Clinical characteristics.

TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS) is a condition within the spectrum of mendelian disorders of the epigenetic machinery (MDEMs) or chromatinopathies. Clinical features typically include intellectual disability / developmental delay ranging from mild to severe affecting both motor and language skills. Most affected individuals are verbal and ambulatory, with most walking by age 15-36 months. Hypotonia in infancy and childhood can exacerbate motor and expressive speech delay and, in some cases, cause feeding difficulties that require nasogastric or gastrostomy tube feeding. Some affected individuals display movement disorders. About one third of affected individuals have epilepsy. Other neurobehavioral features can include autism, anxiety, and attention-deficit/hyperactivity disorder. Strabismus and refractive errors are found in about half of affected individuals. Both conductive and sensorineural hearing loss have been observed. Approximately half of individuals exhibit typical growth and half exhibit growth abnormalities, with overgrowth being more common than undergrowth and macrocephaly being the most common manifestation of altered growth. While many affected individuals have dysmorphic features, these are typically nonspecific. Congenital heart defects, brain malformations, and genitourinary anomalies are less common findings.

Diagnosis/testing.

The diagnosis of TET3-BEFAHRS is established in a proband with suggestive findings and a heterozygous pathogenic variant in TET3 identified by molecular genetic testing. DNA methylation profiling can help confirm variant pathogenicity.

Management.

Treatment of manifestations: Standardized treatment with anti-seizure medication (ASM) by an experienced neurologist; feeding therapy; gastrostomy tube placement may be required for persistent feeding issues; pressure-equalizing tubes for conductive hearing loss; hearing aids for sensorineural hearing loss; standard treatment for constipation, musculoskeletal issues, refractive error, strabismus, nystagmus, behavioral issues, developmental delay / intellectual disability, congenital heart defects, and genitourinary anomalies.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status and safety of oral intake; assessment for new manifestations, such as seizures and changes in tone; monitoring of developmental progress and educational needs; behavioral assessment; assessment for signs and symptoms of constipation; assessment of mobility and self-help skills; clinical evaluation for kyphosis and/or scoliosis. At least annually: complete ophthalmology evaluation and audiology evaluation.

Pregnancy management: Exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

Genetic counseling.

TET3-BEFAHRS is an autosomal dominant disorder. Most probands have a de novo pathogenic variant, though inherited variants have been reported. Rarely, affected individuals can have biallelic pathogenic variants inherited in trans from heterozygous parents who have milder features of TET3-BEFAHRS. This is now thought to represent autosomal dominant inheritance with variable expressivity as opposed to autosomal recessive inheritance. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If one parent of the proband has a TET3 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and being affected is 50%. If both parents of a proband have a TET3 pathogenic variant, sibs have a 75% chance of inheriting one or two pathogenic variants and being affected and a 25% chance of inheriting neither pathogenic variant and not being affected. Once the TET3 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

TET3-BEFAHRS should be considered in individuals with the following clinical findings.

Clinical findings

• Mild-to-severe developmental delay or intellectual disability

AND

• Any of the following features presenting in infancy or childhood:
  • Generalized hypotonia of infancy
  • Infant feeding difficulties
  • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia
  • Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures
  • Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis
  • Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed
  • Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus
  • Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis
  • Nonspecific dysmorphic features (See Clinical Description.)

Establishing the Diagnosis

The diagnosis of TET3-BEFAHRS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in TET3 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous TET3 variant of uncertain significance without finding a second, pathogenic variant does not establish or rule out the diagnosis. (3) A characteristic epigenetic signature for TET3-BEFAHRS has been established and may aid in the determination of the clinical significance of uncertain variants [Levy et al 2021a].

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, exome sequencing, and DNA methylation profiling. Note: Single-gene testing (sequence analysis of TET3, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

An intellectual disability and/or overgrowth multigene panel that includes TET3 and other genes of interest (see Differential Diagnosis) may be considered. 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 TET3-BEFAHRS, some panels for intellectual disability and/or overgrowth 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 that includes TET3 with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. Due to the recent delineation of this disorder, its rarity, and the TET3 gene not being on all panels for intellectual disability, comprehensive genomic testing like exome sequencing may be considered the diagnostic test of choice for TET3-BEFAHRS.

Genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

DNA methylation profiling, sometimes referred to as an epigenetic signature, in whole blood can be performed as a clinical (non-research-based) test [Levy et al 2021b, Sadikovic et al 2021]. TET3-BEFAHRS has a unique DNA methylation profile that can differentiate affected individuals from controls and affected individuals from individuals with other disorders with distinct DNA methylation profiles [Levy et al 2021a]. DNA methylation profiling (or epigenetic signature) can be used either as an initial diagnostic tool to identify TET3-BEFAHRS or to confirm pathogenicity of a DNA sequence variant of uncertain significance identified in TET3 [Levy et al 2021a]. If used as an initial diagnostic tool, subsequent targeted gene sequencing of TET3 may be beneficial to identify the specific pathogenic variant(s) in an affected person.

Clinical Description

TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS) is a condition within the spectrum of mendelian disorders of the epigenetic machinery (MDEMs) [Fahrner & Bjornsson 2014], also called chromatin-modifying disorders or chromatinopathies. The most common phenotypic manifestations of TET3-BEFAHRS and other MDEMs are intellectual disability / developmental delay typically affecting both motor and language skills. Similar to other MDEMs [Fahrner & Bjornsson 2019], individuals with TET3-BEFAHRS have neurologic, behavioral, and psychiatric features, with some individuals exhibiting growth abnormalities as well [Beck et al 2020, Levy et al 2021a, Seyama et al 2022, Sager et al 2023]. Additional tissue-diverse manifestations affecting the eyes, hearing, and musculoskeletal and gastrointestinal systems have also been observed [Beck et al 2020, Levy et al 2021a, Seyama et al 2022]. See Nomenclature for a mnemonic for the most common features of TET3-BEFAHRS.

To date, 28 individuals from 16 families have been identified with pathogenic variants in TET3 [Santos-Cortez et al 2018, Beck et al 2020, Levy et al 2021a, Seyama et al 2022, Sager et al 2023]. Four affected individuals had copy number variants in addition to pathogenic TET3 variants, and one affected individual had biallelic variants in a gene that causes an autosomal recessive disorder that does not fully explain her phenotype [Beck et al 2020, Levy et al 2021a]. It remains unclear if these additional genetic variants are contributing to the phenotypes in these reported individuals.

Developmental delay (DD) / intellectual disability (ID). The most common finding in individuals with TET3-BEFAHRS is DD and/or ID, ranging from mild to severe. DD is often global, meaning that two or more areas are affected, including gross motor, fine motor, and/or speech. However, in some individuals isolated DD (e.g., gross motor delay) has occurred [Levy et al 2021a; J Fahrner, personal observation]. Most individuals with TET3-BEFAHRS are verbal and ambulatory, with most walking by age 15-36 months.

Other neurodevelopmental features

• Hypotonia is present in a subset of affected individuals and is most notable in infancy and childhood. Hypotonia can affect the acquisition of motor skills and expressive speech.
• Infant feeding difficulties occur in some affected individuals, which in some cases have required nasogastric or gastrostomy tube feeding (see Management).
• Spasticity has been described in one individual.
• Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and dystonia have been observed.

Epilepsy. Slightly more than one third of affected individuals have epilepsy.

• Generalized tonic-clonic seizures with occasional sharp- and slow-wave discharges in the right central area on EEG were observed in two brothers from a single family [Levy et al 2021a].
• In another unrelated male, clinical presentation and EEG findings were consistent with electrical status epilepticus during slow-wave sleep, and the affected male experienced regression [Sager et al 2023]. Pulse steroid therapy, intravenous immunoglobulin, and oral valproic acid were administered initially and led to clinical improvement. Subsequently, steroid therapy and intravenous immunoglobulin were discontinued and clobazam was added to valproic acid therapy, leading to improvement on the EEG.
• Absence seizures were observed in an affected female (whose EEG showed an abnormal focus on the right) and in an affected male. The male individual began having seizures around age 33 months, initially febrile partial seizures and then non-febrile absence seizures and myoclonic jerks of the limbs with preserved consciousness. Initial EEG showed bioccipital biphasic spikes, which progressed first to abundant bicentral spikes and waves with increased frequency during sleep and then to continuous spikes and waves of slow-wave sleep, similar to the male with electrical status epilepticus during slow-wave sleep. Seizures were refractory to therapy with sodium valproate, levetiracetam, lamotrigine, and clobazam; only a combination of sultiame and steroids was effective for this individual [Beck et al 2020].
• A female presented with complex partial seizures; her EEG showed an abnormal focus over the left temporal and occipital regions [Seyama et al 2022].
• One affected individual presented with infantile spasms with an abnormal EEG at age six months [Beck et al 2020].

Neuropsychiatric findings. Autistic features or formal diagnoses of autism spectrum disorder were present in roughly two thirds of individuals evaluated for this feature, and an even larger percentage had difficult and/or delayed social interactions suggestive of social communication disorder. Anxiety was present in a large proportion of affected individuals, as was attention-deficit/hyperactivity disorder. A few affected individuals had depression or psychosis in adolescence or adulthood.

Facial features. Twenty-one of twenty-three affected individuals exhibited common craniofacial features. Most affected individuals exhibited a long face with a tall and/or broad forehead. Approximately one half of affected individuals exhibited a myopathic face with an open-mouth appearance, protruding ears, and a highly arched palate. Approximately one third of affected individuals exhibited a short nose with a long philtrum, and a slightly larger proportion had brachycephaly. A few individuals exhibited thick or arched eyebrows, epicanthal folds, or downslanted palpebral fissures. One individual exhibited cleft lip and palate and an asymmetric jaw.

Ophthalmologic involvement. Nine of 22 affected individuals exhibited ophthalmologic findings. The most common manifestation was strabismus, with one individual having ophthalmoplegia. Vision abnormalities were also observed and included myopia and hyperopia. A few individuals had nystagmus or ptosis. A single individual had lacrimal duct stenosis, and another had microphthalmia.

Hearing/ear abnormalities. Seven of ten affected individuals exhibited hearing loss [Levy et al 2021a, Seyama et al 2022].

• Four affected individuals had conductive hearing loss and two experienced accompanying recurrent otitis media requiring tympanostomy tubes.
• Two affected sibs exhibited sensorineural hearing loss.
• Another affected individual had microtia and atresia of the left external ear canal.

Musculoskeletal features. Nine of 19 individuals exhibited musculoskeletal findings, including the following:

• Joint hypermobility (4 affected individuals)
• Hip dysplasia in infancy (3 affected individuals)
• Kyphosis and/or scoliosis (2 affected individuals)
• Inguinal hernia (1 affected individual)

Growth. Nine of 19 individuals had growth abnormalities, six of whom had overgrowth and three of whom had undergrowth. Ten of 19 individuals did not have reported growth abnormalities.

• Of those with overgrowth, four had macrocephaly, one had tall stature, and one had both macrocephaly and tall stature. The latter individual also had nephromegaly and cardiomegaly, suggestive of generalized somatic overgrowth.
• Of those with undergrowth, three had microcephaly, with two of these individuals also exhibiting short stature.

All growth abnormalities were postnatal, except in one individual whose birth length was greater than two standard deviations above the mean for gestational age. Three individuals (including two sibs) had birth weights greater than two standard deviations below the mean for age.

Neuroimaging. Of the 13 individuals who have undergone brain magnetic resonance imaging (MRI), eight had identified abnormalities [Beck et al 2020, Levy et al 2021a, Seyama et al 2022, Sager et al 2023], which in many cases were nonspecific. Findings included the following:

• Increased extra-axial spaces in four unrelated affected individuals
  • Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia.
  • The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum.
• Two related affected individuals – a mother and son – exhibited white matter changes, with the son's abnormality involving the periventricular white matter and the mother's not otherwise specified.
• Two individuals exhibited hypoplasia of the cerebellum and enlarged/mega cisterna magna; one individual exhibited hypoplasia of the tectum mesencephali.

Other associated features

• Gastrointestinal issues. Eight of 18 affected individuals exhibited gastrointestinal manifestations, with seven having infantile feeding difficulties and two having constipation. One had pyloric stenosis.
• Cardiovascular anomalies. Five of 19 individuals exhibited cardiovascular anomalies, including the following:
  • Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual
  • Tetralogy of Fallot (1 affected individual)
  • A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual)
• Genitourinary anomalies. Three individuals had genitourinary anomalies, with one individual having cryptorchidism, another having hypospadias, and a third having nephromegaly in the setting of generalized somatic overgrowth.

Prognosis. It is unclear whether individuals with TET3-BEFAHRS have a decreased life span. One reported individual is alive at age 56 years [Beck et al 2020], demonstrating that survival into adulthood is possible. This condition is not thought to be progressive; however, in the setting of poorly controlled seizures, it is possible that neurologic function could regress. 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

No genotype-phenotype correlations have been confirmed.

Nomenclature

The BEFAHRS abbreviation can be used as a mnemonic for the most common features as follows: Behavioral differences, Epilepsy, common Facial features, Autistic features, Hypotonia, Retardation of psychomotor development, and Size differences [Levy et al 2021a].

Prevalence

The prevalence of TET3-BEFAHRS is unknown. To date, 28 individuals from 16 families have been reported with pathogenic variants in TET3 [Santos-Cortez et al 2018, Beck et al 2020, Levy et al 2021a, Seyama et al 2022, Sager et al 2023]. The author is aware of additional affected individuals and welcomes contact and queries from clinicians who care for affected individuals (see Author Notes).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TET3-BEFAHRS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for TET3-BEFAHRS.

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 5).

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

In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

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

TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS) is an autosomal dominant disorder; individuals with a TET3 pathogenic variant are affected.

In some families reported to date, however, individuals with TET3-BEFAHRS have biallelic pathogenic variants, raising the possibility of an autosomal recessive mode of inheritance. However, the family histories of these individuals are consistent with autosomal dominant inheritance; in most cases the heterozygous parents of these probands also had features consistent with TET3-BEFAHRS, although milder than those in their affected children [Beck et al 2020]. In a more recently reported family in which two affected children had biallelic variants inherited in trans, neither parent was reported to be affected; however, it is unclear whether the parents were fully evaluated [Seyama et al 2022].

Risk to Family Members (Autosomal Dominant Inheritance)

Parents of a proband

• Of the 12 probands reported to date with a heterozygous TET3 pathogenic variant, nine probands had TET3-BEFAHRS as the result of a de novo pathogenic variant, and three probands had the disorder as the result of a pathogenic variant inherited from an affected parent [Beck et al 2020, Levy et al 2021a, Seyama et al 2022, Sager et al 2023].
• Six probands from three families reported to date with biallelic TET3 pathogenic variants inherited pathogenic variants from their heterozygous parents [Beck et al 2020, Seyama et al 2022]. In these families, heterozygous parents often had relatively mild features consistent with TET3-BEFAHRS [Beck et al 2020].
• One proband was initially reported to have biallelic variants inherited in trans in TET3, suggestive of autosomal recessive inheritance. However, only one (the maternally inherited variant) exhibited reduced catalytic activity in vitro [Beck et al 2020]. Subsequent DNA methylation profiling confirmed pathogenicity of the maternally inherited variant but not of the paternally inherited variant. This, and the mother's relatively mild phenotype, suggest a monoallelic pathogenic variant and autosomal dominant inheritance with variable expressivity in this family, though we cannot completely rule out some contribution from the paternal variant in the proband [Levy et al 2021a].
• The above observations suggest that TET3-BEFAHRS is an autosomal dominant condition with variable expressivity and hypomorphic alleles that sometimes mimic autosomal recessive inheritance as opposed to true autosomal recessive inheritance. The methylation signature supports this as well.
• If the proband appears to be the only affected family member (i.e., a simplex case), targeted molecular genetic testing for the pathogenic variant(s) identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the proband has a heterozygous pathogenic variant that 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.
• If the proband has biallelic pathogenic variants and a pathogenic variant is detected in only one parent (and parental identity testing has confirmed biological maternity and paternity), it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].

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

• If one parent of the proband has a TET3 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and being affected is 50%.
• If both parents of a proband have a TET3 pathogenic variant, sibs have a 75% chance of inheriting one or two pathogenic variants and being affected and a 25% chance of inheriting neither pathogenic variant.
• If the TET3 pathogenic variant 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 theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the TET3 pathogenic variant(s) but are clinically unaffected, sibs are still presumed to be at increased risk for TET3-BEFAHRS because of the theoretic possibilities of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband

• Unless a proband with a heterozygous TET3 pathogenic variant has children with an individual who also has a TET3 pathogenic variant, the proband's offspring will have a 50% chance of inheriting a TET3 pathogenic variant. Consanguinity increases the likelihood that an affected individual may have a reproductive partner who is heterozygous for a TET3 pathogenic variant.
• Severely affected individuals with biallelic TET3 pathogenic variants are not known to reproduce.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a TET3 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 young adults who have a TET3 pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Once the TET3 pathogenic variant(s) have 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

TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS) is a mendelian disorder of the epigenetic machinery (MDEM) [Fahrner & Bjornsson 2014], also termed chromatinopathy. MDEMs result from germline pathogenic variants in genes encoding components of the epigenetic or chromatin-modifying machinery [Fahrner & Bjornsson 2014]. Chromatin consists of DNA and associated histone proteins, and epigenetics refers to marks on chromatin (DNA or histones) that alter gene expression without changing the DNA sequence. The MDEM genes are divided into groups based on whether they place ("write"), remove ("erase"), or interpret ("read") epigenetic marks or remodel chromatin [Bjornsson 2015, Fahrner & Bjornsson 2019]. TET3-BEFAHRS is a neurodevelopmental disorder of the DNA methylation eraser system. It results from pathogenic variants in TET3, which is a dioxygenase that oxidizes 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and on to additional intermediates (5-formylcytosine and 5-carboxycytosine), which are eventually removed and replaced with unmethylated cytosine, completing the process of active DNA demethylation [Wu & Zhang 2017].

Hypomorphic or loss-of-function pathogenic variants in TET3 reduce the ability of the enzyme to oxidize 5mC to 5hmC in vitro [Beck et al 2020]. Genome-wide DNA methylation profiling of whole blood revealed a distinct and hypermethylated DNA methylation profile (or episignature) in affected individuals compared to controls [Levy et al 2021a]. This supports a hypomorphic/loss-of-function disease mechanism that leads to broad, epigenomic changes with the potential to disrupt gene expression. It is hypothesized that altered expression of key target genes ultimately leads to disease manifestations of TET3-BEFAHRS. Because epigenetic and chromatin marks differ among tissues, however, it remains unclear whether the DNA methylation changes in blood reflect what is happening in disease-relevant tissues like the brain.

Mechanism of disease causation. Loss of function

Author Notes

Jill A Fahrner, MD, PhD, is an Assistant Professor in the Departments of Genetic Medicine and Pediatrics at the Johns Hopkins University School of Medicine. She is a physician-scientist with a long-standing interest in epigenetics, chromatin, and genetic and epigenetic mechanisms of disease. She is Director of the multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins University, where she and her team care for patients with mendelian disorders of the epigenetic machinery / chromatinopathies (including TET3-BEFAHRS), as well as imprinting disorders. The goal of her ongoing laboratory research is to understand disease mechanisms of and develop therapies for mendelian disorders of the epigenetic machinery.

A main focus of Dr Fahrner's research is TET3-BEFAHRS, which she recently delineated as the first neurodevelopmental disorder of the DNA demethylation machinery. She and her team continue to recruit research participants with TET3-BEFAHRS to collect additional information about the phenotype of affected individuals; this will improve understanding of disease manifestations. In particular, Dr Fahrner's team is interested in collecting detailed neuropsychological information; this type of information could serve as an outcome measure in potential future clinical trials. In addition, the Fahrner laboratory has ongoing studies to refine the DNA methylation profile for TET3-BEFAHRS in whole blood, and they are using human cellular models to better understand the molecular aspects of the disease. These studies may help to identify targeted therapies for TET3-BEFAHRS in the future.

Dr Fahrner's web page: www.hopkinsmedicine.org/profiles/details/jill-fahrner

Email Dr Fahrner (ude.imhj@1enrhafj) if you are interested in learning more about research opportunities for TET3-BEFAHRS or in scheduling an appointment with her in the multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins University.

TET3-BEFAHRS family-specific resources may include the Beck-Fahrner Syndrome Foundation (see Resources) or the TET3-BEFAHRS Facebook group.

Acknowledgments

Thank you to the patients and families and to the clinicians and researchers who have contributed to ongoing TET3-BEFAHRS research. Thank you to the Beck-Fahrner Syndrome Foundation for ongoing support. Dr Fahrner acknowledges research support from the National Institutes of Health (NIH) / National Institute for Child Health and Human Development (NICHD; K08HD086250). She has support from the Maryland Stem Cell Research Fund (2022-MSCRFL-5846) and a Johns Hopkins Catalyst Award for her ongoing TET3-BEFAHRS research.

Revision History

• 18 May 2023 (ma) Review posted live
• 12 September 2022 (jf) Original submission

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