Fig. 1: Workflow in the TRANSLATE NAMSE project and phenotypes in which exome sequencing was performed.

a, Patients with a suspected rare disease were referred to a MDT and deeply phenotyped using HPO terminology. If a genetic etiology was considered likely, exome sequencing was performed. The MDT then evaluated the molecular findings and could order additional analyses for variants of uncertain significance or variants in potentially novel disease candidate genes (created with BioRender.com). b, Exome sequencing was performed predominantly in children. The main indications for exome sequencing in children were neurodevelopmental disorders. In adults, the main indications were neurological/neuromuscular disorders. In both children and adults, the least common disease categories were ‘cardiovascular’, ‘endocrine, metabolic, mitochondrial, nutritional’ (emmn) and ‘hematopoiesis/immune system’ (his). c, Phenotypic similarities between patients, as encoded according to their HPO terms, were visualized with UMAP. As reference, all OMIM diseases were included using their HPO annotations (gray background dots). For each patient, color coding indicates allocation to disease groups, in accordance with the leading clinical feature. An overlap is evident for patients in the neurodevelopmental and neuromuscular groups (aquamarine and blue clusters), which indicates high phenotypic similarity. This precludes the unequivocal assignment of these patients to a diagnostic group. The triangles indicate patients who contributed to the identification of a novel, high-evidence gene–phenotype association.