<i>ARF1</i>-related disorder: phenotypic and molecular spectrum
Jean‐Madeleine de Sainte Agathe, Ben Pode‐Shakked, Sophie Naudion, Vincent Michaud, Benoı̂t Arveiler, Patricia Fergelot, Jean Delmas, Boris Keren, Céline Poirsier, Fowzan S. Alkuraya, Brahim Tabarki, Eric G. Bend, Kellie Davis, Martina Bebin, Michelle L. Thompson, Emily Bryant, Matias Wagner, Iris Hannibal, Jerica Lenberg, Martin Krenn, Kristen Wigby, Jennifer Friedman, Maria Iascone, Anna Cereda, Térence Miao, Éric Leguern, Emanuela Argilli, Elliott H. Sherr, Oana Caluseriu, Timothy Tidwell, Pınar Bayrak‐Toydemir, Caroline Hagedorn, Melanie Brügger, Katharina Vill, Francois-Dominique Morneau-Jacob, Wendy K. Chung, K. Nicole Weaver, Joshua W Owens, Ammar Husami, Bimal P. Chaudhari, Brandon Stone, Katie Burns, Rachel Li, Iris Lange, Margaux Biehler, Emmanuelle Ginglinger, Bénédicte Gérard, Rolf W. Stottmann, Aurélien Trimouille
Abstract
Purpose ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1 -related neurodevelopmental disorder. Methods We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. Results De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. Conclusion We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.