Hildebrand, M. S., Jackson, V. E., Scerri, T. S., Van Reyk, O., Coleman, M., Braden, R., Turner, S., Rigbye, K. A., Boys, A., Barton, S., Webster, R., Fahey, M., Saunders, K., Parry-Fielder, B., Paxton, G., Hayman, M., Coman, D., Goel, H., Baxter, A., Ma, A. and 11 moreHildebrand, M. S., Jackson, V. E., Scerri, T. S., Van Reyk, O., Coleman, M., Braden, R., Turner, S., Rigbye, K. A., Boys, A., Barton, S., Webster, R., Fahey, M., Saunders, K., Parry-Fielder, B., Paxton, G., Hayman, M., Coman, D., Goel, H., Baxter, A., Ma, A., Davis, N., Reilly, S., Delatycki, M., Liégeois, F. J., Connelly, A., Gecz, J., Fisher, S. E., Amor, D. J., Scheffer, I. E., Bahlo, M., & Morgan, A. T.
Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation
Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation. Neurology. Advance online publication
Determining the genetic basis of speech disorders provides insight into the neurobiology of
human communication. Despite intensive investigation over the past 2 decades, the etiology of
most speech disorders in children remains unexplained. To test the hypothesis that speech
disorders have a genetic etiology, we performed genetic analysis of children with severe speech
disorder, specifically childhood apraxia of speech (CAS).
Precise phenotyping together with research genome or exome analysis were performed on
children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment
analyses were conducted on high-confidence gene candidates.
Thirty-four 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 for CAS. Testing of parental DNA was available for 9 probands
and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for
regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated
genes were highly coexpressed in the developing human brain.
We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first
time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous.
Highly penetrant variants implicate shared pathways in broad transcriptional
regulation, highlighting the key role of transcriptional regulation in normal speech development.
CAS is a distinctive, socially debilitating clinical disorder, and understanding its
molecular basis is the first step towards identifying precision medicine approaches.