Clinical characteristics.

KMT2B-related disorders include KMT2B-related dystonia (DYT-KMT2B), reported in 93% families, and KMT2B-related neurodevelopmental disorder (NDD) that is non-dystonic, reported in 7% of families.

DYT-KMT2B is a complex childhood-onset progressive movement disorder (median age of onset: 6 years; range: 0-43 years) typically evolving from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties secondary to articulation difficulties (dysarthria) and low speech volume (hypophonia) are common. Bulbar dysfunction can lead to impaired swallowing with an increased risk of aspiration and need for gastrostomy tube placement in some. Most individuals have additional neurologic or systemic manifestations including intellectual disability (ID) / developmental delay (DD), other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities), and neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder.) Life expectancy is not known; however, individuals in the seventh decade of life have been reported.

KMT2B-related NDD, sometimes described in family members of individuals with DYT-KMT2B, is characterized by DD and ID ranging from mild to severe. Additional findings can include bulbar dysfunction and neurobehavioral/psychiatric manifestations. Life expectancy is not known; to date, too few individuals have been reported.

Diagnosis/testing.

The diagnosis of a KMT2B-related disorder is established in a proband with suggestive findings and either of the following identified by molecular genetic testing: a heterozygous pathogenic variant involving KMT2B (~88% of affected individuals) or a heterozygous deletion of 19q13.11-19q13.12 involving KMT2B (~12% of affected individuals).

Management.

Treatment of manifestations: A movement disorder specialist should be involved early on to discuss pharmacologic and surgical treatment options. Although use of anti-dystonic agents (levodopa and other agents) has not resulted in long-term benefit for most individuals, a trial of these agents would be considered reasonable. Antimuscarinic (anticholinergic) agents have significantly improved motor manifestations in about 50% of individuals and should be considered a first-line pharmacologic treatment in individuals with a KMT2B-related disorder. Bilateral globus pallidus pars interna deep brain stimulation, performed in about 80 individuals to date, has resulted in substantial clinical and functional improvement. Treatment of DD/ID, neurobehavioral/psychiatric manifestations, communication difficulties, feeding difficulties, and other movement disorders should follow standard practice.

Surveillance: Assess for progression of known features and to identify new manifestations such as changes in tone and movement disorders with regularly scheduled follow up; at each visit, assess safety of oral intake, communication needs, mobility, self-help skills, features neurobehavioral/psychiatric manifestations, and family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning); assess developmental progress and educational needs throughout childhood and adolescence; full psychoeducational evaluation for children who have difficulty with school or behavioral changes.

Genetic counseling.

DYT-KMT2B and KMT2B-related NDD are autosomal dominant disorders. The majority of individuals reported to date with a KMT2B-related disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo genetic alteration. Some individuals diagnosed with a KMT2B-related disorder inherited a genetic alteration from a parent (a parent with a KMT2B pathogenic variant may be affected or clinically asymptomatic). Each child of an individual with a KMT2B-related disorder has a 50% chance of inheriting the genetic alteration. Once the KMT2B pathogenic variant or deletion of 19q13.12 involving KMT2B has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

KMT2B-Related Dystonia (DYT-KMT2B)

DYT-KMT2B should be suspected in individuals with the following clinical and imaging findings and family history.

Clinical findings

• Dystonia
  • Typical presentation. Early onset, progressive, and often complex (median age: 6 years; range: 0-43 years) [Lange et al 2021], most commonly with lower-limb manifestations such as foot posturing and new-onset toe walking or gait difficulties that evolve into generalized dystonia with prominent cranial, cervical, oromandibular, and laryngeal involvement
  • Atypical presentation. Upper-limb dystonia or cervical, oromandibular/laryngeal, and/or trunk dystonia without limb involvement
• Developmental delay (DD) /intellectual disability (ID)
  • Developmental delay, in particular speech delay, preceding onset of dystonia
  • Intellectual disability ranging from mild to severe
• Neurobehavioral/psychiatric manifestations including but not limited to autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder, and depression.

Brain imaging. Brain MRI is reported as normal in ~40% of individuals. Brain abnormalities found in ~27% of individuals ranging in age from three to 44 years include subtle and symmetrical hypointense lateral streaks in the external globus pallidus (see Figure 1) on T₂-weighted, T₂*-weighted, and susceptibility-weighted images [Meyer et al 2017, Dafsari et al 2019, Cif et al 2020, Ng et al 2020, Pandey et al 2020, Rajan et al 2021, Monfrini et al 2022, Dhar et al 2023].

Figure 1.

Radiologic MRI features of individuals with KMT2B pathogenic variants a-l. T₂*-weighted (a, d) and T₂-weighted (b, c) images; echo-planar technique diffusion imaging data set images with b value of zero (e-h); susceptibility-weighted sequences (i-l)

Note: This pattern may be an age-dependent phenomenon, as these features may become less prominent over time and are often not evident in adults. Indeed, in five individuals such MRI changes were less evident on subsequent MRIs [Meyer et al 2017, Dafsari et al 2019, Cif et al 2020].

Cerebellar atrophy was described in three individuals [Damásio et al 2021, Dhar et al 2023, Ding et al 2024].

DaTscan was normal in four individuals, while two others showed decreased striatal uptake [Meyer et al 2017, Feuerstein et al 2021, Buzo et al 2022, Shimazaki et al 2022].

Establishing the Diagnosis

The diagnosis of a KMT2B-related disorder is established in a proband with suggestive findings and one of the following identified by molecular genetic testing (see Table 1).

• A heterozygous pathogenic (or likely pathogenic) variant involving KMT2B (~88% of affected individuals) [Meyer et al 2017, Carecchio et al 2019, Zech et al 2019, Cif et al 2020, Li et al 2020, Mirza-Schreiber et al 2022, Monfrini et al 2022, Pérez-Dueñas et al 2022, Dhar et al 2023, Ding et al 2024]
• A heterozygous deletion of 19q13.11-19q13.12 involving KMT2B (12% of affected individuals) [Kulharya et al 1998, Malan et al 2009, Schuurs-Hoeijmakers et al 2009, Forzano et al 2012, Gana et al 2012, Chowdhury et al 2014, Melo et al 2015, Segel et al 2015, Meyer et al 2017, Abe et al 2018, Zhao et al 2018, Carecchio et al 2019, Cif et al 2020, Pérez-Dueñas et al 2022, Ding et al 2024]

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology 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 GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous KMT2B variant of uncertain significance does not establish or rule out the diagnosis (see Molecular Pathogenesis).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel), comprehensive genomic testing (chromosomal microarray analysis [CMA], genomic sequencing, exome array). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of KMT2B, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

KMT2B-related disorders include KMT2B-related dystonia (DYT-KMT2B) (258 individuals from 229 families) and KMT2B-related neurodevelopmental disorder (NDD) (27 individuals from 25 families).

DYT-KMT2B is a complex childhood-onset movement disorder typically characterized by a progressive disease course commonly evolving from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties secondary to articulation difficulties (dysarthria) and low speech volume (hypophonia) are common. Bulbar dysfunction leads to impaired swallowing with an increased risk of aspiration and gastrostomy tube placement in some. In most individuals, the movement disorder is accompanied by additional neurologic or systemic manifestations, as in complex dystonia. Intellectual disability (ID) / developmental delay (DD) is common. Neurobehavioral/psychiatric manifestations can include attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, and obsessive-compulsive disorder.

Although many affected individuals follow a similar disease course, an increasing number have milder and atypical findings. Atypical first disease presentations include isolated upper limb, neck, trunk, or oromandibular/laryngeal dystonia or dystonic tremor [Zech et al 2016, Lange et al 2017, Meyer et al 2017, Zech et al 2017a, Zech et al 2017b, Hackenberg et al 2018, Kawarai et al 2018, Brás et al 2019, Carecchio et al 2019, Cif et al 2020, Grosz et al 2022, Horisawa et al 2020, Li et al 2020, Miyata et al 2020, Mun et al 2020, Winslow et al 2020, Buzo et al 2022, Monfrini et al 2022, Owczarzak et al 2022, Shimazaki et al 2022, Wu et al 2022, Chudy et al 2023, Dy Closas et al 2023, Heiser et al 2023, Lin et al 2023, Ding et al 2024, Makharia et al 2024].

KMT2B-related NDD has been described both in individuals who have family members with an inherited KMT2B pathogenic variant and a dystonic phenotype [Dai et al 2019, Kumar et al 2019, Monfrini et al 2022], as well as in individuals with no family history of a KMT2B-related disorder [Reuter et al 2017, Faundes et al 2018, Cif et al 2020, Monfrini et al 2022, Ding et al 2024]. Ten individuals with deletions involving chromosome 19q13.11-19q13.12 encompassing KMT2B presented with mild-to-severe DD/ID [Kulharya et al 1998, Malan et al 2009, Schuurs-Hoeijmakers et al 2009, Forzano et al 2012, Chowdhury et al 2014, Abe et al 2018]. Additional neurologic or systemic manifestations included poor weight gain / short stature, microcephaly, and skin features.

To date, about 238 individuals with a pathogenic variant in KMT2B and 33 individuals with deletions on chromosome 19q13.11-19q13.12 encompassing KMT2B have been reported. The following description of the phenotypic features associated with KMT2B-related disorders is based on these reports (see Table 2).

Genotype-Phenotype Correlations

Meyer et al [2017] reported statistically significant earlier disease onset in individuals with DYT-KMT2B with loss-of-function variants (e.g., interstitial deletions; frameshift, splice site, and stop-gain variants) compared to those with missense variants. However, the class of pathogenic variant does not appear to influence the rate of disease progression, disease severity, or clinical response to deep brain stimulation.

Cif et al [2020] reported (133 individuals) earlier onset of dystonia and more severe dystonia severity scores in individuals with chromosome 19q13 microdeletions and KMT2B protein-truncating variants than in individuals with missense variants.

Marogianni et al [2021] reported (81 individuals) a statistically significant earlier disease onset in those with a KMT2B insertion (mean age 4.4 years) compared to a KMT2B missense variant (mean age 8.7 years).

Penetrance

DYT-KMT2B is postulated to show reduced penetrance, as asymptomatic heterozygotes have been identified. Although parental status is not always known, to date two of 32 reported KMT2B pathogenic variants have been inherited from a seemingly unaffected parent [Meyer et al 2017].

Nomenclature

KMT2B-related dystonia may be referred to as DYT28 (OMIM 617284), DYT-KMT2B [Lange et al 2022], or KMT2B-deficient dystonia [Oexle et al 2023].

DYT-KMT2B may be categorized as either "isolated dystonia" or "complex dystonia."

• In a cohort of 68 individuals with KMT2B pathogenic variants, 58% had complex or combined dystonia (with myoclonus, parkinsonism, or unspecified) and 41% had isolated dystonia [Lange et al 2021].
• In larger cohorts of individuals with KMT2B pathogenic variants, mostly complex or combined dystonia was reported [Meyer et al 2017, Carecchio et al 2019, Cif et al 2020, Ding et al 2024].

Prevalence

Disease prevalence is not yet established. To date, 246 individuals from 229 families with DYT-KMT2B and 27 individuals from 25 families with KMT2B-related NDD have been described (see Clinical Description).

KMT2B-Related Dystonia

The differential diagnosis of KMT2B-related dystonia (DYT-KMT2B) includes early-onset isolated and complex generalized dystonia.

Complex dystonias (i.e., disorders with dystonia and other neurologic or systemic manifestations) include genetic neurodegenerative and metabolic disorders (see Table 3) and those that are acquired due to brain lesions (e.g., dyskinetic cerebral palsy), drugs (e.g., neuroleptics), or psychogenic causes. (Diagnosis and management of dystonia are reviewed in Albanese et al [2019].)

KMT2B-Related Neurodevelopmental Disorder

The phenotypic features associated with KMT2B-related neurodevelopmental disorder (NDD) are not sufficient to diagnose this condition clinically; all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis.

See OMIM Phenotypic Series for genes associated with:

• Autosomal dominant intellectual developmental disorders;
• Autosomal recessive intellectual developmental disorders;
• Nonsyndromic X-linked intellectual developmental disorders;
• Syndromic X-linked intellectual developmental disorders.

The disorders in Table 4 include disorders in which the specific combination of selected features might make the diagnosis of KMT2B-related NDD more likely.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a KMT2B-related disorder, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for KMT2B-related disorders. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields. A movement disorder specialist should be involved at an early stage to discuss pharmacologic and surgical treatment options.

Pharmacologic treatment of dystonia

• Anti-dystonic agents. Use of levodopa and other agents (e.g., trihexiphenidyl, baclofen, gabapentin, tetrabenazine, benzodiazepines) has not resulted in long-term benefit for most individuals with KMT2B-related disorders [Zech et al 2016, Meyer et al 2017, Zech et al 2017a, Lange et al 2021, Aksoy et al 2022]; nonetheless, a trial of these anti-dystonia agents would be considered reasonable.
• Antimuscarinic (anticholinergic) agents have significantly improved motor manifestations (~50%) in individuals with KMT2B-related disorders [Lange et al 2021, Aksoy et al 2022] and should be considered first-line pharmacologic treatment in individuals with a confirmed diagnosis of a KMT2B-related disorder. Anticholinergics should be started at a low dose according to published guidelines for pediatric [Gorodetsky & Fasano 2022] and adult dystonia [Termsarasab et al 2016], and then titrated up slowly to the lowest effective dose without side effects.

Bilateral globus pallidus pars interna deep brain stimulation (GPi-DBS) has been performed in ~80 individuals and subthalamic nucleus DBS in two individuals. Substantial clinical and functional improvement was reported [Zech et al 2016, Meyer et al 2017, Zech et al 2017a, Zech et al 2017b, Carecchio et al 2019, Mun et al 2020, Li et al 2020, Winslow et al 2020, Cif et al 2020, Rajan et al 2021, Abel et al 2021, Buzo et al 2022, Pérez-Dueñas et al 2022, Ding et al 2024]:

• A mean reduction of ~49.2% (range: 2%-98%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Movement subscale (BFMDRS-M) was reported at follow-up times of two to 16 months after DBS in 45 individuals for whom data were available.
• A mean reduction of ~38.3% (range: 9%-91%) in the Burke-Fahn-Marsden Dystonia Rating Scale, Disability subscale (BFMDRS-D) was reported at follow-up times of two to 12 months after DBS in 45 individuals for whom data were available.
• Sustained clinical effect was observed in five-year long-term follow up, which demonstrated sustained improvement for trunk, neck, upper limb, and oromandibular dystonia [Cif et al 2020, Ding et al 2024].
• However, despite initial improvement, DBS was less effective for lower-limb dystonia, with worsening of gait and loss of ambulation in all individuals [Cif et al 2020].
• DBS has not been effective in the treatment of laryngeal dystonia [Carecchio et al 2019, Cif et al 2020]. An effect on speech was only reported in a minority of individuals [Kawarai et al 2018, Cao et al 2019, Li et al 2020, Abel et al 2021].
• Freezing of gait is increasingly recognized as a complication of GPi-DBS in individuals with truncating KMT2B variants [Cif et al 2020, Feuerstein et al 2021].

Physical therapy. Early initiation of physical therapy and a tailored exercise program helps maintain function and prevent secondary orthopedic complications such as joint contractures, hip dislocation, and/or kyphoscoliosis.

Adaptive aids (e.g., ankle-foot orthoses, walkers) can support and maintain ambulation.

Fine motor dysfunction. Occupational therapy is recommended to address fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Speech-language therapy helps assist in feeding skills and communication.

Alternative means of communication (e.g., augmentative and alternative communication [AAC]) may benefit individuals who have expressive language difficulties.

Neurobehavioral/psychiatric manifestations. Consultation with a developmental pediatrician may help guide parents through appropriate behavior management strategies and/or provide, when necessary, prescription medications (e.g., medication used to treat attention-deficit/hyperactivity disorder).

Children may qualify for and benefit from interventions such as applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses; it is typically performed one on one with a board-certified behavior analyst.

Nutrition specialists / dieticians help assess calorie needs and reduce the risk of malnutrition.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Videofluoroscopy can be used to evaluate the risk of aspiration and the need for alternative means of feeding.

Respiratory. For individuals with respiratory compromise from chest deformities related to scoliosis, prophylactic antibiotics during the winter months, regular chest physical therapy, and influenza immunizations should be considered because of the increased risk of pulmonary infections.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

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

Pregnancy Management

Anti-dystonic medications. Prior to conception, counseling a woman with DYT-KMT2B regarding potential effects of anti-dystonic medications on the pregnancy and developing fetus is recommended to develop a plan for managing these medications during pregnancy.

Data on the use of anti-dystonic agents in pregnancy are limited. Although single case reports of medical treatment with trixhexyphenidyl, levodopa/carbidopa, and clonazepam during pregnancy have not reported adverse effects on the affected mother or the fetus [Watanabe et al 2009, Mendhekar & Andrade 2011, Nageshwaran et al 2011, Robottom & Reich 2011, Serikawa et al 2011, Watanabe & Matsubara 2012, Dostal et al 2013], oral medications may preferably be tapered to the lowest effective dose.

Antiemetics. It is recommended that pregnant women and their care providers be advised about the possible induction of dystonic side effects of antiemetics (i.e., dopamine receptor antagonists [metoclopramide, domperidone] or 5-HT³ serotonin receptor antagonist [ondansetron]) [Nageshwaran et al 2011].

Deep brain stimulation (DBS). In women treated with DBS prior to conception, no adverse effects on the affected mother or the fetus have been reported [Scelzo et al 2015, Ziman et al 2016, Park et al 2017].

See MotherToBaby for further information on medication use during pregnancy.

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

KMT2B-related dystonia (DYT-KMT2B) and KMT2B-related neurodevelopmental disorder (NDD) are autosomal dominant disorders often caused by a de novo genetic alteration (i.e., a KMT2B pathogenic variant or deletion of 19q13.12 involving KMT2B).

Risk to Family Members

Parents of a proband

• Most individuals reported to date with a KMT2B-related disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo genetic alteration. In families in which parents have undergone molecular genetic testing:
  • About 84% of individuals diagnosed with DYT-KMT2B have the disorder as the result of a de novo KMT2B pathogenic variant [Meyer et al 2017, Carecchio et al 2019, Zech et al 2019, Cif et al 2020, Li et al 2020, Mirza-Schreiber et al 2022, Monfrini et al 2022, Pérez-Dueñas et al 2022, Dhar et al 2023, Ding et al 2024];
  • About 91% of individuals diagnosed with KMT2B-related NDD have the disorder as the result of a de novo genetic alteration [Malan et al 2009, Forzano et al 2012, Chowdhury et al 2014, Venegas-Vega et al 2014, Urquhart et al 2015, Reuter et al 2017, Abe et al 2018, Faundes et al 2018, Dai et al 2019, Kumar et al 2019, Cif et al 2020, Monfrini et al 2022, Ding et al 2024].
• Some individuals diagnosed with a KMT2B-related disorder inherited a genetic alteration from a parent. A parent with a KMT2B pathogenic variant may be affected or clinically asymptomatic (see Penetrance).
  • About 16% of individuals diagnosed with DYT-KMT2B inherited a KMT2B pathogenic variant: 63.5% from an affected parent (36.5% dystonic phenotypes, 27% non-dystonic phenotypes) and 36.5% from a clinically asymptomatic parent [Zech et al 2016, Meyer et al 2017, Carecchio et al 2019, Dai et al 2019, Ma et al 2019, Cif et al 2020, Li et al 2020, Ng et al 2020, Pandey et al 2020, Winslow et al 2020, Rajan et al 2021, Monfrini et al 2022, Owczarzak et al 2022, Wu et al 2022].
  • About 11% of individuals diagnosed with KMT2B-related NDD inherited a genetic alteration: 7% from an affected parent (in individuals for whom data were available) [Dai et al 2019, Monfrini et al 2022].
• Intrafamilial variability is reported.
  • 58% of individuals with DYT-KMT2B inherited a KMT2B pathogenic variant from a parent with a dystonic phenotype, while 42% inherited a KMT2B pathogenic variant from a parent with an NDD phenotype [Zech et al 2016, Meyer et al 2017, Carecchio et al 2019, Dai et al 2019, Ma et al 2019, Cif et al 2020, Li et al 2020, Ng et al 2020, Pandey et al 2020, Winslow et al 2020, Rajan et al 2021, Monfrini et al 2022, Owczarzak et al 2022, Wu et al 2022].
  • In some families, the affected parent presents a milder, non-generalized, and later-onset dystonia phenotype compared to their offspring, who exhibit an early-onset, generalized dystonia phenotype [Meyer et al 2017, Zech et al 2016].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of a KMT2B pathogenic variant or 19q13.12 deletion involving KMT2B in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the genetic alteration.
• If the genetic alteration 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 genetic alteration.
  • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) 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 (gonadal) cells only.
    * A parent with somatic/gonadal mosaicism for a genetic alteration 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 affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial variability and reduced penetrance have been observed in KMT2B-related disorders.
• If the genetic alteration identified 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 possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the proband represents a simplex case and the parents are clinically unaffected but have not been tested for the genetic alteration identified in the proband, sibs of the proband are still at increased risk for a KMT2B-related disorder because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with a KMT2B-related disorder has a 50% chance of inheriting the genetic alteration.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the KMT2B pathogenic variant or deletion of 19q13.12 involving KMT2B, 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 young adults who are affected or at risk.
• Prior to conception, counseling a woman with DYT-KMT2B regarding potential effects of anti-dystonic medications on the pregnancy and developing fetus is recommended to develop a plan for managing these medications during pregnancy (see Pregnancy Management).

Prenatal Testing and Preimplantation Genetic Testing

Once a KMT2B pathogenic variant or deletion of 19q13.11-13.12 involving KMT2B 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

KMT2B encodes histone-lysine N-methyltransferase 2B (KMT2B), a ubiquitously expressed lysine-specific histone methyltransferase. KMT2B, a member of the SET/MLL protein family, is specifically involved in histone H3 lysine 4 (H3K4) methylation. Histone methylation is a post-translational epigenetic mechanism that either represses or activates gene transcription in a residue-specific manner [Shi & Whetstine 2007, Shilatifard 2008]. Indeed, Ciolfi et al [2021] confirmed a non-random distribution of hypermethylation in the genome in pathogenic KMT2B variants. Hypermethylation was overrepresented in regulatory regions such as promoters or other regulators that positively control gene expression, indicating a general repression of transcriptional activity in KMT2B-related disorders. Besides gene activation, H3K4 is also thought to be essential for transcriptional stability and enhanced transcriptional consistency [Muramoto et al 2010, Benayoun et al 2014].

The exact pathogenic mechanisms in KMT2B-related disorders remain to be fully elucidated. Given that dysregulated H3K4 methylation affects the transcriptional activation and stability of a variety of genes, it is likely that additional genes or other genetic mechanisms contribute to KMT2B-related disorders.

Mechanism of disease causation. Loss-of-function KMT2B pathogenic variants are predicted to alter gene dosage, leading to KMT2B haploinsufficiency.

KMTB2-specific laboratory technical considerations. Note: Epigenetic signature analysis / methylation array can be useful in evaluating KMT2B variants of uncertain significance [Levy et al 2021, Lee et al 2022, Mirza-Schreiber et al 2022].

Author Notes

Dr Lucia Abela
Department of Child Neurology
University Children's Hospital Zurich
Zurich, Switzerland

Dr Abela is a pediatric neurologist with a special clinical and research interest in childhood movement disorders.

Professor Manju Kurian
Developmental Neurosciences
UCL-Great Ormond Street Institute of Child Health
London, United Kingdom

Professor Kurian is a pediatric neurologist and clinician-scientist with a clinical and research interest in childhood movement disorders.

Dr Kurian's web page

Contact Dr Kurian to inquire about review of KMT2B variants of uncertain significance.

Acknowledgments

Dr Kurian is funded by an NIHR Research Professorship and the Wellcome Trust. Dr Abela was funded by a Swiss National Foundation Advanced Postdoc Mobility fellowship.

Revision History

• 22 May 2025 (bp) Comprehensive update posted live
• 26 April 2018 (bp) Review posted live
• 19 October 2017 (la/mak) Original submission

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