Neuropsychiatric spectrum disorders associated with TANC2 mutations: a familial case series

Introduction

Mutations in TANC2, a protein widely expressed in the developing brain, are associated with pediatric neurodevelopmental disorders—such as autism, intellectual disability, and epilepsy—as well as complex psychiatric dysfunctions in adult carriers (1,2). This study aims to delineate the highly variable clinical manifestations of a single TANC2 variant by presenting a unique familial case series involving dizygotic twin brothers and their father. By illustrating a phenotypic spectrum that ranges from severe early-onset autism and epilepsy to treatment-resistant adolescent psychosis and adult anger control issues, we aim to contribute to the current literature by documenting how the identical genetic mutation can manifest with strikingly distinct neuropsychiatric symptoms within the same family.

Methods

In this study, the clinical follow-up and treatment records of the cases were reviewed retrospectively. The current and past psychiatric diagnoses of the patients were evaluated according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). During clinical evaluation, the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) was administered to determine the cognitive profiles of the patients; additionally, to elucidate etiology, whole-exome sequencing (WES) with copy number variation (CNV) analysis was performed on the cases.

Results

The first twin is being followed up with diagnoses of autism spectrum disorder, intellectual disability, and epilepsy. Medical history revealed that he presented to a child psychiatry clinic at the age of 3, where he was diagnosed with autism and commenced special education. Absence seizures emerged at age 6, prompting the initiation of anticonvulsant therapy, which was discontinued after a 5-year seizure-free period. Two years post-cessation, generalized tonic seizures commenced, which were ultimately controlled with a triple anticonvulsant regimen. Despite ongoing child psychiatry follow-ups and the use of antipsychotic medication, his aggression, alongside self-injurious and hetero-aggressive behaviors, recur periodically.

It was noted that the second twin had exhibited mild autistic symptoms since childhood; his peer relationships were consistently limited, he experienced discomfort in crowded environments, and he faced academic difficulties. At the age of 16, he began experiencing hallucinations and delusions, which were clinically evaluated as a psychotic episode.

The father was reported to have anger management issues, for which he was prescribed antidepressant and antipsychotic medications.

WES with CNV analysis, performed to evaluate the family for behavioral disturbances, intellectual disability, and epileptic seizures, identified a heterozygous variant in the TANC2 gene [NM_001394998.1: c.1202C>G p.(Pro401Arg)] in both the twin brothers and their father.

Conclusions

This case series highlights the broad phenotypic heterogeneity of a rare TANC2 mutation in one family. The mutation manifested as a classic neurodevelopmental syndrome in the first twin, whereas his dizygotic co-twin developed adolescent-onset psychosis. The father presented with isolated anger management issues, indicating adult carriers may exhibit purely psychiatric symptoms. Furthermore, the pharmacological resistance observed in the twins suggests that psychiatric syndromes with underlying genetic etiologies may be more refractory than primary psychiatric disorders. Ultimately, this report enriches the literature by highlighting how an identical genetic mutation can produce strikingly distinct neuropsychiatric profiles within the same family.

References

1-Suzuki, T., Li, W., Zhang, J. P., Tian, Q. B., Sakagami, H., Usada, N., … & Endo, S. (2005). A novel scaffold protein, TANC, possibly a rat homolog of Drosophila rolling pebbles (rols), forms a multiprotein complex with various postsynaptic density proteins. European Journal of Neuroscience, 21(2), 339-350. 2-Guo, H., Bettella, E., Marcogliese, P. C., Zhao, R., Andrews, J. C., Nowakowski, T. J., … & Eichler, E. E. (2019). Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders. Nature communications, 10(1), 4679.