Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation. (19th May 2020)

• Record Type: Journal Article
• Authors: Hildebrand, Michael S.; Jackson, Victoria E.; Scerri, Thomas S.; Van Reyk, Olivia; Coleman, Matthew; Braden, Ruth O.; Turner, Samantha; Rigbye, Kristin A.; Boys, Amber; Barton, Sarah; Webster, Richard; Fahey, Michael; Saunders, Kerryn; Parry-Fielder, Bronwyn; Paxton, Georgia; Hayman, Michael; Coman, David; Goel, Himanshu; Baxter, Anne; Ma, Alan; Davis, Noni; Reilly, Sheena; Delatycki, Martin; Liégeois, Frederique J.; Connelly, Alan; Gecz, Jozef; Fisher, Simon E.; Amor, David J.; Scheffer, Ingrid E.; Bahlo, Melanie; Morgan, Angela T.;
• Is Part Of: Neurology. Volume 94:Number 20(2020)
• Publication Date: 2020-05-19
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000009441
• Languages: English
• ISSNs: 0028-3878

Abstract

Abstract : Objective: 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). Methods: 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. Results: 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. Conclusion: 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.