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Expanding the phenotype associated with biallelic SLC20A2 variants

European Journal of Human Genetics volume 31, pages 725–729 (2023)Cite this article

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Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. Its prevalence is estimated from 4.5/10000 to 3.3/1000 [1]. To date, mutations in five genes have been linked to PFBC [1].

The SLC20A2 gene (MIM * 158378) encodes for the transmembrane type III sodium-dependent phosphate transporter 2 (PiT2), which is largely expressed in the brain, especially in the regions of globus pallidus, thalamus and cerebellum. Heterozygous pathogenic variants in SLC20A2 are predicted to cause a loss of function of the PiT2 protein through haploinsufficiency or dominant negative mechanism, leading to idiopathic basal ganglia calcification-1 (IBGC1) (MIM # 213600), also known as Fahr disease [2]. PiT2 dysfunction results in an accumulation of inorganic phosphate (Pi) in the extracellular matrix, causing insidious and progressive calcium accumulation in the brain parenchyma, typically in the basal ganglia, and vessels [2].

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Fig. 1: Brain MR angiography and MRI of the patient performed at 4 years and 3 months of age.
Fig. 2: Localization of pathogenic SLC20A2 variants in PFBC patients.

Data availability

All data generated or analyzed during this study are included in this published paper. Further inquiries can be directed to the corresponding author.

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Acknowledgements

We gratefully acknowledge the family for their participation in this study.

Funding

This work was supported by a grant of the Italian Ministry of Health (Ricerca Finalizzata RF-2019-12369247).

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Author notes

  1. These authors contributed equally: Gianluca D’Onofrio, Marcello Scala.

Authors and Affiliations

  1. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy

    Gianluca D’Onofrio, Marcello Scala & Pasquale Striano

  2. Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy

    Gianluca D’Onofrio, Marcello Scala & Pasquale Striano

  3. Unit of Medical Genetics, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy

    Marcello Scala, Ferruccio Romano, Patrizia De Marco, Michele Iacomino, Simona Baldassari, Federico Zara & Valeria Capra

  4. Neuroradiology Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy

    Mariasavina Severino

  5. Science of Health Department, School of Medicine, Magna Græcia University, 88100, Catanzaro, Italy

    Roberta Roberti

  6. Clinical Bioinformatics Unit, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy

    Paolo Uva

  7. Department of Neurosurgery, IRCCS Giannina Gaslini Institute, 16147, Genoa, Italy

    Marco Pavanello

  8. Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy

    Stefano Gustincich

Authors
  1. Gianluca D’Onofrio
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  14. Valeria Capra
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Contributions

MS and VC contributed to the study conception and design. GD’O and MS drafted the paper. FR, PDM, and FZ conducted the genetic studies. MS processed the neuroradiological features. RR, MC, and PS were involved in the clinical care of the patients and in collecting clinical and genetic data. All authors have critically revised the paper and approved the final one as submitted.

Corresponding authors

Correspondence to Marcello Scala or Valeria Capra.

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Competing interests

The authors declare no competing interests.

Ethics approval

The family involved in the study provided informed consent for being part of this study. The study was reviewed and approved by the Ethical Committee of the Gaslini Children’s Hospital (Genoa, Italy).

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D’Onofrio, G., Scala, M., Severino, M. et al. Expanding the phenotype associated with biallelic SLC20A2 variants. Eur J Hum Genet 31, 725–729 (2023). https://doi.org/10.1038/s41431-023-01349-1

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