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

Matias Wagner*, Yuliya Skorobogatko, Ben Pode-Shakked, Cynthia M. Powell, Bader Alhaddad, Annette Seibt, Ortal Barel, Gali Heimer, Chen Hoffmann, Laurie A. Demmer, Yezmin Perilla-Young, Marc Remke, Dagmar Wieczorek, Tharsini Navaratnarajah, Peter Lichtner, Dirk Klee, Hanan E. Shamseldin, Fuad Al Mutairi, Ertan Mayatepek, Tim StromThomas Meitinger, Fowzan S. Alkuraya, Yair Anikster, Alan R. Saltiel, Felix Distelmaier

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)246-255
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - 6 Feb 2020


  • GARNL1
  • RalA signaling
  • TULIP1
  • West syndrome
  • epilepsy
  • muscular hypotonia
  • neurodevelopmental disorder


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