Recent exome and transcriptome sequencing efforts indicate that epigenetic modifiers such as histone-lysine N-methyltransferase 2D (KMT2D) play an important role in lymphomagenesis. Somatic mutations impairing KMT2D activity are present in approximately 70% of human non-Hodgkin lymphomas. De novo germline heterozygous inactivating KMT2D mutations are also responsible for the majority of cases of Kabuki syndrome (KS), a rare multi-systemic disorder characterised by distinctive facial features, post-natal growth, skeletal and intellectual developmental delays, and haematological and immunological defects. KS patients show increased susceptibility to infections, reductions in serum immunoglobulin G levels, but also suffer from childhood-onset autoimmunity. The causes of the immunological phenotype of KS remain largely unknown. B cell-conditional deletion of KMT2D early during B cell development has been shown to affect follicular B cell development and enhance germinal centre (GC) formation. Here, we characterise mice with an ENU-mutagenesis-induced missense mutation on the Kabuki Interaction Surface (KIS) of KMT2D. The homozygous mutation is embryonically lethal on a C57BL/6 background but on a C57BL/6 x BALB/c F2 hybrid background, a fraction of homozygotes are viable and reached adulthood. Whole-genome bisulfite sequencing (WGBS) and chromatin immunoprecipitation (ChIP) sequencing of purified splenic B cells showed that KMT2D loss-of-function results in reduced histone 3 lysine 4 (H3K4) mono- and tri-methylation levels, associated with a global loss of DNA methylation and an expansion of promoter un-methylated regions (UMRs). These changes left B and T cell development and peripheral maturation largely unaffected, but resulted in a B cell-intrinsic expansion of the germinal centre response to immunisation. During early bone marrow development, they also expanded the Lineage^- Sca1⁺ c-Kit^high (LSK) progenitor population. These results show that a germline KMT2D-inactiving mutation, two amino acids away from residues mutated in Kabuki syndrome and a somatic mutation in lymphoma, deregulates the germinal centre reaction and may initiate clonal haematopoiesis.