A novel SLC20A2 variant associated with primary brain calcification: A case report

Introduction

Bilateral intracranial calcifications predominantly affecting the basal ganglia represent a rare inherited neurological disorder characterized by wide clinical heterogeneity. This condition is termed primary brain calcification (PBC).^1,2 The clinical spectrum is highly variable and encompasses motor dysfunction, cognitive decline, and psychiatric disturbances, although some individuals may remain asymptomatic.^3,4 Genetic investigations have identified multiple associated genes, including autosomal dominant genes (SLC20A2, PDGFB, PDGFRB, and XPR1) and autosomal recessive genes (MYORG, JAM2, NAA60, and CMPK2).^5,6 Among these, SLC20A2, which encodes the type III sodium-dependent phosphate transporter 2 (PiT-2), is the most commonly implicated gene. PiT-2 is crucial for maintaining phosphate balance in the brain and preventing pathological calcium–phosphate accumulation.^7,8 Loss-of-function variants in SLC20A2 are associated with impaired phosphate transport, resulting in ectopic calcification of neural tissue. ⁹ This report describes a novel frameshift variant in SLC20A2 identified by whole-genome sequencing in a family with PBC.

Clinical presentation

The proband, a patient in her late 50s, presented with acute-onset speech impairment and was admitted to Huizhou Third People’s Hospital in April 2025. She also reported a long-standing history of dizziness and headaches. Her family history was notable: she had three children, one son and two daughters, all reportedly healthy (Figure 1(a)). Her 90-year-old father had been diagnosed with Parkinson’s syndrome, her younger brother had died from a brain tumor at the age of 40 years, and her younger sister remained asymptomatic. Cranial computed tomography (CT) led to the detection of bilateral and symmetric calcifications in the basal ganglia and cerebellar dentate nuclei. Magnetic resonance imaging (MRI) further identified an acute ischemic stroke within the left frontoparietal region (Figure 1(b)). The patient was managed with standard therapy for acute ischemic stroke and hypertension, including antiplatelet agents, statins, and antihypertensive drugs, with appropriate dosing and scheduled clinical follow-up.

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Figure 1.

Pedigree, imaging findings, and genetic testing results. (a) Pedigree of the patient (squares: males; circles: females), in which black and white denote affected and healthy individuals, respectively. The proband is denoted by a filled black circle and an arrow. (b) Proband (I1) cranial computed tomography (CT) revealing symmetrical calcifications in the bilateral basal ganglia and dentate nucleus of the cerebellum. Magnetic resonance imaging (MRI) revealing evidence of an acute cerebral infarction in the left frontoparietal lobe. Cranial CT of the eldest daughter (II1) and son (II2) also demonstrated symmetric bilateral basal ganglia calcifications. However, CT in the youngest daughter (II3) showed no apparent abnormalities. (c) Genetic testing revealing heterozygous SLC20A2 variant (Chr8:42294940:CG>C) in the proband (I1), eldest daughter (II1), and son (II2), whereas the youngest daughter (II3) did not harbor the variant.

Genomic analysis performed using whole-genome sequencing detected a heterozygous frameshift variant in SLC20A2 (NM_001257180.2), which is known to be implicated in PBC. The specific variant (c.1089del) results in a frameshift leading to the substitution of isoleucine with methionine at position 363, followed by a premature termination codon at residue 92 (p.Ile363MetfsTer92) (Figure 1(c)). This variant is novel, as it was not identified in gnomAD, ClinVar, dbSNP, HGMD professional, or LOVD. To investigate inheritance patterns, we conducted Sanger sequencing on the patient and her children. The identified variant was present in the son and eldest daughter (Figure 1(c)), both of whom demonstrated multiple intracranial calcifications on CT (Figure 1(b)). However, both individuals remained clinically asymptomatic, with no neurological or psychiatric abnormalities, and neurological examination findings were normal. The second daughter tested negative for the variant and demonstrated no evidence of intracranial calcification (Figure 1(b)). The SLC20A2 variant c.1089del (p.Ile363MetfsTer92) was classified as likely pathogenic according to the ACMG-AMP guidelines. ¹⁰ This interpretation was supported by PVS1 (very strong), as the frameshift variant (c.1089del) introduces a premature stop codon (p.Ile363MetfsTer92), resulting in a truncated protein consistent with a loss-of-function (LOF) mechanism; PM2 (moderate), as the variant is absent from population frequency databases, including gnomAD, ESP, and the 1000 Genomes Project; and PP1 (supporting), because of co-segregation with radiological disease features in affected family members, including the proband, son, and eldest daughter, whereas the unaffected daughter carried the wild-type allele. This segregation pattern supports an autosomal dominant inheritance pattern.

All patient identifiers were removed to ensure anonymity. Written informed consent for publication of the case and images was obtained from the family. Ethical approval was granted by the Ethics Committees of Huizhou Third People’s Hospital (Approval number: 2025-KY-038-01). The study conforms to the Case Report (CARE) guidelines. ¹¹

Discussion

The proband reported a long-standing history of dizziness and headaches, which are common and nonspecific manifestations of PBC and are considered part of its phenotypic spectrum. ³ The acute ischemic stroke observed in this case is most consistent with an incidental comorbidity rather than a direct consequence of the SLC20A2 variant or PBC. The patient had multiple established vascular risk factors, including hypertension, hyperlipidemia, and extensive intracranial arterial stenosis, which sufficiently explain the cerebrovascular event. Currently, no evidence supports a causal relationship between SLC20A2-associated brain calcification and ischemic stroke risk; therefore, such an association should be interpreted with caution. Patients with PBC may present with multiple coexisting age-related comorbidities, including cerebrovascular disease. As reported by Gugler et al., ¹² complex clinical phenotypes in PBC do not necessarily require a single unifying explanation. The neurological findings in this patient likely reflect overlapping PBC-related manifestations and independent age-associated pathology, highlighting the multifactorial nature of the clinical presentation.

Neuroimaging demonstrated bilateral and symmetric calcifications involving the basal ganglia and cerebellar dentate nuclei, consistent with the characteristic radiological phenotype of PBC. These findings represented a hallmark feature of SLC20A2-related disease and prompted genetic investigation. The novel frameshift variant c.1089del (p.Ile363MetfsTer92) identified in this study is predicted to generate a premature termination codon, resulting in a truncated and nonfunctional PiT-2 transporter. This LOF mechanism disrupts phosphate homeostasis in the central nervous system, leading to ectopic calcium–phosphate deposition, consistent with established pathogenic mechanisms in SLC20A2-associated PBC. ¹³

Segregation analysis, although limited by the small family size, demonstrated co-segregation of the variant with radiological abnormalities across two generations. Together with strong genetic evidence (PVS1 + PM2), these findings support classification of the variant as likely pathogenic. The proband’s father and younger brother were not available for clinical or genetic evaluation; therefore, their disease status remains undetermined, and no definitive conclusion can be drawn regarding a potential association between their clinical phenotypes and familial PBC. The father’s Parkinsonism at an advanced age is most consistent with a separate age-related condition rather than a manifestation of PBC.

Conclusion

A novel frameshift variant in SLC20A2 was identified in this study, contributing to the expansion of the known mutational spectrum of PBC. This variant is predicted to exert a LOF effect through protein truncation, consistent with the established disease mechanism of SLC20A2-related PBC. Although these findings provide incremental evidence supporting the pathogenicity of this variant, further independent case reports and functional studies are required for definitive validation. The results emphasize the importance of genetic testing in facilitating accurate molecular diagnosis, family-based screening, and genetic counseling in familial intracranial calcification cases, particularly in asymptomatic individuals at risk.