Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Abstract

Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery 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 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 Kmt5b 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 KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Neurodevelopmental disorder caused by an inherited novel KMT5B variant: case report

“…Human and mouse KMT5B gene expression models showed altered TGF beta signaling in mutant variants and abnormalities in extracellular matrix metabolism, which could be related to neocortex development (6). Our patient had periventricular nodular heterotopia not previously described in KMT5B patients, a possible new feature of KMT5B-related disorder (Figure 1).…”

“…Our patient had common KMT5B-related features: intellectual disability, epilepsy, autism, and dysmorphic features (Figure 2). However, congenital heart disease and macrocephaly, observed in 30 -60% of the patients, were absent (6). Our patient had hypotonia in infancy, motor delay, and poor skeletal muscle mass, all of which were absent in his mother.…”

“…Pathogenic variants in KMT5B lead to autosomal dominant intellectual developmental disorder 51 (OMIM # 617788), a new entity described a few years ago (5). The largest study focusing on this entity included 43 patients presenting with global developmental delay, epilepsy, intellectual disability, macrocephaly, autism spectrum disorder, and congenital anomalies (6). Most of these variants are de novo variants (90%), missense, nonsense, frame-shift, splice-site, and rarely partial gene deletions or single amino-acid deletions.…”

Novel KMT5B variant associated with neurodevelopmental disorder in a Chinese family: A case report

“…Most of the pathogenic variations were because of missense variation, nonsense variation, and splice site variation in the KMT5B gene. According to a previous study, haploinsufficiency may be the most likely mechanism of pathogenicity for KMT5B , similar to other KMTs and KDMs [ 18 ]. Using a combination of human variation databases and existing animal models, KMT5B haploid deficiency is closely associated with dominant developmental disorders and leads to overgrowth syndrome with intellectual disability [ 9 , 18 ].…”

“…According to a previous study, haploinsufficiency may be the most likely mechanism of pathogenicity for KMT5B , similar to other KMTs and KDMs [ 18 ]. Using a combination of human variation databases and existing animal models, KMT5B haploid deficiency is closely associated with dominant developmental disorders and leads to overgrowth syndrome with intellectual disability [ 9 , 18 ]. There are three domains in the encoded KMT5B protein: an N domain (pre-SET domain), a SET catalytic domain, and a C domain containing a zinc binding site (post-SET domain).…”