A patient derived missense mouse model of Kabuki syndrome 1

Kabuki syndrome (KS) 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 KS exhibits key phenotypic features, and therapeutic trials in this mouse model suggest postnatal malleability of neurological symptoms. However, 15-30% of individuals with KS, carry missense variants. To investigate whether missense variants lead to similar phenotypic presentation in mice, we used CRISPR-Cas9 to introduce the KS patient variant R5230H into C57BL/6NTac. Computational and in vitro testing suggests that the R5230H variant does not impair protein stability or loss of enzyme function of KMT2D. Despite a distinct mechanistic basis, our new mouse model ( Kmt2d ^+/R5230H ) recapitulates 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 show perinatal lethality and a high frequency of unilateral kidney agenesis, a novel phenotype in KS 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 KS.