Clinical comparison of Kabuki syndrome with KMT2D and KDM6A mutations. N. Miyake1, E. Koshimizu1, N. Matsumoto1, N. Niikawa2 1) Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 2) Research Institute of Personalized Health Sciences, Health Science University of Hokkaido, Hokkaido, Japan.

   Kabuki syndrome (KS; MIM 147920) is a congenital anomaly syndrome characterized with the characteristic facial appearance including long palpebral fissures and ectropion of the lateral third of the lower eyelids, developmental delay, intellectual disability, prominent digit pads, skeletal anomalies and visceral abnormalities. Until now, KMT2D (previously known as MLL2) and KDM6A are known to cause this syndrome. In our cohort, 81 individuals clinically diagnosed as KS were incorporated. We screened them in two genes and identified a pathogenic mutation in KMT2D or KDM6A in 50 (61.7%) and five (6.2%) patients, respectively. To see the clinical difference among the mutation types, we compared 58 clinical features between two groups classified by these three conditions; (1) Mutation positive and negative groups, (2) KMT2D mutated and KDM6A mutated groups, (3) KMT2D truncating-type and non-truncating type mutation groups. Interestingly, mutation positive groups frequently showed cleft lip/palate. In addition, blue sclera, lower lip pits, lib abnormality, hip joint dislocation, kidney dysfunction, liver abnormality, spleen abnormality, premature thelarche were observed only in mutation positive group. When we compared the patients with KMT2D mutation and KDM6A mutation, high arched eyebrow, short fifth fingers and hypotonia in infancy were frequently observed in KMT2D mutated group. On the other hand, short stature was observed in all patients with KDM6A while about half of the patients with KMT2D mutation. As the KDM6A mutated male mice (Xutx-/Yyty+) were reported to show small body size (Shpargel et al., 2012), short stature could be one of the core feature of KMT2D mutated KS. When we compared the KMT2D truncating-type and non-truncating type mutation groups, prominent ears and hypotonia were statistically frequent in truncating-type group. However, the facial expression in truncating type seemed more typical than other non-truncating group. This might indicate that our current comparison is rather quantitative, not qualitative, so the degree of the each feature was not reflected.