P311: Use of a DNA methylation signature for the diagnosis of TET3-related Beck-Fahrner syndrome and expansion of its related phenotype

Chromatin modifying disorders are genetic conditions caused by germline pathogenic variants in genes encoding the epigenetic machinery. Epigenetic machinery regulates gene expression through DNA methylation, chromatin remodeling, and post-translational modifications of histone tails. TET3 belongs to the ten-eleven translocase (TET) family of methylcytosine dioxygenase enzymes, which play a key role in initiating DNA demethylation. TET3 deficiency, or TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS), is an autosomal dominant condition characterized by developmental delay along with neurological, growth, ophthalmologic or musculoskeletal manifestations. Recently, a genome-wide DNA methylation signature, or episignature, was developed for TET3-BEFAHRS capable of distinguishing between affected and unaffected individuals. Epigenetic testing has been proposed as a powerful functional test for the interpretation of variants of uncertain significance (VUS) in epigenetic machinery genes. Herein, we report an individual identified with TET3-BEFAHRS where both genetic and epigenetic assessments were used to establish a diagnosis. We also expand the phenotype of TET3-BEFAHRS to include bilateral chorioretinal and right iris colobomata. A 5-year-old male was seen in the genetics clinic for evaluation of global developmental delay and dysmorphic features. He was born at term via an uncomplicated spontaneous vaginal delivery to a 25-year-old primigravida female. The pregnancy was uneventful, with no known teratogenic exposures. At 4 months of age, he was diagnosed with bilateral chorioretinal colobomata and a right iris coloboma, with horizontal nystagmus. He was also found to have right anisometropic amblyopia at 3.5 years of age. The patient was diagnosed with global developmental delay, with significant delays in expressive language and social skills. At 3 years 10 months, he was able to babble, say “mama” and “baba,” point to objects of interest, and understand single step commands. He smiled and made eye contact but was not yet playing with other children. At 5 years of age, he was able to recognize animals and some letters. He had sensory issues with food and was diagnosed with autism spectrum disorder. The patient’s mother, father, and maternal grandmother had variable levels of intellectual disability with no diagnoses. Brain magnetic resonance imaging (MRI) was pursued following an episode of decreased level of consciousness at 4 years 9 months of age, revealing poor organization of the cerebellar folia in the posterior vermis. On examination at 5 years 4 months of age, his weight was 16.9 kg (17th percentile) and height was 107 cm (13th percentile). He had a broad forehead, high anterior hairline, downslanting palpebral fissures, triangular facies, prominent nose bridge, slightly broad nasal tip, and low-set left ear. Postnatal chromosomal microarray revealed a 1q25.2 chromosomal microduplication of uncertain clinical significance spanning 538 Kb, not suspected to be contributory to the phenotype. Trio exome sequencing (ES) revealed a paternally-inherited heterozygous TET3 variant, c.5020G>A (p.Ala1674Thr). While the initial analysis of the ES data classified the variant as a VUS, epigenetic testing through the national EpiSign-CAN study found the patient to be positive for the previously established TET3-BEFAHRS episignature with moderate confidence. As episignature findings are considered functional evidence of pathogenicity (ACMG/AMP: PS3), the variant was reclassified as likely pathogenic thus supporting a diagnosis of TET3-BEFAHRS upon correlation with clinical features. We report a novel TET3 variant with pathogenicity established through episignature analysis, as well as the first individual with TET3-BEFAHRS presenting with chorioretinal and iris colobomata. While ophthalmic manifestations such as refractive errors, strabismus, nystagmus, lacrimal duct stenosis, and microphthalmia have been previously described, this patient is the first reported individual with TET3-BEFAHRS to exhibit colobomata. Our case suggests a broader ophthalmic phenotype to TET3-BEFAHRS and demonstrates the utility of episignatures in the reinterpretation of VUS to establish a clinical diagnosis.

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