Developmental Convergence Across Diverse Genetic Architectures in Childhood Apraxia of Speech

Childhood apraxia of speech (CAS) is a neurodevelopmental disorder that impacts speech-motor planning and programming. This condition can lead to literacy, academic, and psychosocial challenges for affected individuals. To explore the genetic underpinnings of CAS, researchers conducted whole-exome sequencing on 11 families with 21 affected and 15 unaffected members, covering various aspects of speech, language, cognition, literacy, and motor function.

From the sequencing data, 60 prioritized variant observations were identified across 20 genes, with 5 variants arising de novo. The study found that CAS often co-occurred with multiple speech and literacy impairments, as well as oral-motor, feeding, and fine-motor difficulties. Using BrainSpan co-expression analysis, researchers identified MECP2 and ANK2 as the genes with the highest connectivity within the sampled postnatal network.

In an exploratory analysis, the KOLF2.1J perturbation atlas in undifferentiated human induced pluripotent stem cells revealed a positive LMO3 expression-response score following NIPBL repression, while LMO3 and ANK2 showed opposing response directions within a cohesin-associated perturbation cluster. These findings suggest the need for further investigation in human neural cells.

The functional enrichment, protein-association, and developmental-expression analyses supported shared biological themes, including chromatin regulation, neuronal signaling, and extracellular-matrix organization. In six families, multiple affected relatives shared prioritized variants across a unique set of several genes, indicating the presence of multilocus candidate profiles that might contribute to CAS susceptibility.

Based on these results, the researchers propose four novel CAS candidate genes: LMO3, PCDH10, MYCBP2, and PTPRS.

This study offers multiple hypotheses for future variant-specific functional validation in speech-motor development, shedding light on the complex genetic architecture of childhood apraxia of speech.