Lawrence D. Shriberg, PhD – Slide of the Week

Shriberg Slide of the Week

Title: A Set of Regulatory Genes Co-expressed in Embryonic Human Brain is Implicated in Disrupted Speech Development.

Legend: Co-expression network analysis. A co-expression network was calculated using gene expression data of brain samples collected between 8 weeks post conception up to 1 year of age from the cortex, hippocampus, amygdala, striatum and thalamus. A total of 16 modules were detected. Module 3 (indicated by black arrow) was highly enriched for the genes we implicated in CAS through whole-genome sequencing (CAS-WGS). [CAS: childhood apraxia of speech; see figure for complete legend].

Citation: Eising E, Carrion-Castillo A, Vino A, Strand EA, Jakielski K J, Scerri TS, . . . Shriberg LD, Fisher SE (2018). A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molecular Psychiatry. Advance online publication.

Abstract: Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

About the Investigator: Speech sound disorders (SSD) put children at risk for literacy development, reduced peer acceptance, and limitations in vocational options. Our research goals are to understand the causal pathways that lead to subtypes of SSD so that clinicians can select the appropriate intervention approach for each child, and researchers can conduct studies leading to the prevention of some subtypes of SSD. We are studying genomic, motoric, and speech processing correlates of idiopathic SSD and SSD in the context of complex neurodevelopmental disorders (e.g., autism, Down syndrome, fragile X syndrome, galactosemia, FOXP2 disruptions, 22q11.2 deletion, and 16p11.2 deletions and duplications).

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