GSE184953
Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice
Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM#?617788). Given the novelty of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n=43) patient cohort to date identified that hypotonia and congenital heart defects are novel prominent features. 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 wildtype littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA-sequencing of patient lymphoblasts and Kmt5b-haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified novel pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.? Overall design: Whole brain RNA-seq from E14.5 Kmt5b gene trap mice; 3 brains per genotype (WT, HET, KO) for both males and females. RNA-seq from patient derived lymphoblast cell lines; 7 KMT5B patients and 7 age- and sex-matched controls.