Importance of copy number variants in childhood apraxia of speech and other speech sound disorders

Childhood apraxia of speech (CAS) is a severe and rare form of speech sound disorder (SSD). CAS is typically sporadic, but may segregate in families with broader speech and language deficits. We hypothesize that genetic changes may be involved in the etiology of CAS. We conduct whole-genome sequencing in 27 families with CAS, 101 individuals in all. We identify 17 genomic regions including 19 unique copy number variants (CNVs). Three variants are shared across families, but the rest are unique; three events are de novo. In four families, siblings with milder phenotypes co-inherited the same CNVs, demonstrating variable expressivity. We independently validate eight CNVs using microarray technology and find many of these CNVs are present in children with milder forms of SSD. Bioinformatic investigation reveal four CNVs with substantial functional consequences (cytobands 2q24.3, 6p12.3-6p12.2, 11q23.2-11q23.3, and 16p11.2). These discoveries show that CNVs are a heterogeneous, but prevalent, cause of CAS.