ARF1-related disorder: phenotypic and molecular spectrum.
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de Sainte Agathe Jean-Madeleine, Pode-Shakked Ben, Naudion Sophie, Michaud Vincent, Arveiler Benoit, Fergelot Patricia, Delmas Jean, Keren Boris, Poirsier Céline, Alkuraya Fowzan S, Tabarki Brahim, Bend Eric, Davis Kellie, Bebin Martina, Thompson Michelle L, Bryant Emily M, Wagner Matias, Hannibal Iris, Lenberg Jerica, Krenn Martin, Wigby Kristen M, Friedman Jennifer R, Iascone Maria, Cereda Anna, Miao Térence, LeGuern Eric, Argilli Emanuela, Sherr Elliott, Caluseriu Oana, Tidwell Timothy, Bayrak-Toydemir Pinar, Hagedorn Caroline, Brugger Melanie, Vill Katharina, Morneau-Jacob Francois-Dominique, Chung Wendy, Weaver Kathryn N, Owens Joshua W, Husami Ammar, Chaudhari Bimal P, Stone Brandon S, Burns Katie, Li Rachel, de Lange Iris M, Biehler Margaux, Ginglinger Emmanuelle, Gérard Bénédicte, Stottmann Rolf W, Trimouille Aurélien
Аннотация
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.