Biallelic Variation In The Choline And Ethanolamine Transporter Flvcr1 Underlies A Severe Developmental Disorder Spectrum Daniel G Calame by Daniel G. Calame 101016/JGIM2024101273 instant download after payment.

Purpose: FLVCR1 encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1−/− mice exhibit skeletal malformations and defective erythReceived in revised formropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in13 September 2024humans have previously only been linked to childhood or adult-onset ataxia, sensoryAccepted 13 September 2024neuropathy, and retinitis pigmentosa.Available online 19 September 2024Methods: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functionalKeywords:consequences of their FLVCR1 variants.Results: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variantsCholineDiamond-Blackfan anemiaand characterized a novel FLVCR1-related phenotype: severe developmental disorders withFLVCR1profound developmental delay, microcephaly (z-score −2.5 to −10.5), brain malformations,Neurodegenerationepilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volumereduction to hydranencephaly. Severely affected patients share traits, including macrocyticNeurodevelopmental disordersanemia 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 fromsevere multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration.Our study expands our understanding of Mendelian choline and ethanolamine disorders andillustrates the importance of anticipating a wide phenotypic spectrum for known diseasegenes and incorporating model organism data into genome analysis to maximize genetictesting yield.© 2024 American College of Medical Genetics and Genomics.Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AItraining, and similar technologies.