This study had the following aims: (a) to ascertain HRQoL outcomes using valid and reliable measures during COVID-19 for children diagnosed with three genetic disorders which strongly predispose a child to syndromic ASD: Phelan–McDermid syndrome (PMD), Rett Syndrome (RTT) and SYNGAP1-related intellectual disability (SYNGAP1-ID) and (b) to determine the relationship between the pandemic-induced lifestyle changes, HRQoL, behavior problems and the mechanisms around which environmental changes can impact behaviors. This evidence concerns the gene SYNGAP1 and atypical Rett syndrome.