Biallelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Hypotonia, Infantile Spasms and Feeding Difficulties

בן פודה-שקד ^1,2,18 Matias Wagner ^3,4,5 Yuliya Skorobogatko ⁶ Cynthia M Powell ⁷ Bader Alhaddad ⁴ Annette Seibt ⁸ Ortal Barel ⁹ Gali Heimer ^2,10,18 Chen Hoffmann ^11,18 Laurie A Demmer ¹² Yezmin Perilla-Young ⁷ Marc Remke ¹³ Dagmar Wieczorek ¹⁴ Dirk Klee ¹⁵ Hanan Shamseldin ¹⁶ Fuad Al Mutairi ¹⁷ Ertan Mayatepek ⁸ Tim Strom ⁴ Thomas Meitinger ⁴ Fowzan S Alkuraya ¹⁶ Alan R Saltiel ⁶ Felix Distelmaier ⁸ Yair Anikster ^1,18,19

¹Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, ישראל
²The Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, ישראל
³Institute of Human Genetics, Technical University München, Munich, גרמניה
⁴Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, גרמניה
⁵Institute for Neurogenomics, Helmholtz Zentrum München, Neuherberg, גרמניה
⁶Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, ארצות הברית
⁷Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, ארצות הברית
⁸Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children´s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, גרמניה
⁹Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, ישראל
¹⁰Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, ישראל
¹¹Department of Radiology, Sheba Medical Center, Tel-Hashomer, ישראל
¹²Medical Genetics, Atrium Health Levine Children’s Hospital, Charlotte, NC, ארצות הברית
¹³Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, גרמניה
¹⁴Institute of Human Genetics, Medical Faculty, Heinrich Heine University, Düsseldorf, גרמניה
¹⁵Department of Diagnostic and Interventional Radiology, Heinrich-Heine University, Düsseldorf, גרמניה
¹⁶Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, סעודיה
¹⁷Division of Genetics, Department of Pediatrics, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, סעודיה
¹⁸Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, ישראל
¹⁹The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, ישראל

Ral (Ras-like) GTPases play an important role in the control of cell proliferation and have been implicated in Ras-mediated tumorigenicity. Only recently, variants in RALA were described as a cause of intellectual disability and developmental delay, indicating the importance of this pathway in neuropediatric diseases. Here, we report the identification of biallelic variants in RALGAPA1 (also termed TULIP1; encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated families with profound neurodevelopmental disability, muscular hypotonia, feeding difficulties, recurrent febrile episodes, and infantile spasms. RalGAPA1 protein was absent in fibroblasts derived from affected individuals suggesting a loss of function effect of the RALGAPA1 variants. As a consequence, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes constitutive activation of RalA. Additionally, protein levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically downregulated, indicating a dysfunctional RalGAP complex. Our findings indicate that dysregulation of the RalA-pathway has an important impact on neuronal function and brain development. In view 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, which we suggest to be named RALopathies.