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Novel variant identified in the TET3 gene: a mother-daughter case that expands the phenotype of TET3-related disorders.

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Mono- and biallelic variants in the TET3 gene are associated with TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS; OMIM #618798), a rare genetic disorder with only 30 individuals from 17 families described to date. This condition is characterized by a wide spectrum of clinical manifestations with variable expressivity, including: neurocognitive differences; autism spectrum and attention deficit hyperactivity disorders; hypotonia; epilepsy; facial dysmorphic features such as long face, tall/broad forehead, protruding ears, epicanthal folds, downslanted palpebral fissures, short nose, and long philtrum; growth abnormalities; ophthalmological abnormalities including chorioretinal and iris coloboma, refractive errors, strabismus, and nystagmus; hearing loss; and psychiatric symptoms.

Case Presentation
Here, we report on a female proband and her mother who were found to harbor a novel variant in the TET3 gene, and expand on the phenotype of TET3-BEFAHRS. At the time of diagnosis, the proband was thirteen years old and was admitted to the hospital for management of her multiple psychiatric concerns, namely: generalized anxiety disorder, major depressive disorder, psychogenic seizures, cyclic vomiting syndrome, self-injury disorder, and suicide behavior disorder. In addition, she had a diagnosis of intellectual disability with documented cognitive decline over the years and suspected hearing loss. Her mother was forty-four years old at the time of diagnosis and her phenotype was characterized by generalized anxiety disorder, cyclic vomiting syndrome, psychogenic seizures, severe migraines with reported episodes of stroke-like events, and vision loss.

Diagnostic Workup
Genetic testing via duo whole exome sequencing with mitochondrial DNA analysis identified a heterozygous maternally inherited likely pathogenic variant in the TET3 gene (c.7 C>T; p.Gln3*). This variant had not been published in the medical literature and was not present in genomAD. Additionally, the exome identified: a heterozygous maternally inherited likely pathogenic variant in the PNPLA6 gene (c.3151 C>T; p.Arg1051*), associated with autosomal recessive PNPLA6-related disorders; and a variant of uncertain significance in the candidate regulator of proneural genes RFX4 (c.2192 C>T; p.Thr731Ile), predicted not to alter protein structure and function by in silico analysis, and for which inheritance could not be determined.

Discussion
The proband’s phenotype overlapped with several of the TET3-BEFAHRS features described in the literature, including neurocognitive differences, gastrointestinal motility disorders, feeding difficulties, dysmorphic features (large and protruding ears), scoliosis, and psychiatric symptoms such as psychosis and difficulty with social interactions. In addition, she had a history of psychogenic seizures, spinal canal stenosis, cyclical vomiting syndrome, migraines, and insomnia that have not been previously reported in affected individuals. Her mother presented non-specific white matter changes on brain MRI, EEG abnormalities, dysmorphic features (large ears), feeding difficulties, short-term memory impairment, and attention deficit hyperactivity disorder, that have been previously described in individuals with TET3-BEFAHRS. In addition, she exhibited peripheral field vision loss, thyroid dysfunction, distal neuropathy, and psychogenic seizures that have not previously been reported.

The proband and her mother’s phenotypes and their genotype were consistent with the clinical features and loss-of-function disease mechanism of TET3-BEFAHRS. For these reasons, they were ultimately diagnosed with TET3-BEFAHRS.

Conclusion
Psychiatric disorders are often labeled as multifactorial, and a possible underlying genetic cause is frequently overlooked. Determining a genetic etiology for individuals with a strong and preponderant history of psychiatric symptoms, like the case described here, can improve care and management, individual comprehension of a complex phenotype, empower individuals, and advance the destigmatization of mental illness in the healthcare system. This case expands on the genotype and phenotype of TET3-BEFAHRS, and serves as a precedent denoting the importance of genetic evaluation for individuals with complex psychiatric phenotypes.

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