Phenotypic Description of A Patient with ODLURO Syndrome and Functional Characterization of the Pathogenetic Role of A Synonymous Variant c.186G>A in KMT2E Gene.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the KMT2E gene. The clinical phonotype of the affected individuals is typically characterized by global developmental delay, autism, epilepsy, hypotonia, macrocephaly, and very mild dysmorphic facial features. In this report, we describe the case of a 6-year-old boy with ODLURO syndrome who is a carrier of the synonymous mutation c.186G>A (p.Ala62=) in the KMT2E gene, predicted to alter splicing by in silico tools. Given the lack of functional studies on the c.186G>A variant, in order to assess its potential functional effect, we sequenced the patient's cDNA demonstrating its impact on the mechanism of splicing. To the best of our knowledge, our patient is the second to date reported carrying this synonymous mutation, but he is the first whose functional investigation has confirmed the deleterious consequence of the variant, resulting in exon 4 skipping. Additionally, we suggest a potential etiological mechanism that could be responsible for the aberrant splicing mechanism in KMT2E.

Genome sequencing identifies KMT2E-disrupting cryptic structural variant in a female with O'Donnell-Luria-Rodan syndrome.

We describe a patient from the 100,000 Genomes Project with a complex de novo structural variant within KMT2E leading to O'Donnell-Luria-Rodan syndrome. This case expands the mutational spectrum for this syndrome and highlights the importance of revisiting unsolved cases using better SV prioritisation tools and updated gene panels.

KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice.

Autism spectrum disorders (ASD) are highly heterogeneous neurodevelopmental disorders characterized by impaired social interaction skills. Whole exome sequencing has identified loss-of-function mutations in lysine methyltransferase 2E (KMT2E, also named MLL5) in ASD patients and it is listed as an ASD high-risk gene in humans. However, experimental evidence of KMT2E in association with ASD-like manifestations or neuronal function is still missing. Relying on KMT2E+/- mice, through animal behavior analyses, positron emission tomography (PET) imaging, and neuronal morphological analyses, we explored the role of KMT2E haploinsufficiency in ASD-like symptoms. Behavioral results revealed that KMT2E haploinsufficiency was sufficient to produce social deficit, accompanied by anxiety in mice. Whole-brain 18F-FDG-PET analysis identified that relative amygdala glycometabolism was selectively decreased in KMT2E+/- mice compared to wild-type mice. The numbers and soma sizes of amygdala neurons in KMT2E+/- mice were prominently increased. Additionally, KMT2E mRNA levels in human amygdala were significantly decreased after birth during brain development. Our findings support a causative role of KMT2E in ASD development and suggest that amygdala neuronal development abnormality is likely a major underlying mechanism.

Aberrant H3K4me3 modification of epiblast genes of extraembryonic tissue causes placental defects and implantation failure in mouse IVF embryos.

Assisted reproductive technology has been widely applied in the treatment of human infertility. However, accumulating evidence indicates that in vitro fertilization (IVF) is associated with a low pregnancy rate, placental defects, and metabolic diseases in offspring. Here, we find that IVF manipulation notably disrupts extraembryonic tissue-specific gene expression, and 334 epiblast (Epi)-specific genes and 24 Epi-specific transcription factors are abnormally expressed in extraembryonic ectoderm (ExE) of IVF embryos at embryonic day 7.5. Combined histone modification analysis reveals that aberrant H3K4me3 modification at the Epi active promoters results in increased expression of these genes in ExE. Importantly, we demonstrate that knockdown of the H3K4me3-recruited regulator Kmt2e, which is highly expressed in IVF embryos, greatly improves the development of IVF embryos and reduces abnormal gene expression in ExE. Our study therefore identifies that abnormal H3K4me3 modification in extraembryonic tissue is a major cause of implantation failure and abnormal placental development of IVF embryos.

Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient.

Background: O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant systemic disorder characterized by global developmental delay caused by mutations in the KMT2E gene. The aim of this study was to investigate the role of KMT2E mutations as a cause of ODLURO syndrome in a Chinese boy. Methods: We reported the clinical course of a Chinese boy who was diagnosed with ODLURO syndrome by the whole exome sequencing. We extracted genomic DNA of the proband and parents, gene variations were screened using whole-exome sequencing, followed by validation using direct Sanger sequencing. The effect of mRNA splicing variants were analyzed through a minigene splice assay and in vitro reverse transcription PCR (RT-PCR). Results: The proband presented with recurrent seizures and developmental delay. Using genetic analysis, we identified that the proband carried a de novo heterozygous splicing variant (c.1248+1G>T) in the KMT2E gene. In vivo transcript analysis showed that the proband did not carry any KMT2E mRNA transcript, while a specific exon11-exon13 (440 bp) transcript was detected in the unaffected parents. The in vitro minigene splice assay conducted in HEK293 cells confirmed that the c.1248+1G>T variant resulted in exon 12 skipping, which in turn caused an alteration in KMT2E mRNA splicing. The mutant transcript created a premature stop codon at the 378 amino acid position that could have been caused nonsense-mediated mRNA decay (NMD). Conclusion: We verified the pathogenic effect of the KMT2E c.1248+1G>T splicing variant, which disturbed normal mRNA splicing and caused mRNA decay. Our findings suggest that splice variants play an important role in the molecular basis of ODLURO, and that careful molecular profiling of these patients could play an essential role in tailoring of personalized treatment options soon.

Novel truncating variant in KMT2E associated with cerebellar hypoplasia and velopharyngeal dysfunction.

KMT2E-related neurodevelopmental disorder is a recently described intellectual disability syndrome often with speech difficulties. Here, we describe an individual with a heterozygous frameshift variant in KMT2E (NM_182931.2:c.2334_2337delTTAC, p.[Tyr779AlafsTer41]), intellectual disability, cerebellar hypoplasia, and velopharyngeal dysfunction. This case suggests potential mechanisms of speech disturbance in the disorder, requiring further investigation.

239-kb Microdeletion Spanning KMT2E in a Child with Developmental Delay: Further Delineation of the Phenotype.

Pathogenic KMT2E variants underly O'Donnell-Luria-Rodan syndrome, a recently described neurodevelopmental disorder characterized by global developmental delay, variable degrees of intellectual disability, and subtle facial dysmorphism. Less common findings include autism, seizures, gastrointestinal (GI) problems, and abnormal head circumference. Occurrence of mostly truncating variants as well as the similar phenotype observed in individuals with deletions spanning KMT2E suggest haploinsufficiency of this gene as a common mechanism for the disorder, while a gain-of-function or dominant-negative effect cannot be ruled out for some missense variants. Deletions reported in the literature encompass several additional known or presumed haploinsufficient genes, thus leading to more complex phenotypes. Here, we describe a male with antenatal onset hydronephrosis, hypotonia, global developmental delay, prominent GI symptoms as well as facial dysmorphism. Chromosomal microarray revealed a 239-kb de novo microdeletion spanning KMT2E and LHFPL3. Clinical presentation of our proband, harboring one of the smallest deletions of the region confirms the core features of this disorder, suggests GI symptoms as a prominent finding in affected individuals while expanding the phenotypic spectrum to abnormalities of the urinary tract.

Case Report: De novo Variants of KMT2E Cause O'Donnell-Luria-Rodan Syndrome: Additional Cases and Literature Review.

Introduction: O'Donnell-Luria-Rodan syndrome was recently identified as an autosomal dominant systemic disorder caused by variants in KMT2E. It is characterized by global developmental delay, some patients also exhibit autism, seizures, hypotonia, and/or feeding difficulties. Methods: Whole-exome sequencing of family trios were performed for two independent children with unexplained recurrent seizures and developmental delay. Both cases were identified as having de novo variants in KMT2E. We also collected and summarized the clinical data and diagnosed them with O'Donnell-Luria-Rodan syndrome. Structural-prediction programs were used to draw the variants' locations. Results: A 186 G>A synonymous variant [NM_182931.3:exon4: c.186G>A (p.Ala62=)] was found in one family, resulting in alternative splicing acid. A 5417 C>T transition variant [NM_182931.3:exon27: c.5417C>T (p.Pro1806Leu)] was found in another family, resulting in 1806 Pro-to-Leu substitution. Both variants were classified as likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines and verified by Sanger sequencing. Conclusion: To date, three studies of O'Donnell-Luria-Rodan syndrome have been reported with heterogeneous clinical manifestations. As a newly recognized inherited systemic disorder, O'Donnell-Luria-Rodan syndrome needs to be paid more attention, especially in gene testing.

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one 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. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was 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 might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study.

The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2-year overall survival (OS) (P = 0·005) and 2-year disease-free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71-30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08-0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49-43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05-0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99-1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.