Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum.
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Calame Daniel G, Wong Jovi Huixin, Panda Puravi, Nguyen Dat Tuan, Leong Nancy C P, Sangermano Riccardo, Patankar Sohil G, Abdel-Hamid Mohamed S, AlAbdi Lama, Safwat Sylvia, Flannery Kyle P, Dardas Zain, Fatih Jawid M, Murali Chaya, Kannan Varun, Lotze Timothy E, Herman Isabella, Ammouri Farah, Rezich Brianna, Efthymiou Stephanie, Alavi Shahryar, Murphy David, Firoozfar Zahra, Nasab Mahya Ebrahimi, Bahreini Amir, Ghasemi Majid, Haridy Nourelhoda A, Goldouzi Hamid Reza, Eghbal Fatemeh, Karimiani Ehsan Ghayoor, Begtrup Amber, Elloumi Houda, Srinivasan Varunvenkat M, Gowda Vykuntaraju K, Du Haowei, Jhangiani Shalini N, Coban-Akdemir Zeynep, Marafi Dana, Rodan Lance, Isikay Sedat, Rosenfeld Jill A, Ramanathan Subhadra, Staton Michael, Oberg Kerby C, Clark Robin D, Wenman Catharina, Loughlin Sam, Saad Ramy, Ashraf Tazeen, Male Alison, Tadros Shereen, Boostani Reza, Abdel-Salam Ghada M H, Zaki Maha, Mardi Ali, Hashemi-Gorji Farzad, Abdalla Ebtesam, Manzini M Chiara, Pehlivan Davut, Posey Jennifer E, Gibbs Richard A, Houlden Henry, Alkuraya Fowzan S, Bujakowska Kinga, Maroofian Reza, Lupski James R, Nguyen Long N
Аннотация
METHODS: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants.
RESULTS: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (z-score -2.5 to -10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits, including macrocytic anemia and skeletal malformations, with Flvcr1-/- mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing.
CONCLUSION: These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.