Childhood apraxia of speech (CAS), a severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors significantly contribute to CAS etiology. This study aimed to identify molecular causation in 70 unrelated probands with CAS using trio genome sequencing and bioinformatic analysis. High-confidence variants were identified in 18/70 (26%) probands, nearly doubling the number of candidate genes for CAS. Three variants confirmed the roles of SETBP1, SETD1A, and DDX3X, while 15 occurred in novel genes. The findings highlight the roles of chromatin organization and gene regulation in CAS and confirm co-expression of CAS-related genes during brain development. This diagnostic yield is comparable to other neurodevelopmental disorders. The study underscores the overlap between genes conferring risk for various neurodevelopmental disorders.

Antony Kaspi, Michael S. Hildebrand, Victoria E. Jackson, Ruth Braden, Olivia van Reyk, Tegan Howell, Simone Debono, Mariana Lauretta, Lottie Morison, Matthew J. Coleman, Richard Webster, David Coman, Himanshu Goel, Mathew Wallis, Gabriel Dabscheck, Lilian Downie, Emma K. Baker, Bronwyn Parry-Fielder, Kirrie Ballard, Eva Harrold, Shaun Ziegenfusz, Mark F. Bennett, Erandee Robertson, Longfei Wang, Amber Boys, Simon E. Fisher, David J. Amor, Ingrid E. Scheffer, Melanie Bahlo, Angela T. Morgan