Publicly funded exome sequencing for outpatients with neurodevelopmental disorders demonstrates a high rate of unexpected findings impacting medical management.

PURPOSE

Exome sequencing (ES) is a powerful tool that facilitates the diagnosis of patients with rare Mendelian syndromes. In 2018 the Israeli Ministry of Health initiated a national pilot program that funds ES for outpatients with global developmental delay (GDD). Here, we describe the 3-year impact of this program on patient care in a single tertiary hospital.

METHODS

From 2018 to 2020, trio ES was performed on 170 participants fulfilling Israeli Ministry of Health criteria: (1) moderate to severe GDD and (2) mild GDD with epilepsy or a major congenital anomaly. We retrospectively analyzed this cohort.

RESULTS

A diagnosis was achieved in 74 individuals (43%). There were 82 clinically significant variants, the majority being novel. Consanguinity was reported in 22% and was not associated with a higher diagnostic rate. The presence of autism spectrum was associated with a lower diagnostic rate of 8/33 (24%). Autosomal dominant inheritance was identified in 14% of participants, and the parental phenotype ranged between fully affected and asymptomatic. Among the diagnosed participants, 16% had an unexpected diagnosis that did not fit the typical clinical presentation. In 9%, the diagnosis changed short-term active clinical management, in 19%, the surveillance recommendations, and in 23%, the family-focused outcomes.

CONCLUSION

The introduction of a national program that funds ES for GDD has transformed patient care, leading to a significant effect on medical management and treatment. The high rate of an unexpected inheritance mode and variable phenotypes emphasizes the diagnostic complexity of neurodevelopmental disorders and the strength of a non-targeted approach.