The clinical spectrum of Phelan-McDermid syndrome (PMS) is varied, with wide-ranging degrees of intellectual disability, developmental delays, behavioral abnormalities, and medical features. Different types of genetic variation lead to PMS, and differing genotypes (e.g., size of deletion or type of variant) account for some of this variability, with strong associations between genotype and phenotype observed with degree of intellectual disability and presence of specific medical features such as renal abnormalities. To date, no studies have assessed how genotype is associated with the natural history of developmental or behavioral features in PMS over time. Here, we report on longitudinal data in developmental and behavioral domains from 154 individuals with PMS, comparing those with Class 1 (minimal) deletions, Class 2 deletions, and sequence variants, assessing both within-subject (individual change over time) and between-subject (across age) differences. Consistent with previous results, average scores per group differed in most adaptive and developmental domains, with individuals with Class 1 deletions performing best, followed by individuals with Class 2 deletions and sequence variants, who often performed similarly. However, in most domains of adaptive behavior, intellectual functioning, and behavioral features, genetic groups did not differ in their rate of change over time or in differences in scores across ages. Exceptions, notably in expressive language, existed. These results suggest that, although genotype may be related to overall degree of impairment, individuals with PMS, regardless of genotype, tend to have a similar rate of change over time and age in developmental and behavioral domains. A significant caveat is that sequencing is a relatively recent diagnostic approach, which will bias the results.