Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities

Am J Hum Genet. 2020 Feb 6;106(2):246-255. doi: 10.1016/j.ajhg.2020.01.002. Epub 2020 Jan 30.


Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.

Keywords: GARNL1; RalA signaling; TULIP1; West syndrome; epilepsy; muscular hypotonia; neurodevelopmental disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cell Movement
  • Cell Proliferation
  • Child, Preschool
  • Family
  • Feeding and Eating Disorders / etiology*
  • Feeding and Eating Disorders / pathology
  • Female
  • GTPase-Activating Proteins / genetics*
  • Humans
  • Infant
  • Male
  • Muscle Hypotonia / etiology*
  • Muscle Hypotonia / pathology
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Neurodevelopmental Disorders / etiology*
  • Neurodevelopmental Disorders / pathology
  • Phenotype
  • Spasms, Infantile / etiology*
  • Spasms, Infantile / pathology


  • GTPase-Activating Proteins
  • Nerve Tissue Proteins
  • RALGAPA1 protein, human