Fig. 2: Missense KMT2D variants described in this study result in phenotype distinct from type 1 Kabuki and CHARGE syndromes.

(a) Photographs of individuals described here with missense KMT2D variants. Note the wide range of facial features. P2, proband from family 2, is shown at two different ages. Note facial asymmetry, hypertelorism, bilateral epicanthic folds, bulbous nasal tip, downturned corners of the mouth, microtia, and hypoplastic nipples. P3, proband from family 3, has a box-shaped head, bilateral microphthalmia, severely hypoplastic left pinna, and ectopic left external auditory canal. P5 and P7, probands from families 5 and 7 respectively, have prominent forehead, broad nasal root, flat midface, and thin upper lip. P7’s eyebrows are laterally flared. One individual with Kabuki syndrome type 1 (KS1) is shown for comparison. Note arched eyebrows, long palpebral fissures, eversion of the lateral part of the lower eyelids, large cupped ears, short columella, bulbous nasal tip, and pillowed lower lip. In individual with CHARGE syndrome note hypertelorism, bulbous and large nasal tip, and a repaired cleft lip. (b) Computerized tomography (CT) (i and ii) and T2-weighted magnetic resonance imaging (MRI) (iii) of P2 demonstrating absence of the posterior part of the semicircular canals (red arrows) and normal anatomy of the lateral and anterior semicircular canals. Brain MRI of P3 (iv) to show well-formed right and left middle ear cavities, with the right cavity being smaller than the left. Bilaterally the cochlea, semicircular canals, and inner auditory canals appear normal. T1-weighted MRI to demonstrate a small left optic globe with ballooning of the optic disc bilaterally (red arrows) and optic disc colobomata (v). CT imaging of P5 (vi, vii) demonstrating the presence of cysts in the lower jaw (red arrows). (c) Face2Gene analysis with confusion matrix showing that the system is able to predict correctly each group with a mean accuracy of 75.44%. (d) Receiver operating characteristic (ROC) graphs show the probability curve where the area under the curve (AUC) (0–1) represents the measure of separability between two groups. Score distributions show the distribution of those probabilities. The higher the AUC, the better the model is at distinguishing between two groups. (e) Principal component analysis (PCA) shows the four groups analyzed in the DNA methylation array clustering separately (p < 0.001). Importantly, the samples from individuals described in this study cluster together and separate from those with type 1 Kabuki syndrome. MV missense variant.