Reduced dosage of Kmt2d modifies the transcriptional landscape of Tbx1 haploinsufficiency towards phenotypes of 22q11.2DS

The variability in syndromic presentation between patients may be partially explained by variants in chromatin regulatory genes that act to further modify TBX1 function. To investigate this relationship, we selected KMT2D as a candidate gene due to its role in the etiology of Kabuki syndrome which shares overlapping features with 22q11.2DS.

We demonstrate that conditional inactivation of Kmt2d in the Tbx1 lineage in Tbx1 heterozygous mice leads to fully penetrant perinatal lethality and increased incidence of craniofacial dysmorphism, thymus and parathyroid gland hypoplasia, and aortic arch anomalies. At early stages, mutant embryos were found to have defects of the caudal pharyngeal apparatus, including abnormal patterning of the 3rd pouch endoderm, hypoplastic 4th arches, and defective 4th arch arteries.