Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy

Abstract

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort

“…The comparison showed that for ‘confirmed’ genes classified by the DECIPHER, only three genes, KMT2E , TBL1XR and TRIP12 , were not covered by the CES. These three genes were all rarely reported in previous studies, which should have little influence on the diagnosis of DD patients with behavioural troubles in this study 34–37. Additionally, we used ‘behavioural abnormalities’ as the search term and extracted a list containing 99 genes from the OMIM database.…”

Clinical Characteristics and Genotype–Phenotype Correlation in Children with KMT2E Gene-Related Neurodevelopmental Disorders: Report of Two New Cases and Review of Published Literature

“…Out of the 38 patients described by O'Donnell-Luria et al, 10 30 patients had protein-truncating mutations, 4 had missense mutations, and 4 had microdeletions in the KMT2E gene. There was a definite male prevalence, with 22 patients among them being male.…”

“…Pathogenic KMT2E mutation was initially described in a child with nonsyndromic autism from China by Dong et al in 2014, 11 and later two similar cases by Wang et al 12 and Iossifov et al 13 Subsequently, in 2019, O'Donnell-Luria et al described a detailed phenotype of 38 patients with KMT2E mutations, including the previous three reported cases. 10 KMT2E gene codes for a histone methyltransferase protein, which is a transcriptional regulator. It plays an important role in various biological processes such as hematopoiesis, cell-cycle progression, spermatogenesis, and maintenance of genomic stability.…”

“…They also demonstrated variantspecific alterations leading to diverse phenotypic features. 10,14 Moreover, they suspected that the missense variants might have some gain of function or dominant-negative effect leading to paradoxically increased severity of clinical features. Some other genes also have distinct neurodevelopmental syndromes depending on whether the underlying mutation is a missense or protein-truncating one.…”

“…9 O'Donnell-Luria-Rodan's syndrome is one such neurodevelopmental syndrome due to pathogenic mutations in the KMT2E gene, first described in detail in 2019. 10 It is characterized by a variable combination of developmental disability, autistic features, isolated speech delay, subtle dysmorphism, and variable functional gastrointestinal complaints. Here, we are reporting two new cases of this rare neurogenetic syndrome and the review of all the previous reported cases in the English literature.…”