ArticleGenetics in medicine : official journal of the American College of Medical Genetics2025
Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Biosynthesis of Phosphatidylethanolamine and Phosphatidylcholine via the Kennedy Pathway in Cancer and Other Pathological Conditions.International journal of molecular sciences · 2026Review
- Expanding the ocular and genetic spectrum of FLVCR1-associated disease in a Chinese cohort.Documenta ophthalmologica. Advances in ophthalmology · 2026Article
- miR-30b-5p suppresses prostate cancer progression by targeting FLVCR1 through the cAMP/PKA/CREB pathway.Scientific reports · 2026Article
- Improved red blood cell storage quality of blood from donors carrying the hypermorphic PIMT I120 variant.HemaSphere · 2026Article
- A hypomorphic FLVCR2 variant resulting in moderate transport deficiency causes hydranencephaly syndrome with brain calcifications.European journal of human genetics : EJHG · 2026Article
- Mitochondrial energetic failure underlies FLVCR1-related sensory neuropathy.Communications biology · 2026Article
- FLVCR1-related diseases: from clinical heterogeneity to mechanistic insights.Brain communications · 2026Review
- New Phenotype in Two Siblings with FamilialTurkish journal of ophthalmology · 2025Article
- Axonal motor polyneuropathy in a 13 years old Girl with a de Novo variant in ADNP.Neurogenetics · 2025Article
- Cellular and organismal function of choline metabolism.Nature metabolism · 2025Review
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
Corrections and comments
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Authors and funding
67 authors.
Daniel G CalameSection of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX. Electronic address: daniel.calame@bcm.edu.
Jovi Huixin WongDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Puravi PandaDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Dat Tuan NguyenDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Nancy C P LeongDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Riccardo SangermanoOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
Sohil G PatankarOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
Mohamed S Abdel-HamidMedical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Lama AlAbdiDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Sylvia SafwatDepartment of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt; Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ.
Kyle P FlanneryDepartment of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ.
Zain DardasDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
Jawid M FatihDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
Chaya MuraliDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
Varun KannanSection of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Timothy E LotzeSection of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Isabella HermanSection of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Boys Town National Research Hospital, Boys Town, NE.
Farah AmmouriBoys Town National Research Hospital, Boys Town, NE; The University of Kansas Health System, Westwood, KS.
Brianna RezichMunroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE.
Stephanie EfthymiouDepartment of Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
Shahryar AlaviDepartment of Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
David MurphyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, United Kingdom.
Zahra FiroozfarPalindrome, Isfahan, Iran.
Mahya Ebrahimi NasabMeybod Genetic Research Center, Yazd, Iran; Yazd Welfare Organization, Yazd, Iran.
Amir BahreiniKaryoGen, Isfahan, Iran; Department of Human Genetics, University of Pittsburgh, PA.
Majid GhasemiDepartment of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.
Nourelhoda A HaridyDepartment of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt.
Hamid Reza GoldouziDepartment of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Fatemeh EghbalDepartment of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
Ehsan Ghayoor KarimianiMolecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom.
Amber BegtrupGeneDx, Gaithersburg, MD.
Houda ElloumiGeneDx, Gaithersburg, MD.
Varunvenkat M SrinivasanDepartment of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
Vykuntaraju K GowdaDepartment of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
Haowei DuDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
Shalini N JhangianiHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
Zeynep Coban-AkdemirDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Dana MarafiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait.
Lance RodanDepartment of Neurology, Boston Children's Hospital, Boston, MA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
Sedat IsikayGaziantep Islam Science and Technology University, Medical Faculty, Department of Pediatric Neurology, Gaziantep, Turkey.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Baylor Genetics Laboratories, Houston, TX.
Subhadra RamanathanDivision of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA.
Michael StatonDivision of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA.
Kerby C ObergDepartment of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA.
Robin D ClarkDivision of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA.
Catharina WenmanRare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
Sam LoughlinRare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
Ramy SaadNorth East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
Tazeen AshrafNorth East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
Alison MaleNorth East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
Shereen TadrosNorth East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; Genetics and Genomic Medicine Department, University College London, United Kingdom.
Reza BoostaniDepartment of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
Ghada M H Abdel-SalamDepartment of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
Maha ZakiDepartment of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
Ali MardiCenter for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Farzad Hashemi-GorjiGenomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Ebtesam AbdallaDepartment of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
M Chiara ManziniDepartment of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ.
Davut PehlivanSection of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
Jennifer E PoseyDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
Richard A GibbsDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
Henry HouldenDepartment of Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
Kinga BujakowskaOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
Reza MaroofianDepartment of Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
James R LupskiTexas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX. Electronic address: jlupski@bcm.edu.
Long N NguyenDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Immunology Program, Life Sciences Institute, National University of Singapore, Singapore; Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore; Cardiovascular Disease Research (CVD) Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: bchnnl@nus.edu.sg.
Funding
The Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3MBaylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MFrequency of variants of unknown significance by ancestry groups in the All of Us Research Program cohortU01HG011758 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI RICHARD A GIBBS, JAMES R. LUPSKI · 2021 to 2026
$13.8MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MFinding Missing Genetic Causality of Inherited Retinal DegenerationsR01EY035717 · NEI · MASSACHUSETTS EYE AND EAR INFIRMARY · PI Kinga Bujakowska · 2024 to 2026
$2.1MNHGRI NIH HHS U01 HG011758NHGRI NIH HHS U54 HG003273NHGRI NIH HHS UM1 HG006542NINDS NIH HHS R35 NS105078
Abstract
purposeFLVCR1 encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1
methodsWe identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants.
resultsWe 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
conclusionThese 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.
Indexed as
Developmental DisabilitiesMembrane Transport ProteinsAdolescentAdultAllelesAnimalsChildChild, PreschoolCholineEthanolamineFemaleHumansInfantMaleMiceMutationCholineEthanolamineFLVCR1 protein, humanMembrane Transport ProteinsReceptors, VirusCholineDiamond-Blackfan anemiaFLVCR1NeurodegenerationNeurodevelopmental disorders
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