Aplicações clínicas de sequenciamento de nova geração: da genômica em neuropsiquiatria ao desenvolvimento de um protocolo de metagenômica clínica no Ceará

Abstract

The etiological elucidation of complex neuropsychiatric and infectious disorders represents a critical challenge within Brazil’s Unified Health System, often resulting in prolonged diagnostic journeys. This study aimed to evaluate the clinical applications of next-generation sequencing through genomic and metagenomic approaches conducted at Fiocruz Ceará in complex clinical cases referred from tertiary care in Fortaleza. The genomic approach (whole-exome sequencing) was applied to a cohort of 17 patients, subdivided into a psychiatric cohort (n=9) and a neurological cohort (n=8), while metagenomics was employed to investigate a case of neuroinfection without confirmatory diagnosis using conventional methods. Concurrently, an operational research component, including a participatory assessment with the technical team, mapped systemic barriers in the diagnostic pathway. Genomic investigation revealed clinically relevant findings across the cohort and enabled the establishment of a highly probable molecular diagnosis in 37.5% of the neurological subcohort with specialized clinical curation, notably highlighting the identification of a rare NIT1 variant in a 50-year-old patient with a history of leukodystrophy. Metagenomic analysis was decisive for the confirmatory diagnosis of progressive multifocal leukoencephalopathy caused by John Cunningham virus in an HIV-positive patient. Operational research quantified barriers, identifying the lack of clinical information as the main communication gap (reported by 100% of the team). These results, integrating clinical and operational evidence, supported the development of a collaborative technical-operational protocol, structured under the Clinical–Wet–Dry model, to integrate next-generation sequencing into Ceará’s health network in articulation with Fiocruz Ceará. In conclusion, the application of next-generation sequencing, when guided by a translational approach, not only substantially increases diagnostic yield but also generates a feasible, evidence-based implementation model for incorporating precision technologies into the healthcare system, with the potential to optimize clinical management and strengthen health surveillance.