DOI: 10.5061/dryad.zkh189363
title: Data from: Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation

description: 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 for CAS.
 Testing of parental DNA was available for nine 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 co-expressed in the developing
 human brain. Conclusion: We identify the likely genetic aetiology 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.
description: Supplementary Material for
 <b>Severe childhood speech disorder: gene discovery highlights
 transcriptional dysregulation.</b>   <em><strong>1.
 Contents of
 "Supplemental_Material_Neurology_2019_010520.pdf":</strong></em> SUPPLEMENTARY MATERIALS AND METHODS Replication of Gene co-expression analysis   SUPPLEMENTARY FIGURES Figure e-1 Evidence of co-expression of ten high confidence genes Figure e-2: Network resulting from Brain co-expression analysis for the combined set of the ten newly identified candidate CAS genes and eight genes previously shown to carry pathogenic variants in an independent speech apraxia cohort (Eising et al.) Figure e-3 Evidence of co-expression of ten high confidence genes, and eight Eising candidates Figure e-4: GO Pathways for which there is significant over-representation of our candidate genes Figure e-5: Replication results for the brain co-expression analysis   SUPPLEMENTARY TABLES Table e-1a - Proband language, literacy & cognitive assessments Table e-1b - Assessment battery used with adult family members to determine affected status Table e-2 – List of known pathogenic loci, examined in the STR Analysis Table e-3 – Summary of samples from the BrainSpan dataset, included in the discovery gene co-expression analyses Table e-4 - Summary of samples from the Colantuoni and Miller datasets, included in the replication gene co-expression analyses Table e-5 – Damaging variants in probands without an identified pathogenic (deemed causal) variant Table e-6: Gene set Enrichment analysis   SUPPLEMENTARY REFERENCES   <em><strong>2. "Table_</strong></em>e-<em><strong>5_Neurology_2019_010520.csv" </strong></em> This is a comma separated text file, containing the results shown in e-5 of "Supplemental_Material_Neurology_2019_010520.pdf": Damaging variants in probands without an identified pathogenic (deemed causal) variant.