The WES analysis also led to valuable insights into the potential disease-modifying influence of additional genetic variations.29 In F.4 family with HEXB +SH3TC2 variants, the reduction of SH3TC2 levels may have modified the presentation of Sandhoff disease and exacerbated the patient’s neuropathy.30 When applicable and feasible, we used blood and tissue samples from patients to validate the biological consequence of the candidate pathogenic variant. Here, SH3TC2 is linked to Sandhoff disease.