TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study

Purpose to perform comprehensive genotyping ofTSC1andTSC2in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. methods Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection inTSC1/TSC2. results pathogenic variants inTSC1orTSC2were identified in 93 of 94 (99%) subjects, with 23 inTSC1and 70 inTSC2. Nine (10%) subjects had mosaicism. eight of 24 clinical features assessed at age 2 years were significantly less frequent in those withTSC1versusTSC2variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume forTSC1versusTSC2. conclusion TSC2pathogenic variants are associated with a more severe clinical phenotype than mosaicTSC2orTSC1variants in TSC infants. early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.