotypes associated with respiratory, multiple congenital anomalies, neuromuscular, or metabolic disorders were the most common. Twenty patients (74.1%) accompanied severe infection, 19 patients (70.1%) died. In summary, our findings expanded the genotypes and phenotypes of 19 rare diseases from PICU with complex characteristics. K E Y W O R D Sexome sequencing (ES), genetic disease, pediatric intensive care unit (PICU), phenotype, variant | INTRODUCTIONCritical diseases caused by undiagnosed genetic conditions are challenging for pediatric intensive care units (PICUs). For most PICU patients, the symptoms are usually complicated by emergency admission, and some of them are in critical condition with unexplained liver failure, renal trauma, or consciousness disturbances. It is now known that genetic disorders (congenital defects) are the major reasons for hospitalization and mortality in infants in neonatal intensive care units (NICUs) or PICUs (Weiner et al., 2011). In the past 6 years, by using exome sequencing (ES) or whole-genome sequencing (WGS) in 1185 children in PICUs/NICUs, the diagnostic rate of genetic disorders reached about 19%-69.7% globallyThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Clinical impact of exome sequencing in the setting of a general pediatric ward for hospitalized children with suspected genetic disorders

“…While the diagnostic yield and medical implications of clinical ES in neonatal and pediatric intensive care units have been widely studied ( Meng et al, 2017 ; Freed et al, 2020 ; Lunke et al, 2020 ; Liu et al, 2021 ; Ouyang et al, 2021 ; Scholz et al, 2021 ), its clinical utilization in the in-patient setting of a general pediatric ward has scarcely been reported. We identified a monogenic etiology in 38% of children suspected to have undiagnosed genetic conditions.…”