Novel De Novo RALA Missense Variants Expand the Genotype Spectrum of Hiatt-Neu-Cooper Neurodevelopmental Syndrome.

backgroundRALA is a small GTPase from the RAS superfamily implicated in signal transduction and cytoskeletal dynamics. Recently, de novo variants in RALA have been associated with a neurodevelopmental syndrome characterized by intellectual disability (ID), developmental delay (DD), and seizures. So far, only < 12 patients have been reported.

methodsIn this study, we report two novel patients with neurodevelopmental impairment and epilepsy carrying previously unreported RALA variants. We performed a thorough clinical investigation of these patients and performed brain MRI to detect potential abnormalities. Trio-exome sequencing and/or NGS panel testing were conducted to identify the genetic variants. Then, we reviewed previous cases reported in the literature.

resultsAffected individuals showed a complex neurodevelopmental phenotype consistent with Hiatt-Neu-Cooper neurodevelopmental syndrome. Brain MRI in both subjects showed abnormalities including megalencephaly and ventricular enlargement, previously unreported in RALA patients. Genetic testing revealed two novel de novo missense variants in RALA: c.217G>A, p.(Glu73Lys) in case #1 and c.73G>C, p.(Val25Leu) in case #2. Both variants affect highly conserved residues within the GTP/GDP-binding site of the protein. These changes are predicted to be deleterious by in silico tools, interfering with the GTPase activity of RALA.

conclusionOur findings expand the genotype and phenotype spectrum of Hiatt-Neu-Cooper neurodevelopmental syndrome. Our observations also support the important role of variants affecting the GTP/GDP-binding site of the RALA protein in the pathogenesis of Hiatt-Neu-Cooper neurodevelopmental syndrome.