Clinical characteristics.

KMT2E-related neurodevelopmental disorder (KMT2E-NDD) is a condition characterized by global developmental delay, variable intellectual disability (typically in the mild-to-moderate range), and hypotonia. The majority of affected individuals are verbal but experience speech delays with or without articulation problems. All reported individuals who are older than infants have been able to obtain independent ambulation. About one third of affected individuals develop seizures, with no consistent seizure semiology or epilepsy syndrome. However, females may be more likely to develop seizures compared to males. Similarly, about one third of affected individuals have an autism spectrum disorder diagnosis, of which most to date are male. Growth parameters are typically in the normal range for length/height and weight, although about half of affected individuals have macrocephaly or relative macrocephaly. Constipation is the most frequent gastrointestinal issue, although gastroesophageal reflux, vomiting, and/or reduced bowel motility have been reported in almost half of affected individuals. About half of affected individuals experience some type of sleep disturbance, including frequent awakening and difficulties falling asleep.

Diagnosis/testing.

The diagnosis of KMT2E-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2E identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment for developmental delay / intellectual disability, neuropsychiatric issues, seizures, constipation, gastroesophageal reflux/dysmotility, vomiting, and sleep disturbance.

Surveillance: At each visit, measure growth parameters (including head circumference); assess for new neurologic manifestations and monitor those with seizures as clinically indicated; monitor developmental progress and educational need; assess for behavioral issues, including anxiety, ADHD, aggression, and self-injury; and assess for chronic vomiting, constipation, and signs/symptoms of sleep disturbance.

Genetic counseling.

KMT2E-NDD is an autosomal dominant disorder. Most probands reported to date with KMT2E-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Rarely, individuals diagnosed with KMT2E-NDD inherited a pathogenic variant from an affected parent who typically has mild intellectual disability. Each child of an individual with KMT2E-NDD has a 50% chance of inheriting the pathogenic variant. Once the KMT2E pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

KMT2E-NDD should be considered in individuals with the following clinical and brain MRI findings.

Clinical findings

• Mild-to-profound developmental delay (DD) or intellectual disability (ID), although most individuals fall within the mild-to-moderate range

AND

• Any of the following features presenting in infancy or childhood:
  • Generalized hypotonia of infancy
  • Gastrointestinal symptoms, including vomiting and reduced bowel motility
  • Seizures, including febrile seizures
  • Autism spectrum disorder
  • Behavioral issues
  • Macrocephaly (often relative to length/height)
  • Microcephaly (in some individuals with missense pathogenic variants) (See Genotype-Phenotype Correlations.)
  • Sleep disturbance, including frequent awakenings and difficulty falling asleep
  • Minor dysmorphic features (See Clinical Description and Figure 1.)
  • Nonspecific brain abnormalities, including hypoplasia of the corpus callosum, ventriculomegaly, cerebral cysts, and/or delayed myelination

Figure 1.

Consistent facial features of individuals with KMT2E-related neurodevelopmental disorder include dolichocephaly, tall forehead, and deep-set eyes, often with downslanting palpebral fissures, periorbital fullness, prominent cheeks, and prominent nasolacrimal (more...)

Family history. Because KMT2E-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of KMT2E-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathoge variant in KMT2E identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this chapter is understood to include likely pathogenic variants. (2) Identification of a heterozygous KMT2E variant of uncertain significance (KMT2E missense variants of uncertain significance are a common finding [Author, personal observation]) does not establish or rule out the diagnosis. Segregation in parents should be considered in these situations to determine if the variant is de novo or inherited from an affected parent (supporting pathogenicity) or inherited from an unaffected parent (suggesting it may be benign).

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or exome/genome sequencing. Note: Single-gene testing (sequence analysis of KMT2E, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability multigene panel that includes KMT2E and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of KMT2E-NDD, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not.
  Genome sequencing is also possible; this method has been proposed to be able to improve variant detection in coding regions, expand the assessment of noncoding regions (i.e., identifying variants that may alter splicing of KMT2E), and detect copy-neutral (e.g., inversions, translocations) or noncoding structural variants.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

KMT2E-related neurodevelopmental disorder (KMT2E-NDD) is a condition characterized by global developmental delay, variable intellectual disability (typically mild to moderate), and hypotonia [O'Donnell-Luria et al 2019, Velmans et al 2022]. To date, 61 individuals have been reported in the medical literature with a pathogenic variant in KMT2E [O'Donnell-Luria et al 2019, Conforti et al 2021, Li et al 2021, Sharawat et al 2021, Abreu et al 2022, Cao et al 2022, Lee et al 2022, Velmans et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). Almost all individuals with KMT2E-NDD present with global developmental delay. The majority are verbal but experience speech delays with or without articulation problems. A few individuals were reported to have speech regression. Four individuals with pathogenic missense variants were not verbal [O'Donnell-Luria et al 2019]. All reported individuals older than infants have been able to obtain independent ambulation, though many were delayed in achieving this milestone, and most presented with additional motor delays [O'Donnell-Luria et al 2019, Velmans et al 2022]. Intellectual disability, usually in the mild-to-moderate range, has been reported in a majority of affected individuals [O'Donnell-Luria et al 2019, Velmans et al 2022].

Seizures. Almost one third of reported individuals have developed seizures. There is no consistent seizure semiology or epilepsy syndrome described in individuals with KMT2E-NDD.

• About 14% of individuals with protein-truncating pathogenic variants have been reported to have seizures (two with unprovoked seizures, one with a single seizure, and two with treatment-resistant epilepsy).
• All five individuals with pathogenic missense variants had epilepsy, four of whom had treatment-resistant infantile epilepsy [O'Donnell-Luria et al 2019, Li et al 2021].
• Three affected individuals were noted to have febrile seizures [Li et al 2021, Velmans et al 2022].
• Sex-related differences have also been noted, with epilepsy reported in 43% of females (3/7) but in only 5% of males (1/21) in one study [O'Donnell-Luria et al 2019]. This suggests the possibility of decreased penetrance or variable expressivity of the seizure phenotype in females with de novo protein-truncating pathogenic variants.

Two individuals (one with a missense pathogenic variant and the other with a frameshift pathogenic variant) are known to have experienced developmental regression with some improvement in epilepsy when started on a ketogenic diet, so careful monitoring should be in place if this therapy is considered (see Management) [O'Donnell-Luria et al 2019; A O'Donnell-Luria, personal observation]. More evidence is needed to determine if ketogenic diet is contraindicated in individuals with this condition.

Neurobehavioral/psychiatric problems

• Autism spectrum disorder (ASD) is seen more frequently in males with KMT2E-NDD than in affected females [O'Donnell-Luria et al 2019, Conforti et al 2021, Li et al 2021, Sharawat et al 2021, Velmans et al 2022].
• Some affected individuals have behavioral concerns other than ASD; stereotypies, skin-picking behavior, self-injurious behavior, aggression, anxiety, and sensory integration disorder has been reported in 17% of individuals. At least two affected individuals have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) [O'Donnell-Luria et al 2019, Velmans et al 2022].

Musculoskeletal features / tone abnormalities

• Hypotonia is reported in about 46% of individuals with KMT2E-NDD. In two individuals, this presented as feeding difficulties in the newborn period. There is not enough data to determine if hypotonia resolves with time, although it tends to improve with age.
• General joint laxity is reported in some affected individuals [O'Donnell-Luria et al 2019, Abreu et al 2022, Velmans et al 2022, Cao et al 2022]. No joint dislocations have been reported.

Growth. Growth parameters can be variable, but most are in the normal range for length/height and weight, both at birth and later in life. About half of individuals have macrocephaly (>2 standard deviations above the mean, i.e., z score for age >2) or relative macrocephaly (defined as head circumference z score for age 1 or more points higher than the length z score). Several individuals with pathogenic missense variants had microcephaly (see Genotype-Phenotype Correlations) [O'Donnell-Luria et al 2019, Velmans et al 2022].

Gastrointestinal issues, including gastroesophageal reflux, vomiting, and/or reduced bowel motility has been reported in almost 50% of affected individuals [O'Donnell-Luria et al 2019, Velmans et al 2022]. Constipation was the most frequently reported gastrointestinal issue and is likely related to low muscle tone.

Sleep disturbance. About half of affected individuals have some type of sleep disturbance, including frequent awakening and difficulties falling asleep [Velmans et al 2022]. While data on sleep issues are limited, mild sleep apnea has only been reported in one affected individual [A O'Donnell-Luria, personal observation].

Facial features. If present, dysmorphic features are usually subtle and nonspecific. Facial features including dolichocephaly, tall forehead, deep-set eyes, periorbital fullness, malar prominence, and prominent nasolabial folds are seen in a subset of affected individuals (see Figure 1) [O'Donnell-Luria et al 2019, Li et al 2021, Velmans et al 2022]. A composite facial phenotype is provided in Figure 2. However, no recognizable dysmorphic pattern has been observed in individuals with this condition.

Figure 2.

Composite figure analysis of the facial phenotype of individuals with KMT2E-related neurodevelopmental disorder in Figure 1, excluding Individual 30, who is wearing glasses Reprinted with permission from O'Donnell-Luria et al [2019]

Neuroimaging. Brain imaging was reported as normal in most affected individuals who underwent imaging. About 20% showed nonspecific findings, such as abnormal corpus callosum, signal abnormalities in the white matter, decreased volume, ventriculomegaly, pachygyria, delayed myelination, small areas of heterotopia, or small localized cysts [O'Donnell-Luria et al 2019, Velmans et al 2022]. Hydrocephalus has not been reported.

Prognosis. It is unknown whether life span in KMT2E-NDD is abnormal. One reported individual is alive at age 54 years [Conforti et al 2021], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Only five individuals have been reported with pathogenic missense variants.

Individuals with pathogenic missense variants in KMT2E have been reported to have microcephaly (as opposed to macrocephaly) and more severe seizures compared to those who have pathogenic protein-truncating variants [O'Donnell-Luria et al 2019, Conforti et al 2021, Li et al 2021, Sharawat et al 2021, Velmans et al 2022].

Prevalence

To date, 61 individuals have been identified with a pathogenic variant in KMT2E [O'Donnell-Luria et al 2019, Conforti et al 2021, Li et al 2021, Sharawat et al 2021, Abreu et al 2022, Cao et al 2022, Velmans et al 2022]. There is no evidence to indicate a higher prevalence in any particular population.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with KMT2E-NDD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for KMT2E-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

KMT2E-related neurodevelopmental disorder (KMT2E-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with KMT2E-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo KMT2E pathogenic variant.
• Rarely, individuals diagnosed with KMT2E-NDD inherited a KMT2E pathogenic protein-truncating variant from an affected parent with (typically) mild intellectual disability. Confirmed parental transmission of a KMT2E pathogenic protein-truncating variant has been reported in two families with one affected child (one maternally and one paternally inherited) and one family with two affected children (paternally inherited); presumed parental transmission has been reported in one family with three affected children (the pathogenic variant was not maternally inherited and the father was not available for testing) [O'Donnell-Luria et al 2019, Velmans et al 2022].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * Theoretically, a parent with somatic and germline mosaicism for a KMT2E pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the KMT2E pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the KMT2E pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with KMT2E-NDD has a 50% chance of inheriting the KMT2E pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the KMT2E pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the KMT2E pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

KMT2E encodes a histone methyltransferase protein, inactive histone-lysine N-methyltransferase 2E (KMT2E), but studies suggest lack of an intrinsic methyltransferase activity. The gene product functions as a transcriptional regulator in diverse biological processes, including cell cycle progression, maintenance of genomic stability, adult hematopoiesis, and spermatogenesis. KMT2E is ubiquitously expressed in most tissues including the developing fetal brain [Fagerberg et al 2014]. However, how disruption of KMT2E results in a neurodevelopmental condition is currently not understood.

Mechanism of disease causation. Likely loss of function. The majority of individuals with KMT2E-related neurodevelopmental disorder have protein-truncating pathogenic variants, including nonsense, frameshift, and splice-disrupting pathogenic variants, suggesting that haploinsufficiency is the likely disease mechanism, but this has not been confirmed. Some individuals with de novo pathogenic missense variants presented with a more severe phenotype, leading authors to hypothesize an alternate mechanism such as gain of function and dominant-negative, though additional research is needed [O'Donnell-Luria et al 2019].

Author Notes

Dr Anne O'Donnell-Luria is Board-certified in clinical genetics, biochemical genetics, and pediatrics. She is an attending physician in the Division of Genetics and Genomics at Boston Children's Hospital and an Assistant Professor in Pediatrics at Harvard Medical School. She co-directs the EpiChroma Clinic at Boston Children's Hospital for children and adults with known or suspected disorders involving the genes that are important for chromatin. She is also the Co-Director of the Center for Mendelian Genomics (CMG) and Institute Member at the Broad Institute of MIT and Harvard, where she leads a team analyzing the genetic variants found in thousands of families affected with rare disease to improve genetic diagnosis and novel disease gene discovery.

Web page: bchgenetics.org/people/anne-odonnell-luria

Email: ude.dravrah.snerdlihc@llennodo.enna

Dr Lance Rodan is Board-certified in clinical genetics, biochemical genetics, and neurology. He is an attending physician in the Division of Genetics and Genomics and the Department of Neurology at Boston Children's Hospital. He is an Assistant Professor in Pediatrics at Harvard Medical School. Dr Rodan is a member of the multidisciplinary team for the Brain Development and Genetics (BrDG) Clinic, and a clinician in the Harvard Undiagnosed Diseases Network (UDN). Dr Rodan's clinical and research interests include diagnosis and management of neurogenetic and neurometabolic disorders.

Web page: bchgenetics.org/people/lance-h-rodan

Email: ude.dravrah.snerdlihc@nador.ecnal

Lynn Pais is a Board-certified clinical genetic counselor in the Division of Genetics and Genomics at Boston Children's Hospital. She is also a Senior Clinical Genomic Variant Analyst at the Center for Mendelian Genomics (CMG) at the Broad Institute of MIT and Harvard, where she analyzes genomic data of individuals with rare disease to improve genetic diagnosis and novel disease gene discovery.

Web page: epichromaclinic.com

Email: ude.dravrah.snerdlihc@siap.nnyl

Acknowledgments

Support was provided by the National Institutes of Health's National Institute of Child Health and Human Development (NICHD) (K12HD052896), the National Human Genome Research Institute-funded Broad Center for Mendelian Genomics (UM1HG008900, U01HG011755), and the Manton Center for Orphan Disease Research to A.O'D.L.

Revision History

• 18 April 2024 (ma) Review posted live
• 1 February 2023 (aol) Original submission

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