Exome Sequencing in Complex Pediatric Patients – Expect the Unexpected

Introduction: Whole exome sequencing WES is a powerful tool that facilitates the diagnosis of patients with unclear complex clinical manifestations. Accurate genetic diagnosis is expected to improve patient management and enable reproductive counseling. However, there are only a few studies that investigated these effects. Recently, the Israeli Ministry of Health (MOH) has implemented a national pilot program that funds exome sequencing under certain criteria including mainly for patients with neurodevelopmental disorders. Here, we describe the experience of a single tertiary hospital in Northern Israel participating in this program. We provide information on the diagnostic yield and the effect on case management, including unexpected findings and diagnoses resulting in new treatment options for selected cases.

Materials and methods WES was performed at Rambam Health Care Campus (RHCC) using standard methods on patients suspected to have monogenic disorders. We evaluated the diagnosis rate and its effect on patient management and treatment.

Results: Between 2018 and 2019 WES was performed on 100 patients at RHCC. The main indications for testing were moderate to severe developmental delay and\or epilepsy with or without congenital anomalies. A likely or definite diagnosis was achieved in 38%. Among the patients with a diagnosis: unexpected findings were reported in 21%, and patient management and treatment were significantly altered in 16%.

Conclusions: The introduction of WES into clinical practice in Israel has transformed patient care. Unexpected diagnoses have altered and improved patient management and treatment. Expansion of the eligibility criteria to critically ill pediatric patients and non-neurologic complex phenotypes should be considered.