Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Abstract

Pathogenic variants in <i>KMT5B</i>, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM<b>#</b> 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (<i>n</i> = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and <i>Kmt5b</i> haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in <i>KMT5B</i>-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.