Fig. 1: Affected individuals have missense variants in parts of exons 38 or 39 of KMT2D.

We studied multiple affected individuals from seven families with missense KMT2D variants restricted to a region that encodes for 54 amino acids flanked by Val3527 and Lys3583 (ENST00000301067.7; NM_003482.3). (a) Schematic representation of KMT2D exons with each alternating exon represented in dark or light red shade (introns are not depicted). (b) Frequency of KMT2D missense variants (from gnomAD) in the general population is shown in yellow. Deeper troughs represent higher frequency at that particular ___location. (c) Green lollipop graph denoting the missense KMT2D variants in individuals with Kabuki syndrome from the published literature.⁶ The y-axis in this graph represents the frequency of the variant in the published literature. The x-axis is a schematic for the protein denoting the ___location of important domains and regions of KMT2D. Note that variants identified in this study are located in parts of exons 38 and 39 with high missense constraint but without any variants in individuals with Kabuki syndrome. (d) The region of interest of the KMT2D gene and protein in more detail. The red horizontal bar shows parts of exons 38 (amino acid 3503–3580) and 39 (amino acid 3581–4510). The blue vertical bars denote the coiled-coil regions. Red lines indicate the ___location of the variants identified in this study. Pedigree of each family is shown under the corresponding variant. Standard symbols are used to denote affected (filled symbols) and unaffected (unfilled) individuals. All individuals who were tested but not found to carry familial KMT2D variants are denoted by “N”. Father in family 4 (F4; I:1) was found to be likely mosaic and is denoted by gray square. In this family, genetic testing was not possible for the first born child (F4; II:1) but is shown as affected based on the clinical history.