This study presents a systematic characterization of a NDD associated with missense variants in PRKAR1B. In addition to the observed enrichment of de novo missense variants of this gene in two large, independent cohorts of individuals with NDDs,15,16 the recurrent finding of the de novo variant c.1003C>T in phenotypically similar individuals strongly suggests that this variant is causative for the observed phenotype (see Supplemental Note 1), and indicates a potential mutational hotspot in the Arg335 residue. The gene discussed is PRKAR1B; the disease is Neurodevelopmental delay.