KMT5B-related neurodevelopmental disorder

Inspired by a patient

Chen G, Han L, Tan S, Jia X, Wu H, Quan Y, Zhang Q, Yu B, Hu Z, Xia K, Guo H. Loss-of-function of KMT5B leads to neurodevelopmental disorder and impairs neuronal development and neurogenesis. J Genet Genomics. 2022 Sep;49(9):881-890. doi: 10.1016/j.jgg.2022.03.004. Epub 2022 Mar 21. PMID: 35331928.

Abstract

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that cause severe social, communication, and behavioral problems. Recent studies show that the variants of a histone methyltransferase gene KMT5B cause neurodevelopmental disorders (NDDs), including ASD, and the knockout of Kmt5b in mice is embryonic lethal. However, the detailed genotype-phenotype correlations and functional effects of KMT5B in neurodevelopment are unclear. By targeted sequencing of a large Chinese ASD cohort, analyzing published genome-wide sequencing data, and mining literature, we curated 39 KMT5B variants identified from NDD individuals. A genotype-phenotype correlation analysis for 10 individuals with KMT5B pathogenic variants reveals common symptoms, including ASD, intellectual disability, languages problem, and macrocephaly. In vitro knockdown of the expression of Kmt5b in cultured mouse primary cortical neurons leads to a decrease in neuronal dendritic complexity and an increase in dendritic spine density, which can be rescued by expression of human KMT5B but not that of pathogenic de novo missense mutants. In vivo knockdown of the Kmt5b expression in the mouse embryonic cerebral cortex by in utero electroporation results in decreased proliferation and accelerated migration of neural progenitor cells. Our findings reveal essential roles of histone methyltransferase KMT5B in neuronal development, prenatal neurogenesis, and neuronal migration.

Tong J, Chen X, Wang X, Men S, Liu Y, Sun X, Yan D, Wang L. Novel KMT5B variant associated with neurodevelopmental disorder in a Chinese family: A case report. Heliyon. 2024 Mar 23;10(7):e28686. doi: 10.1016/j.heliyon.2024.e28686. PMID: 38571636; PMCID: PMC10988039.

Abstract

Background: We report here the clinical and genetic features of KMT5B-related neurodevelopmental disorder caused by a novel heterozygous frameshift variant in KMT5B in a Chinese family.

Case presentation: A 7-year-old Chinese boy with mild-to-moderate intellectual disability, significant language impairment, motor disability, and coordination difficulties presented to our hospital because he "could not speak and did not look at others." He was diagnosed with autism spectrum disorder previously owing to developmental delays in cognition, language expression, and understanding. The child also had variable nonspecific features including macrocephaly, wide button-hole space and nasal bridge, low ear, social behavior disorder, and foot deformities. Exome sequencing (ES) revealed that both the proband and his younger brother had inherited a novel heterozygous frameshift variant c.438_439ins[ASD; KT192064.1:1_310] of the KMT5B gene from their father. Bioinformatics analysis showed that the novel mutation affected the structure of the KMT5B pre-SET domain, mainly in the α-helix region. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this type of variant was eventually determined to be likely pathogenic (PVS1+PM2_P).

Conclusions: Our investigation expands the mutation spectrum of KMT5B to help us to better understand KMT5B-related neurodevelopmental disorder.

Odak L, Vulin K, Meašić AM, Šamadan L, Tripalo Batoš A. Neurodevelopmental disorder caused by an inherited novel KMT5B variant: case report. Croat Med J. 2023 Oct 31;64(5):334-338. doi: 10.3325/cmj.2023.64.334. PMID: 37927187; PMCID: PMC10668041.

Abstract

Neurodevelopmental disorders are a large group of disorders that affect ~ 3% of children and represent a serious health problem worldwide. Their etiology is multifactorial and includes genetic, epigenetic, and environmental causes. Mounting evidence shows the importance of genetic causes, especially genes involved in the central nervous system development. As recently discovered, the KMT5B gene is related to abnormal activities of the enzymes that regulate histone activity and gene expression during brain development. Pathogenic KMT5B gene variants lead to autosomal dominant, intellectual developmental disorder 51 (OMIM # 617788). Also, reports on patients with additional features suggest that the KMT5B gene alterations lead to multisystem involvement. Here, we report on a male patient with a severe neurodevelopmental disorder caused by a novel KMT5B gene variant inherited from his mother. The patient had severe intellectual disability, absent speech, marked autistic behavior, attention deficit hyperactivity disorder, and different clinical features, including thoracic scoliosis, dysmorphic facial features, and tall stature. In contrast, his mother, with the same KMT5B variant, had mild intellectual disability and some autistic traits (stereotype hand movement). We elucidated pathogenetic mechanisms that could influence phenotype characteristics. Our findings emphasize the importance of a comprehensive clinical and molecular approach to these patients in order to provide optimal health care.