Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation

Objective: Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past two decades, the etiology of most children with speech disorder remains unexplained. Here we searched for a genetic etiology in children with severe speech disorder, specifically childhood apraxia of speech (CAS).

Methods: Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS, as well as other medical or neurodevelopmental co-morbidities. Gene co-expression and gene set enrichment analyses analyses were conducted on high confidence gene candidates.

Results: 34 probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n=10, CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1, 5q14.3q21.1 locus) variants in novel genes or loci f...