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Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation


Hildebrand, MS; Jackson, VE; Scerri, TS; Van Reyk, O; Coleman, M; Braden, RO; Turner, S; Rigbye, KA; 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; Liegeois, FJ; Connelly, A; Gecz, J; Fisher, SE; Amor, DJ; Scheffer, IE; Bahlo, M; Morgan, AT
2020-04-28
Neurology
Journal epub ahead of print
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.
American Academy of Neurology
Population Health and Immunity
10.1212/WNL.0000000000009441
32345733
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Creation Date 2020-05-04 10:30:33 Last Modified 2020-05-04 11:52:58