PRODH and biotinidase deficiency: When aggregating variant frequencies by gene, we find the highest frequency of pathogenic variants in PRODH (7.4%), associated with hyperprolinemia (OMIM 239500), followed by BTD (3.5%) and HFE (3.4%), which are linked to biotinidase deficiency (OMIM 253260) and type I hemochromatosis, respectively (Fig. 1e).