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

Abstract

Background In recent years, many new candidate genes are being identified as putative pathogenic factors in children with developmental delay and autism. Recently, heterozygous mutations in the KMT2E gene have been identified as a cause of a unique neurodevelopmental disorder with variable combination of global developmental delay or isolated speech delay, intellectual disability, autistic features, and seizures. Methods Here, we present two new cases of KMT2E mutation-associated neurodevelopmental disorder in a 4-year-old girl and 5-year-old boy. We also performed a pooled review of the previously published cases of KMT2E-related neurodevelopmental disorder. Articles were identified through search engines using appropriate search terms. Results Along with the presented 2 cases, 40 cases were analyzed. Out of them, 30, 6, and 4 children had protein-truncating mutations, missense mutations, and copy number variants, respectively. The common features were global developmental delay (97%) followed by macrocephaly (35%), seizures (30%), and autism (25%). Children with missense variants had severe phenotype, with microcephaly, profound developmental delay, and increased frequency of seizures. Neuroimaging revealed nonspecific changes, including cerebral white matter signal abnormalities. Conclusion KMT2E-related neurodevelopmental disorder remains one of the clinical differentials in children with global developmental delay and/or autistic features/seizure. With the reporting of more cases in the future, the already heterogeneous clinical spectrum of this disease is likely to be widened.

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

“…The proband demonstrates many overlapping features with previously described patients, including intellectual disability, large head size, hypotonia, and gastrointestinal symptoms 1,3,4 . His frameshift variant is located outside of the two known functional domains but is expected to lead to loss of function because of nonsense‐mediated decay.…”

“…Often VPD occurs in the setting of a structural oropharyngeal anomaly like a cleft palate, however, this was not seen in our patient nor previously reported. 1 , 3 , 4 We believe this may be an important finding to help inform speech and language therapy interventions for individuals with this disorder, but this aspect of the phenotype requires further investigation across a larger cohort. A number of genetic and neurologic causes of non‐cleft VPD exist, 6 and so we recommend that KMT2E ‐related neurodevelopmental disorder be considered in the list of possible etiologies, especially when there is co‐existing intellectual disability.…”

“…The proband demonstrates many overlapping features with previously described patients, including intellectual disability, large head size, hypotonia, and gastrointestinal symptoms. 1 , 3 , 4 His frameshift variant is located outside of the two known functional domains but is expected to lead to loss of function because of nonsense‐mediated decay. Our case is consistent with previous findings that truncating variants are more likely to be associated with larger head size as well as reduced likelihood of seizures compared to individuals with missense variants.…”

“…Here, we analyzed the proband's speech difficulties, which is a common symptom of KMT2E ‐related neurodevelopmental disorder reported in at least 44% of affected individuals, 4 and found VPD and apraxia of speech. Often VPD occurs in the setting of a structural oropharyngeal anomaly like a cleft palate, however, this was not seen in our patient nor previously reported 1,3,4 .…”

239-kb Microdeletion Spanning <b><i>KMT2E</i></b> in a Child with Developmental Delay: Further Delineation of the Phenotype

“…Phenotypic similarities between 30 individuals with KMT2E truncating variants and 4 with microdeletions spanning this gene suggested haploinsufficiency as the mechanism underlying pathogenicity of these variants. Observation of more severe phenotypes in 6 additional subjects harboring missense variants as well as the occurrence of microcephaly in 2, led to the speculation that a gain-of-function or dominant-negative effect may apply for this category of variants [O'Donnell-Luria et al, 2019;Sharawat et al, 2021]. Most microdeletions reported in literature, with the exception of a 52-kb intragenic deletion, encompass several other genes possibly contributing to the neurodevelopmental outcome and/or occurrence of additional features in these patients [O'Donnell-Luria et al, 2019;Conforti et al, 2021].…”