Bulk RNA-seq of brain samples from fetuses with Tay-Sachs Disease

Treatment of monogenic disorders has historically relied on symptomatic management with limited ability to target primary molecular deficits. However, recent advances in gene therapy and related technologies aim to correct these underlying deficiencies, raising the possibility of disease management or even prevention for diseases that can be treated pre-symptomatically. Tay–Sachs disease (TSD) would be one such candidate, however very little is known about the presymptomatic stage of TSD. To better understand the effects of TSD on brain development, we evaluated the transcriptomes of human fetal brain samples with biallelic pathogenic variants in HEXA. We identified dramatic changes in the transcriptome, suggesting a perturbation of normal development. We also observed a shift in the expression of the sphingolipid metabolic pathway away from production of the HEXA substrate, GM2 ganglioside, presumptively to compensate for dysfunction of the enzyme. However, we do not observe transcriptomic signatures of end-stage disease, suggesting that developmental perturbations precede neurodegeneration. To our knowledge, this is the first report of the relationship between fetal disease pathology in juvenile onset TSD and the analysis of gene expression in fetal TSD tissues. This study highlights the need to better understand the “pre-symptomatic” stage of disease to set realistic expectations for patients receiving early therapeutic intervention. To better understand the effects of Tay-Sachs disease on brain development, we evaluated the transcriptomes of human fetal brain samples with biallelic pathogenic variants in HEXA. This study is, to our knowledge, the first analysis of fetal tissues with juvenile-onset Tay-Sachs and the first investigation of gene expression in fetal Tay-Sachs tissues.