Ryan N. Doan, Boston Children's Hospital, Boston, MA, United States; Paulina Gonzalez Tovar, Boston Children's Hospital, Boston, MA, United States; Julieta Bonacina, Boston Children's Hospital, Boston, MA, United States; William Barbaresi, Boston Children’s Hospital, Boston, MA, United States; Anne Arnett, Boston Children's Hospital, Boston, MA, United States
Assistant Professor of Pediatrics Boston Children's Hospital Boston, Massachusetts, United States
Background: Despite high heritability (75%), the genetic basis of attention-deficit/hyperactivity disorder (ADHD) remains complex. While common polygenic risk variants explain only 28% of phenotypic variance, rare monogenic variants likely play an important role in ADHD. Objective: This study investigated the role of rare genetic variants in youth with ADHD who had comprehensive diagnostic information and assessment of family members. Design/Methods: We assessed the contribution of de novo and inherited rare genetic variants through exome sequencing in an expanded sample of families with pediatric onset of primary ADHD (i.e., individuals without comorbid autism spectrum disorder (ASD), intellectual disability (ID), or other etiological risk, such as fetal alcohol exposure) (n=123). Families were enrolled and genomic data were collected from the Developmental Medicine Center at Boston Children’s Hospital from 2019 to 2023. Diagnoses were made via comprehensive diagnostic assessments including multi-informant report, behavioral observations, and neuropsychological testing for accurate variant interpretation. Family pedigrees, including ADHD and psychiatric histories, were obtained through caregiver report. Results: As in our previous publication, 50% (61/123) of families harbored a likely genetic cause (22% likely pathogenic, 28% VUS), with enrichment for de novo variants in simplex families (OR=13.1, p=3.7x10-6) and rare inherited variants in multiplex families (OR=1.12, p=0.012). Pathway analyses confirmed significant enrichment for chromatin-modifying enzymes (p=2.16x10-11), with multiple variants detected in DIP2C [n=2], DOT1L [2], EP400 [4], KMT2B [3], and SETD1B [2]. Functional analyses revealed distinct methylation patterns in DIP2C and SETD1B among cases versus controls.
Conclusion(s): This study provides additional evidence for significant contribution of rare variants to the etiology of pediatric ADHD in up to 50% of ADHD cases and indicates a causal role of chromatin modifying pathways.
