Milestone Development in Genetic Conditions from SFARI Registries

Background Several recent initiatives have sought to better understand characteristic behaviors of rare genetic conditions associated with autism spectrum disorder (ASD). The onset of developmentally expected skills, such as walking and talking, serve as readily quantifiable aspects of the behavioral phenotype. The goals of this study were to describe attainment of major motor and language milestones in genetic conditions implicated in the etiology of ASD and other neurodevelopmental disorders and to compare those phenotypes to idiopathic ASD. Methods Participants ages 3 years and older were drawn from two Simons Foundation Autism Research Initiative-funded registries with consistent phenotyping protocols. Inclusion criteria consisted of a confirmed genetic diagnosis for one of 16 specific genetic conditions (Simons Searchlight), and absence of pathogenic genetic findings in idiopathic ASD controls (SPARK). Parent-reported age of acquisition of three motor and two language milestones was described and quantified as on-time or delayed relative to normative expectations. Results Delay was more common among participants with rare genetic conditions than idiopathic ASD for all milestones. Compared to the idiopathic ASD group, the median odds of delay among the genetic groups were 8.3 times (IQR 5.8-16.3) higher for sitting, 12.4 times (IQR 5.3-19.5) higher for crawling, 26.8 times (IQR 7.7-41.1) higher for walking, 2.7 times (IQR 1.7-5.5) higher for single words, and 5.7 times (IQR 2.8-18.3) higher for combined words. Conclusion Delays in major developmental milestones, particularly in motor skills, may be among the earliest clues that developmental processes may be differentially affected in specific genetically defined conditions versus a behaviorally defined disorder such as idiopathic ASD.