Genetic aetiologies for childhood speech disorder: Novel pathways co-expressed during brain development

Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1, SETD1A and DDX3X, thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected individuals are poised for precision medicine trials

Towards the identification of a genetic basis for Landau-Kleffner syndrome.

OBJECTIVE: To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases. METHODS: We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment. RESULTS: A variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2. SIGNIFICANCE: A single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here

Dorsal language stream anomalies in an inherited speech disorder

Speech articulation disorders are highly prevalent in the preschool years, but frequently resolve. The neurobiological basis of the most persistent and severe form, apraxia of speech, remains elusive. Current neuroanatomical models of speech processing in adults propose two parallel streams. The dorsal stream is involved in sound to motor speech transformations, while the ventral stream supports sound/letter to meaning. Data-driven theories on the role of these streams during atypical speech and language development are lacking. Here we provide comprehensive behavioural and neuroimaging data on a large novel family where one parent and eleven children presented with features of childhood apraxia of speech (the same speech disorder associated with FOXP2 variants). The genetic cause of the disorder in this family remains to be identified. Importantly, in this family the speech disorder is not systematically associated with language or literacy impairment. Brain MRI scanning in seven children revealed large grey matter reductions over the left temporoparietal region, but not in the basal ganglia, relative to typically developing matched peers. In addition, we detected white matter reductions in the arcuate fasciculus (dorsal language stream) bilaterally, but not in the inferior fronto-occipital fasciculus (ventral language stream) nor in primary motor pathways. Our findings identify disruption of the dorsal language stream as a novel neural phenotype of developmental speech disorders, distinct from that reported in speech disorders associated with FOXP2 variants. Overall, our data confirm the early role of this stream in auditory-toarticulation transformations

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 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.Michael S. Hildebrand, Victoria E. Jackson, Thomas S. Scerri, Olivia Van Reyk, Matthew Coleman ... Josef Gecz ... et al