Five-year outcomes of next-generation sequencing implementation at a Brazilian public health system reference centre for rare diseases.

Clinical or whole-exome sequencing guided by standardised HPO-based phenotyping within a rare disease reference service of the Brazilian public health system.

This study evaluates five years of next-generation sequencing implementation at a rare disease reference service within the Brazilian public health system (SUS), in a cohort of 385 patients tested by clinical or whole-exome sequencing between 2019 and 2024. Analyses guided by standardised HPO-based phenotyping yielded an overall diagnostic rate of 38.7% (149/385). A total of 249 variants were identified across 165 genes, including 75 not previously reported in the literature or in public databases. Actionable secondary findings were detected in 3.2% of cases, involving genes related to cardiac disease, cancer predisposition and anaesthesia risk. The authors emphasise that success depended on a multidisciplinary approach and close clinical-laboratory integration, and that the 75 novel variants illustrate the difficulty of interpreting variants of uncertain significance in an under-represented admixed population.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The figure worth keeping is not the 38.7% yield, comparable to what reference centres selecting their indications usually report, but the 75 novel variants out of 249: in an admixed population the share of variants with no frequency or literature data becomes the leading constraint on interpretation, well ahead of the technology. This is a concrete argument against extrapolating population frequency thresholds calibrated on largely European cohorts to patients of different ancestry. Caveat: a retrospective single-centre series, whose indications and mix of targeted and whole-exome testing make the yield hard to transpose as such.

Analysis by Dr Thibaut Benquey