TET-Related Beck-Fahrner Syndrome

1. TET3-Related
Beck-Fahrner
Syndrome
Epigenetics Course presentation
Presented by: Khadija Tariq

2. Introduction
• TET3-related Beck-Fahrner syndrome (TET3-
BEFAHRS) is a condition within the spectrum of
mendelian disorders of the epigenetic
machinery (MDEMs) or chromatinopathies.
• Symptoms: intellectual disability,
developmental delay, hypotonia, speech delay,
some may have movement disorders and even
epilepsy, strabismus and refractive error affect
the vision, macrocephaly and other congenital
abnormalities.
• Neuro-behavorial symptoms: autism, anxiety
and attention-deficit/hyperactivity disorder.

3. Introduction
• Diagnosis: pathogenic variant in TET3
identified by molecular genetic testing and
confirmed by DNA methylation profiling
• Genotype-Phenotype correlation: No
genotype-phenotype correlations have been
confirmed.
• Prevalence: The prevalence of TET3-
BEFAHRS is unknown. To date, 28
individuals from 16 families have been
reported with pathogenic variants in TET3

4. Molecular Genetics

5. Molecular Pathogenesis
• MDEMs result from germline pathogenic variants in genes
encoding components of the epigenetic or chromatin-
modifying machinery.
• 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

6. Contd..
• Hypomorphic or loss-of-function pathogenic variants in TET3 reduce
the ability of the enzyme to oxidize 5mC to 5hmC in vitro.
• Hypomorphic or loss-of-function pathogenic variants in TET3 reduce
the ability of the enzyme to oxidize 5mC to 5hmC in vitro.
• Genome-wide DNA methylation profiling of whole blood revealed a
distinct and hypermethylated DNA methylation profile (or
episignature) in affected individuals compared to controls.

7. Genetic
Counselling
and
Management
• Mode of inheritance: Autosomal Dominant
• There is no proper cure for the disease
however strategies are applied to manage
the symptoms, which may include ASM for
epilepsy, rehab for body tone and physical
abnormalities, Gastrostomy tube
placement for feeding problems and
Referral to developmental pediatrician,
neuropsychologist, or psychiatrist including
other management strategies for rest of
the symptoms.

8. Reference
• Fahrner, J. A. (2023). "TET3-Related Beck-Fahrner Syndrome."