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

Diamond-Blackfan anemia FLVCR1 choline neurodegeneration neurodevelopmental disorders

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
19 Sep 2024
Historique:
received: 21 03 2024
revised: 13 09 2024
accepted: 13 09 2024
medline: 22 9 2024
pubmed: 22 9 2024
entrez: 22 9 2024
Statut: aheadofprint

Résumé

FLVCR1 encodes a solute carrier (SLC) protein implicated in heme, choline, and ethanolamine transport. While Flvcr1 We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants. 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 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.

Identifiants

DOI: 10.1016/j.gim.2024.101273 PMID: 39306721
pubmed: 39306721
pii: S1098-3600(24)00207-7
doi: 10.1016/j.gim.2024.101273
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101273

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Auteurs

Daniel G Calame (DG)

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.

Jovi Huixin Wong (JH)

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.

Puravi Panda (P)

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.

Dat Tuan Nguyen (DT)

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.

Nancy C P Leong (NCP)

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.

Riccardo Sangermano (R)

Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.

Sohil G Patankar (SG)

Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.

Mohamed S Abdel-Hamid (MS)

Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.

Lama AlAbdi (L)

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.

Sylvia Safwat (S)

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.

Kyle P Flannery (KP)

Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ, USA.

Zain Dardas (Z)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Jawid M Fatih (JM)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Chaya Murali (C)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Varun Kannan (V)

Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Timothy E Lotze (TE)

Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Isabella Herman (I)

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.

Farah Ammouri (F)

Boys Town National Research Hospital, Boys Town, NE, USA; The University of Kansas Health System, Westwood, KS, USA.

Brianna Rezich (B)

Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA.

Stephanie Efthymiou (S)

Department of Neuromuscular diseases, UCL Institute of Neurology, WC1N 3BG, London, UK.

Shahryar Alavi (S)

Department of Neuromuscular diseases, UCL Institute of Neurology, WC1N 3BG, London, UK.

David Murphy (D)

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, United Kingdom.

Zahra Firoozfar (Z)

Palindrome, Isfahan, Iran.

Mahya Ebrahimi Nasab (ME)

Meybod Genetic Research Center, Yazd, Iran; Yazd Welfare Organization, Yazd, Iran.

Amir Bahreini (A)

KaryoGen, Isfahan, Iran; Department of Human Genetics, University of Pittsburgh, PA, USA.

Majid Ghasemi (M)

Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran.

Nourelhoda A Haridy (NA)

Department of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt.

Hamid Reza Goldouzi (HR)

Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Fatemeh Eghbal (F)

Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.

Ehsan Ghayoor Karimiani (EG)

Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace London, London, UK.

Amber Begtrup (A)

GeneDx, Gaithersburg MD 20877 USA.

Houda Elloumi (H)

GeneDx, Gaithersburg MD 20877 USA.

Varunvenkat M Srinivasan (VM)

Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.

Vykuntaraju K Gowda (VK)

Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.

Haowei Du (H)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Shalini N Jhangiani (SN)

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

Zeynep Coban-Akdemir (Z)

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.

Dana Marafi (D)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait.

Lance Rodan (L)

Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.

Sedat Isikay (S)

Gaziantep Islam Science and Technology University, Medical Faculty, Department of Pediatric Neurology, Gaziantep, Turkey.

Jill A Rosenfeld (JA)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics Laboratories, Houston, TX, USA.

Subhadra Ramanathan (S)

Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.

Michael Staton (M)

Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.

Kerby C Oberg (KC)

Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA, USA.

Robin D Clark (RD)

Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.

Catharina Wenman (C)

Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3BH, UK.

Sam Loughlin (S)

Rare & Inherited Disease Laboratory, NHS North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3BH, UK.

Ramy Saad (R)

North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Tazeen Ashraf (T)

North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Alison Male (A)

North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Shereen Tadros (S)

North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Reza Boostani (R)

Department of Neurology Mashhad University of Medical Sciences, Mashhad, Iran.

Ghada M H Abdel-Salam (GMH)

Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.

Maha Zaki (M)

Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.

Ali Mardi (A)

Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Farzad Hashemi-Gorji (F)

Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Ebtesam Abdalla (E)

Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.

M Chiara Manzini (MC)

Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ, USA.

Davut Pehlivan (D)

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.

Jennifer E Posey (JE)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Richard A Gibbs (RA)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

Henry Houlden (H)

Department of Neuromuscular diseases, UCL Institute of Neurology, WC1N 3BG, London, UK.

Fowzan S Alkuraya (FS)

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.

Kinga Bujakowska (K)

Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.

Reza Maroofian (R)

Department of Neuromuscular diseases, UCL Institute of Neurology, WC1N 3BG, London, UK.

James R Lupski (JR)

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.

Long Nam Nguyen (LN)

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.

Classifications MeSH