De novo <i>TANC2</i> stop‐loss variant associated with developmental impairment and drug‐resistant epilepsy

TANC2 (OMIM 615047) encodes tetratricopeptide repeat-, ankyrin repeat-, and coiled-coil-containing protein 2, a postsynaptic scaffolding protein involved in regulating dendritic spine density and synaptic function.1, 2 Heterozygous pathogenic TANC2 variants are implicated in a range of neurodevelopmental and neuropsychiatric disorders; affected individuals may have any of autism spectrum disorder (ASD), intellectual disability (ID), global developmental impairment, epilepsy, and/or psychiatric disorders.3 Most reported TANC2 pathogenic variants occur de novo and are predicted to result in loss of function, such as nonsense, frameshift, or splice-site variants. While seizures are reported in 55% of people with TANC2-related disorders, the associated epilepsy phenotype is not well understood.3 Here, we report the first patient with a TANC2 stop-loss variant, provide details on their epilepsy presentation, and review previously published patients with TANC2 pathogenic variants and epilepsy. A 12-year-old male was diagnosed with epilepsy at age 3 years, experiencing both absence and generalized tonic–clonic (GTC) seizures. His epilepsy is drug-resistant, with seizures not completely controlled for prolonged periods despite trials of valproic acid, lamotrigine, levetiracetam, ethosuximide, and clobazam; he currently takes brivaracetam, lacosamide, and topiramate, and has absence seizures lasting about 1 min every 2–3 months, and GTC seizures lasting up to 5 min approximately twice per year. From a developmental perspective, he had mild global developmental delay. He walked at 18–19 months and can now run and jump but is clumsier than age-matched peers. His first word was at age of 2.5 years, but he can now speak in generally well-formed sentences. A neuropsychology and behavioral assessment at the age of 9 years diagnosed him with level 3 ASD and suspected mild ID. His psychiatrist also diagnosed generalized anxiety disorder, obsessive compulsive disorder, and attention deficit hyperactivity disorder; he was treated with aripiprazole, fluoxetine, and methylphenidate. There was no known family history of seizures, developmental impairment, or psychiatric disorders. Parents are both from Quebec, Canada, of Greek ancestry, with no known consanguinity. On EEG, he has occasional interictal generalized spike-wave and polyspike-wave discharges (Figure 1A). With absence seizures, 3 Hz generalized spike–wave discharges were seen (Figure 1B). Brain MRI at age 5 years was normal. Initial genetic testing, including chromosomal microarray, fragile X testing, Epilepsy Comprehensive gene panel (Fulgent; done in 2018) and an Autism/ID Xpanded gene panel (GeneDx; done in 2021), was nondiagnostic, though he was found to carry a maternally-inherited .846 Mb deletion at 5q35.1 classified as uncertain significance (arr[GRCh37]5q35.1(169518187-170364242)x1). In 2025, a Blueprint Developmental Disorders gene panel trio identified a de novo frameshift stop-loss variant in TANC2 (NM_025185.4; c.5971T>C; p.(*1991Glnext*29)), which abolishes the canonical stop codon and is predicted to result in translational extension of the protein by 29 amino acids. This variant is absent in the Genome Aggregation Database (gnomAD).4 By American College of Medical Genetics and Genomics (ACMG) criteria,5 the variant is classified as “likely pathogenic”—de novo (PS2), absent from control databases (PM2), and protein length changes due to stop-loss variant (PM4). This patient's presentation is generally consistent with previous reports of TANC2-related disorders; however, there are also unique features that expand the phenotypic spectrum. Of the 15 patients previously published with details on epilepsy presentation, all but three have had either developmental and epileptic encephalopathy or epilepsy with a concurrent neurodevelopmental disorder.3, 6-8 Seizure onset has typically been in early childhood, with the reported seizure types including GTC (10), myoclonic (6), focal onset (4), absence (3), tonic (2), atonic (2), myoclonic-atonic (1), epileptic spasms (1), and unspecified head drops (1). Our patient's presentation is consistent with genetic generalized epilepsy with concurrent neurodevelopmental disorders, but he is the first to be reported with only GTC and typical absence seizures. From a molecular perspective, this is the first report of a stop-loss TANC2 variant causing disease. Stop-loss variants are relatively uncommon, accounting for <.2% of unique genetic variants in one study.9 The loss of the stop codon can have deleterious effects by altering protein stability, disrupting folding, or triggering mRNA surveillance pathways. Further research is necessary to evaluate the broader clinical significance of stop-loss variants in people with epilepsy, particularly as the molecular impacts are likely to be gene-specific. MAH was involved in data collection and wrote the initial manuscript draft. KAM conceived the study, was involved in data collection and figure preparation, and reviewed and revised the manuscript. The authors thank the patient and their family. This study was not supported by specific funding. MAH has no conflicts of interest. KAM has served as a paid consultant for Jazz Pharmaceuticals, UCB, and Pendopharm. Written consent was obtained from the patient's family for publication of non-identifying clinical information. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. What percentage of people with TANC2-related disorders have seizures? What are the two most commonly reported seizure types in TANC2-related disorders? Answers may be found in the Supporting Information.