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

Abstract

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.

Childhood apraxia of speech, oral motor apraxia, and velopharyngeal insufficiency in a young woman with a de novo pathogenic variant in the ZNF292 gene

“…The expanding list of genes associated with CAS highlights the importance of performing genetic testing for monogenic disorders. 4 Our report expands the documented phenotypes associated with ZNF292-related NDD by characterizing more fully the feeding and speech difficulties as OMA, VPI, and CAS. This report also expands the list of genes to consider in the differential diagnosis of ID, ASD, and CAS.…”

“…A novel de novo pathogenic variant [c.3432_3436del; p.(N1114Kfs*5)] was discovered in our patient, which has not been previously described. The expanding list of genes associated with CAS highlights the importance of performing genetic testing for monogenic disorders 4 …”

The clinical and genetic spectrum of paediatric speech and language disorders in 52,143 individuals

“…Second, speech and language disorders have considerable overlap with neurodevelopmental disorders, movement disorders, and epilepsy. 13,32 Lastly, distinct speech phenotypes can be associated with specific genotypic findings and demonstrate genetic overlap with known neurodevelopmental genetic conditions. 2,4,6 As expected, our analysis of speech diagnoses showed that, even though there were a total of twenty-six ICD-10 codes corresponding to this broad clinical presentation, the broader phenotypic diagnoses were the most frequent.…”

“…Second, speech and language disorders have considerable overlap with neurodevelopmental disorders, movement disorders, and epilepsy. 13,32 Lastly, distinct speech phenotypes can be associated with specific genotypic findings and demonstrate genetic overlap with known neurodevelopmental genetic conditions. 2,4,6…”

Genome Sequencing of Idiopathic Speech Delay

“…Following this, additional inherited and de novo disruptive FOXP2 variants have been implicated in speech/language deficits (with CAS as the most prominent phenotype) in multiple independent families and probands [11], but these still explain only a small proportion of cases overall [12]. In recent years, systematic exome/genome sequencing screens of CAS cohorts have begun to identify potential high-penetrance pathogenic variants in genes beyond FOXP2 [6,[13][14][15]. Most of the genetic loci highlighted by such CAS screens have also been implicated in heterogeneous neurodevelopmental disorders, in which speech problems may occur in the context of a more pervasive syndrome, with notable examples including CHD3 [16] (MIM: 618205), SETD1A [17] (MIM: 619056), WDR5 [18], and SETBP1 [19] (MIM: 616078).…”