Ultra-rare biallelic THAP12 variants cause loss of function and underlie severe epileptic encephalopathy

Developmental and epileptic encephalopathies (DEEs) are a group of severe childhood-onset neurological disorders, often caused by rare genetic variants affecting brain development and excitability. Despite advances in genomic sequencing, a substantial proportion of DEE cases remain unsolved. Here, we identify THAP12 as a novel disease-causing gene associated with autosomal recessive DEE. Whole-genome sequencing in two siblings who presented with infantile spasms and progressed to Lennox-Gastaut syndrome revealed compound heterozygous variants in THAP12, leading to a reduction in protein abundance, consistent with a loss-of-function mechanism. To confirm this mechanism in vivo, we generated mouse models carrying either of the two patient-specific alleles. Both homozygous and compound heterozygous animals exhibited embryonic lethality, confirming the essential and dosage-sensitive role of Thap12 during early development. Zebrafish loss-of-function models recapitulated major aspects of the human phenotype, including microcephaly, brain hypoplasia, abnormal neuronal activity, and increased seizure sensitivity. Transcriptomic profiling of larval zebrafish brains revealed dysregulation of cell cycle and apoptotic pathways, in line with increased cell death and reduced proliferation observed in mutant embryos. Notably, overexpression of wild-type human THAP12 mRNA rescued these in vivo phenotypes, while the patient-derived variants allele failed to do so. Altogether, our findings demonstrate that THAP12 is essential for early brain development and neuronal survival, and that biallelic loss-of-function variants in this gene underlie a previously unrecognized etiology of autosomal recessive DEE. These results provide a mechanistic framework linking, for the first time, THAP12 dysfunction to neurodevelopmental pathology and open new avenues for diagnosis in undiagnosed DEE cases.