Identifying Candidate Genes for Neurodevelopmental Disorders Through Convergent Rare-Variant Analysis

Neurodevelopmental disorders (NDDs) arise from atypical brain development and encompass a broad spectrum of conditions and phenotypes, including autism spectrum disorder (ASD), intellectual disability, attention-deficit/hyperactivity disorder, and language and reading disorders. These conditions are highly prevalent and strongly heritable, establishing the genome as a central focus for understanding their etiology. Two defining genetic features of NDDs, heterogeneity and comorbidity, account for much of the difficulty in elucidating their underlying causes. This dissertation addresses that problem by shifting the analytical focus from broad diagnostic categories to specific, measurable phenotypes that recur within and across NDDs. The phenotypes examined here fall into two categories: abnormal head circumference and communication impairment. The central hypothesis of this work is that studying these specific, shared phenotypes leads to the identification of the genetic mechanisms that contribute to broader, more complex NDDs. To this end, this dissertation are structured across three aims to address these core research objectives. Across all three aims, the central research objective was to identify candidate genes underlying specific neurodevelopmental phenotypes, such as macrocephaly, microcephaly, and language impairment. Several promising genes with strong biological relevance were identified across these phenotypes, such as USP34, GIGYF2, FRAT2, KMT2C, SCAPER, and XYLT1. Additionally, several promising pathways were identified for their role in abnormal neurodevelopmental processes, such as the Wnt signaling pathway. Collectively, the work of this dissertation contributes both a validated approach for gene discovery in complex disorders and a set of high-confidence candidate genes and pathways that advance the understanding of genetic mechanisms underlying NDDs.