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

Daniel G Calame; Jovi Huixin Wong; Puravi Panda; Dat Tuan Nguyen; Nancy C P Leong; Riccardo Sangermano; Sohil G Patankar; Mohamed S Abdel-Hamid; Lama AlAbdi; Sylvia Safwat; Kyle P Flannery; Zain Dardas; Jawid M Fatih; Chaya Murali; Varun Kannan; Timothy E Lotze; Isabella Herman; Farah Ammouri; Brianna Rezich; Stephanie Efthymiou; Shahryar Alavi; David Murphy; Zahra Firoozfar; Mahya Ebrahimi Nasab; Amir Bahreini; Majid Ghasemi; Nourelhoda A Haridy; Hamid Reza Goldouzi; Fatemeh Eghbal; Ehsan Ghayoor Karimiani; Amber Begtrup; Houda Elloumi; Varunvenkat M Srinivasan; Vykuntaraju K Gowda; Haowei Du; Shalini N Jhangiani; Zeynep Coban-Akdemir; Dana Marafi; Lance Rodan; Sedat Isikay; Jill A Rosenfeld; Subhadra Ramanathan; Michael Staton; Kerby C Oberg; Robin D Clark; Catharina Wenman; Sam Loughlin; Ramy Saad; Tazeen Ashraf; Alison Male; Shereen Tadros; Reza Boostani; Ghada M H Abdel-Salam; Maha Zaki; Ali Mardi; Farzad Hashemi-Gorji; Ebtesam Abdalla; M Chiara Manzini; Davut Pehlivan; Jennifer E Posey; Richard A Gibbs; Henry Houlden; Fowzan S Alkuraya; Kinga Bujakowska; Reza Maroofian; James R Lupski; Long Nam Nguyen

doi:10.1016/j.gim.2024.101273

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

Genet Med. 2024 Sep 19:101273. doi: 10.1016/j.gim.2024.101273. Online ahead of print.

Authors

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 Tadros³⁴, Reza Boostani³⁵, Ghada M H Abdel-Salam³⁶, Maha Zaki³⁶, Ali Mardi³⁷, Farzad Hashemi-Gorji³⁸, Ebtesam Abdalla³⁹, M Chiara Manzini⁷, Davut Pehlivan⁴⁰, Jennifer E Posey⁸, Richard A Gibbs⁴¹, Henry Houlden¹³, Fowzan S Alkuraya⁴², Kinga Bujakowska³, Reza Maroofian¹³, James R Lupski⁴³, Long Nam Nguyen⁴⁴

Affiliations

¹ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: Daniel.calame@bcm.edu.
² Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
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 Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia; 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, USA.
⁷ Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ, USA.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁹ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁰ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Boys Town National Research Hospital, Boys Town, NE, USA.
¹¹ Boys Town National Research Hospital, Boys Town, NE, USA; The University of Kansas Health System, Westwood, KS, USA.
¹² Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA.
¹³ Department of Neuromuscular diseases, UCL Institute of Neurology, WC1N 3BG, London, UK.
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, USA.
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, Cranmer Terrace London, London, UK.
²³ GeneDx, Gaithersburg MD 20877 USA.
²⁴ Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
²⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
²⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 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, USA.
²⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait.
²⁸ Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
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, USA; Baylor Genetics Laboratories, Houston, TX, USA.
³¹ Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.
³² Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, USA.
³³ Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3BH, UK.
³⁴ North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
³⁵ Department of Neurology Mashhad University of Medical Sciences, Mashhad, Iran.
³⁶ Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
³⁷ Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
³⁸ Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
³⁹ Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
⁴⁰ Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁴² 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.
⁴³ Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: jlupski@bcm.edu.
⁴⁴ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; Immunology Program, Life Sciences Institute, National University of Singapore, Singapore 117456; Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, Singapore 117456; Cardiovascular Disease Research (CVD) Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545; Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456. Electronic address: bchnnl@nus.edu.sg.

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

Abstract

Purpose: FLVCR1 encodes a solute carrier (SLC) protein implicated in heme, choline, and ethanolamine transport. While 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: Diamond-Blackfan anemia; FLVCR1; choline; neurodegeneration; neurodevelopmental disorders.