Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay

Abstract

The role of lysine methyltransferases (KMTs) and demethylases (KDMs) in the regulation of chromatin modification is well-established. Recently, deleterious heterozygous variants in <i>KMT5B</i> were implicated in individuals with intellectual disability (ID) and/or autism spectrum disorder. We describe three unrelated patients with global developmental delay (GDD) or ID, macrocephaly and additional features. Using whole exome sequencing, each of the probands was found to harbor a distinct <i>de novo</i> heterozygous disease-causing variant in <i>KMT5B</i>: c.541C > G (p.His181Asp); c.833A > T (p.Asn278Ile); or c.391_394delAAAG (p.Lys131GlufsTer6). We discuss herein their clinical presentations, and compare them to those of previously reported patients. Furthermore, using a three-dimensional computational model of the <i>KMT5B</i> protein, we demonstrate the predicted structural effects of the two missense variants. Our findings support the role of <i>de novo</i> missense and nonsense variants in <i>KMT5B</i>-associated GDD/ID, and suggest that this gene should be considered in the differential diagnosis of neurodevelopmental disorders accompanied by macrocephaly and/or overgrowth.