Exome Sequencing in Hospitalized Chronically ill Children- a Case Series

Introduction: Data regarding utility of exome sequencing in non-critical children hospitalized with unexplained persistent symptoms is limited.

Methods: Singleton whole exome sequencing (WES) for in-patients detected by primary physicians and a medical geneticist at a tertiary pediatric hospital. Criteria included prolonged hospitalization due to symptoms suggestive of a genetic syndrome; bone marrow failure or severe growth delay prior to treatment decisions.

Results: Twelve children (January-December 2021, age range 4 days-13 years) were selected for in-house singleton WES. Admitting departments included neonatal and pediatric intensive care and general pediatrics. Phenotypes (10/12) included white matter and gastrointestinal abnormalities (1), febrile encephalopathy and prior retinal detachment (1), osteopetrosis (2), refractory epilepsy (1), multiple fractures (1), syndromic failure to thrive (2) and suspected Diamond Blackfan Anemia (2).

WES was diagnostic in 8/12 (5 pathogenic, 3 likely pathogenic) and normal in 2/12. Rapid results (4-18 days, mean 9 days) were obtained in 8/12. Diagnoses included SOX10-Waardenburg syndrome, Stickler syndrome (COL2A1), Osteopetrosis, autosomal recessive 7 & 8 (TNFRSF11A & SNX10), Developmental and Epileptic Encephalopathy 12 (PLCB1), TTC37-Trichohepatoenteric syndrome, BRAF-Cardiofasciocutaneous syndrome and ADA2 deficiency. Two additional children were heterozygote for variants of unknown significance. A child surviving ventricular fibrillation, with SCN5A and KCNH2 variants; and a child with recurrent apnea with a RET variant. WES affected in-patient management in 9/12 children.

Conclusions: WES is highly diagnostic (66%) and may affect management in hospitalized children manifesting various unexplained persistent symptoms. Further studies will characterize clinical and economic benefits of advanced rapid genomic evaluation in this patient group.