Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum

Daniel G Calame¹, Jovi Huixin Wong², Puravi Panda², Dat Tuan Nguyen², Nancy C P Leong², Riccardo Sangermano³, Sohil G Patankar³, Mohamed S Abdel-Hamid⁴, Lama AlAbdi⁵, Sylvia Safwat⁶, Kyle P Flannery⁷, Zain Dardas⁸, Jawid M Fatih⁸, Chaya Murali⁸, Varun Kannan⁹, Timothy E Lotze⁹, Isabella Herman¹⁰, Farah Ammouri¹¹, Brianna Rezich¹², Stephanie Efthymiou¹³, Shahryar Alavi¹³, David Murphy¹⁴, Zahra Firoozfar¹⁵, Mahya Ebrahimi Nasab¹⁶, Amir Bahreini¹⁷, Majid Ghasemi¹⁸, Nourelhoda A Haridy¹⁹, Hamid Reza Goldouzi²⁰, Fatemeh Eghbal²¹, Ehsan Ghayoor Karimiani²², Amber Begtrup²³, Houda Elloumi²³, Varunvenkat M Srinivasan²⁴, Vykuntaraju K Gowda²⁴, Haowei Du⁸, Shalini N Jhangiani²⁵, Zeynep Coban-Akdemir²⁶, Dana Marafi²⁷, Lance Rodan²⁸, Sedat Isikay²⁹, Jill A Rosenfeld³⁰, Subhadra Ramanathan³¹, Michael Staton³¹, Kerby C Oberg³², Robin D Clark³¹, Catharina Wenman³³, Sam Loughlin³³, Ramy Saad³⁴, Tazeen Ashraf³⁴, Alison Male³⁴, Shereen Tadros³⁵, Reza Boostani³⁶, Ghada M H Abdel-Salam³⁷, Maha Zaki³⁷, Ali Mardi³⁸, Farzad Hashemi-Gorji³⁹, Ebtesam Abdalla⁴⁰, M Chiara Manzini⁷, Davut Pehlivan⁴¹, Jennifer E Posey⁸, Richard A Gibbs⁴², Henry Houlden¹³, Fowzan S Alkuraya⁴³, Kinga Bujakowska³, Reza Maroofian¹³, James R Lupski⁴⁴, Long N Nguyen⁴⁵

Affiliations

¹ Section 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.
² Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
⁴ Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
⁵ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
⁶ Department 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.
⁷ Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
⁹ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
¹⁰ Section 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.
¹¹ Boys Town National Research Hospital, Boys Town, NE; The University of Kansas Health System, Westwood, KS.
¹² Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE.
¹³ Department of Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
¹⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, United Kingdom.
¹⁵ Palindrome, Isfahan, Iran.
¹⁶ Meybod Genetic Research Center, Yazd, Iran; Yazd Welfare Organization, Yazd, Iran.
¹⁷ KaryoGen, Isfahan, Iran; Department of Human Genetics, University of Pittsburgh, PA.
¹⁸ Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.
¹⁹ Department of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt.
²⁰ Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
²¹ Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
²² Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom.
²³ GeneDx, Gaithersburg, MD.
²⁴ Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
²⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
²⁶ Department 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.
²⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait.
²⁸ Department of Neurology, Boston Children's Hospital, Boston, MA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
²⁹ Gaziantep Islam Science and Technology University, Medical Faculty, Department of Pediatric Neurology, Gaziantep, Turkey.
³⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Baylor Genetics Laboratories, Houston, TX.
³¹ Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA.
³² Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA.
³³ Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
³⁴ North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
³⁵ North 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.
³⁶ Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
³⁷ Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
³⁸ Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
³⁹ Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁴⁰ Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
⁴¹ Section 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.
⁴² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
⁴³ Department 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.
⁴⁴ Texas 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.
⁴⁵ Department 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.

PMID: 39306721
DOI: 10.1016/j.gim.2024.101273

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum

Daniel G Calame et al. Genet Med. 2025 Jan.

. 2025 Jan;27(1):101273.

doi: 10.1016/j.gim.2024.101273. Epub 2024 Sep 19.

Authors

Affiliations

¹ Section 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.
² Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
⁴ Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
⁵ Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
⁶ Department 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.
⁷ Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
⁹ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
¹⁰ Section 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.
¹¹ Boys Town National Research Hospital, Boys Town, NE; The University of Kansas Health System, Westwood, KS.
¹² Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE.
¹³ Department of Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
¹⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, United Kingdom.
¹⁵ Palindrome, Isfahan, Iran.
¹⁶ Meybod Genetic Research Center, Yazd, Iran; Yazd Welfare Organization, Yazd, Iran.
¹⁷ KaryoGen, Isfahan, Iran; Department of Human Genetics, University of Pittsburgh, PA.
¹⁸ Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.
¹⁹ Department of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt.
²⁰ Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
²¹ Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
²² Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom.
²³ GeneDx, Gaithersburg, MD.
²⁴ Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
²⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
²⁶ Department 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.
²⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait.
²⁸ Department of Neurology, Boston Children's Hospital, Boston, MA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
²⁹ Gaziantep Islam Science and Technology University, Medical Faculty, Department of Pediatric Neurology, Gaziantep, Turkey.
³⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Baylor Genetics Laboratories, Houston, TX.
³¹ Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA.
³² Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA.
³³ Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
³⁴ North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
³⁵ North 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.
³⁶ Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
³⁷ Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
³⁸ Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
³⁹ Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁴⁰ Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
⁴¹ Section 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.
⁴² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
⁴³ Department 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.
⁴⁴ Texas 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.
⁴⁵ Department 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.

PMID: 39306721
DOI: 10.1016/j.gim.2024.101273

Abstract

Purpose: FLVCR1 encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although Flvcr1^-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.

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.

Keywords: Choline; Diamond-Blackfan anemia; FLVCR1; Neurodegeneration; Neurodevelopmental disorders.

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Conflict of interest statement

Conflict of Interest James R. Lupski has stock ownership in 23andMe, is a paid consultant for Genome International, and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. Amber Begtrup and Houda Elloumi are employees of GeneDx, LLC. All other authors declare no conflicts of interest.

Update of

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.
Calame DG, Wong JH, Panda P, Nguyen DT, Leong NCP, Sangermano R, Patankar SG, Abdel-Hamid M, AlAbdi L, Safwat S, Flannery KP, Dardas Z, Fatih JM, Murali C, Kannan V, Lotze TE, Herman I, Ammouri F, Rezich B, Efthymiou S, Alavi S, Murphy D, Firoozfar Z, Nasab ME, Bahreini A, Ghasemi M, Haridy NA, Goldouzi HR, Eghbal F, Karimiani EG, Srinivasan VM, Gowda VK, Du H, Jhangiani SN, Coban-Akdemir Z, Marafi D, Rodan L, Isikay S, Rosenfeld JA, Ramanathan S, Staton M, Kerby C Oberg, Clark RD, Wenman C, Loughlin S, Saad R, Ashraf T, Male A, Tadros S, Boostani R, Abdel-Salam GMH, Zaki M, Abdalla E, Manzini MC, Pehlivan D, Posey JE, Gibbs RA, Houlden H, Alkuraya FS, Bujakowska K, Maroofian R, Lupski JR, Nguyen LN. Calame DG, et al. medRxiv [Preprint]. 2024 Feb 13:2024.02.09.24302464. doi: 10.1101/2024.02.09.24302464. medRxiv. 2024. Update in: Genet Med. 2025 Jan;27(1):101273. doi: 10.1016/j.gim.2024.101273. PMID: 38405817 Free PMC article. Updated. Preprint.

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Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum

Affiliations

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases