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

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Author information

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.
      Authors
    • Calame DG 1
    • Pehlivan D 1
    (2 authors)
  • 2. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
      Authors
    • Wong JH 2
    • Panda P 2
    • Nguyen DT 2
    • Leong NCP 2
    (4 authors)
  • 3. Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
      Authors
    • Sangermano R 3
    • Patankar SG 3
    • Bujakowska K 3
    (3 authors)
  • 4. Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
      Authors
    • Abdel-Hamid MS 4
    (1 author)
  • 5. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
      Authors
    • AlAbdi L 5
    (1 author)
    • Show all (44)

ORCIDs linked to this article

Genetics in Medicine : Official Journal of the American College of Medical Genetics, 19 Sep 2024, :101273
https://doi.org/10.1016/j.gim.2024.101273 PMID: 39306721 

This is an update of "Biallelic variation in the choline and ethanolamine transporter <i>FLVCR1</i> underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders." medRxiv. 2024 Feb 13:2024.02.09.24302464. doi: 10.1101/2024.02.09.24302464.

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.

Full text links 

Read article at publisher's site: https://doi.org/10.1016/j.gim.2024.101273

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Funding 

Funders who supported this work.

National Human Genome Research Institute