ARHGEF39, a Gene Implicated in Developmental Language Disorder, Activates RHOA and Is Involved in Cell De-Adhesion and Neural Progenitor Cell Proliferation.

ARHGEF39 was previously implicated in developmental language disorder (DLD) via a functional polymorphism that can disrupt post-transcriptional regulation by microRNAs. ARHGEF39 is part of the family of Rho guanine nucleotide exchange factors (RhoGEFs) that activate small Rho GTPases to regulate a wide variety of cellular processes. However, little is known about the function of ARHGEF39, or how its function might contribute to neurodevelopment or related disorders. Here, we explore the molecular function of ARHGEF39 and show that it activates the Rho GTPase RHOA and that high ARHGEF39 expression in cell cultures leads to an increase of detached cells. To explore its role in neurodevelopment, we analyse published single cell RNA-sequencing data and demonstrate that ARHGEF39 is a marker gene for proliferating neural progenitor cells and that it is co-expressed with genes involved in cell division. This suggests a role for ARHGEF39 in neurogenesis in the developing brain. The co-expression of ARHGEF39 with other RHOA-regulating genes supports RHOA as substrate of ARHGEF39 in neural cells, and the involvement of RHOA in neuropsychiatric disorders highlights a potential link between ARHGEF39 and neurodevelopment and disorder. Understanding the GTPase substrate, co-expression network, and processes downstream of ARHGEF39 provide new avenues for exploring the mechanisms by which altered expression levels of ARHGEF39 may contribute to neurodevelopment and associated disorders.

Hyperkinetic stereotyped movements in a boy with biallelic CNTNAP2 variants.

BACKGROUND: Heterozygous variants in CNTNAP2 have been implicated in a wide range of neurological phenotypes, including intellectual disability (ID), epilepsy, autistic spectrum disorder (ASD), and impaired language. However, heterozygous variants can also be found in unaffected individuals. Biallelic CNTNAP2 variants are rarer and cause a well-defined genetic syndrome known as CASPR2 deficiency disorder, a condition characterised by ID, early-onset refractory epilepsy, language impairment, and autistic features. CASE-REPORT: A 7-year-old boy presented with hyperkinetic stereotyped movements that started during early infancy and persisted over childhood. Abnormal movements consisted of rhythmic and repetitive shaking of the four limbs, with evident stereotypic features. Additional clinical features included ID, attention deficit-hyperactivity disorder (ADHD), ASD, and speech impairment, consistent with CASPR2 deficiency disorder. Whole-genome array comparative genomic hybridization detected a maternally inherited 0.402 Mb duplication, which involved intron 1, exon 2, and intron 2 of CNTNAP2 (c.97 +?_209-?dup). The affected region in intron 1 contains a binding site for the transcription factor FOXP2, potentially leading to abnormal CNTNAP2 expression regulation. Sanger sequencing of the coding region of CNTNAP2 also identified a paternally-inherited missense variant c.2752C > T, p.(Leu918Phe). CONCLUSION: This case expands the molecular and phenotypic spectrum of CASPR2 deficiency disorder, suggesting that Hyperkinetic stereotyped movements may be a rare, yet significant, clinical feature of this complex neurological disorder. Furthermore, the identification of an in-frame, largely non-coding duplication in CNTNAP2 points to a sophisticated underlying molecular mechanism, likely involving impaired FOXP2 binding.