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

## TL;DR

Two new RALA gene mutations are found in patients with neurodevelopmental issues and epilepsy, expanding the known genetic causes of this condition.

## Contribution

Identification of two novel de novo RALA missense variants associated with Hiatt-Neu-Cooper neurodevelopmental syndrome.

## Key findings

- Two novel RALA missense variants (c.217G>A and c.73G>C) were identified in patients with neurodevelopmental impairment and epilepsy.
- The variants affect conserved residues in the GTP/GDP-binding site of RALA, likely disrupting its GTPase activity.
- Brain MRI showed megalencephaly and ventricular enlargement, previously unreported in RALA-related cases.

## Abstract

RALA 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.

In 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.

Affected 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.

Our 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.

RALA is a small GTPase from the RAS superfamily involved in signal transduction and cytoskeletal dynamics. In this study, we identified two novel de novo missense variants in RALA (c.217G>A p.(Glu73Lys) and c.73G>C p.(Val25Leu)) in patients with developmental delay, epilepsy, and brain abnormalities. These rare variants affect conserved residues within the GTP/GDP‐binding site, likely disrupting RALA's GTPase activity, which is crucial for neurodevelopment.