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The following is a summary of “Cohort expansion and genotype-phenotype analysis of RAB11A-associated neurodevelopmental disorder,” published in the July 2024 issue of Pediatrics by Borroto et al.

Rab family GTPases play crucial roles in membrane trafficking, and their dysregulation has been associated with various neuropathologies. In 2017, the researchers identified a causal link between RAB11A variants and developmental and epileptic encephalopathy. This study aims to expand the clinical spectrum of RAB11A-associated neurodevelopmental disorders and analyze genotype-phenotype correlations.

The study group examined 16 patients with pathogenic or likely pathogenic RAB11A variants, predominantly de novo heterozygous missense variants. One patient exhibited a homozygous nonsense variant, complicated by a concurrent pathogenic LAMA2 variant, making it challenging to delineate each variant’s specific contributions to the phenotype.

The findings corroborate that certain RAB11A missense variants are associated with intellectual disability and developmental delays. Additional clinical manifestations may include gait disturbances, hypotonia, MRI abnormalities, visual anomalies, dysmorphisms, early adrenarche, and obesity. Notably, epilepsy appears less common and is typically linked to variants outside the binding sites. Patients with variants within the binding sites tend to exhibit a broader, non-epileptic, multisystemic phenotype.

In conclusion, akin to other Rab-related disorders, RAB11A-associated neurodevelopmental disorder affects gait, muscle tone, brain anatomy and physiology, vision, adrenarche, and body weight and structure. Epilepsy is observed in a minority of patients and is predominantly associated with variants outside the binding sites. These insights enhance the understanding of the diverse phenotypic presentations and underlying genetic mechanisms of RAB11A-associated neurodevelopmental disorder, paving the way for improved diagnostic and therapeutic strategies.

Source: sciencedirect.com/science/article/pii/S0887899424002613