Structural variation in families with speech and language disorder provides a deeper understanding of the genetic basis for naturally acquired speech

Abstract

Childhood apraxia of speech (CAS) is a severe and rare form of speech sound disorder (SSD) with an estimated prevalence of 0.01-2%. CAS typically occurs in isolation (sporadic), but may segregate in families with broader speech and language deficits. We hypothesized that disruptive genetic changes may be involved in the etiology of CAS, and were resolvable by examination of whole genome sequence. We sequenced 27 families with a CAS child within the Cleveland Family Speech and Reading Study, examining 101 individuals in all. CAS subjects displayed errors on single word articulation (75%), multisyllabic real word repetition (93%), multisyllabic non-word repetition (82%), and oral motor function (82%); many also exhibited problems with fine and gross motor skills. We identified 17 genomic regions including 19 unique structural variants (SVs) present in children with CAS. Three variants were shared across families, but the rest were unique; some events were de novo. In four families, siblings with milder phenotypes co-inherited the same SVs, suggesting that some SVs display variable expressivity. In an independent sample, we replicated eight SVs using microarray technology and found that many of these SVs were present in children with milder forms of SSD. Bioinformatic examination of the deletions/duplications identified four SVs with substantial functional consequences (cytobands 2q24.3, 6p12.3-6p12.2, 11q23.2-11q23.3, and 16p11.2). Of these, the 16p11.2 deletion is the most well-established variant that causes a broad array of neurological features. These discoveries show that SVs are a heterogeneous, but prevalent cause of CAS, identifiable by standard genetic testing.