A patient-derived missense mouse model of Kabuki syndrome 1

Kabuki syndrome type 1 (KS1) is a rare cause of intellectual disability resulting from heterozygous pathogenic variants in the gene encoding the histone methyltransferase KMT2D. A previously established loss-of-function mouse model of KS1 exhibits key phenotypic features, and therapeutic trials in this mouse model suggest postnatal malleability of neurological symptoms. However, 15-30% of individuals with KS1 carry missense variants. To investigate whether missense variants lead to similar phenotypic presentation in mice, we used CRISPR-Cas9 to introduce the KS1 patient variant R5179H, corresponding to R5230H in mice, into C57BL/6NTac animals. Computational and in vitro testing suggested that the R5230H variant does not impair protein stability or enzyme function of KMT2D. Despite a distinct mechanistic basis, our new mouse model (Kmt2d+/R5230H) recapitulated most phenotypes of our prior loss-of-function model, including growth deficiency, craniofacial anomalies and IgA deficiency, but not altered neurological function. Kmt2d+/R5230H mice showed perinatal lethality and a high frequency of unilateral kidney agenesis, a novel phenotype in KS1 mouse models. Kmt2d+/R5230H mice provide a unique opportunity to understand the impact of missense variants on KMT2D function and uncover developmental and perinatal abnormalities in KS1.