Objective: To systematically identify monogenic disorders associated with intracranial intraparenchymal brain calcification and synthesise their clinical, radiological and molecular features.

Background: Brain calcification is a neuroradiological phenotype with a broad differential diagnosis. While primary familial brain calcification (PFBC) is the prototypic inherited form, published data suggest a much wider spectrum of genetic disorders involving phosphate homeostasis, neurovascular integrity, mitochondrial function, interferon signalling and mineral metabolism.

Method: We performed a systematic review of PubMed from inception to 30 September 2025 in accordance with PRISMA 2020. Records were screened independently by 2 reviewers using a broad search strategy for brain calcification. Studies reporting human cases with intracranial brain calcification and a genetic cause were included for full-text review and patient-level data extraction where possible. Extracted variables included demographics, phenotype, neuroimaging pattern, investigations and genetic findings. Descriptive analyses were performed in R.

Results: Of 7,312 records identified, eligible studies were included in the final analysis, comprising patients with pathogenic variants across a broad range of genes. Disorders extended beyond canonical PFBC genes and included mitochondrial disorders, interferonopathies, microangiopathies, developmental syndromes and disorders of mineral metabolism. Calcification most commonly involved the basal ganglia, dentate nuclei and subcortical white matter, although anatomical distribution varied by molecular class, supporting distinctions between PFBC and non-PFBC disorders.

Conclusion: Genetic brain calcification extends well beyond PFBC and represents a biologically heterogeneous group of disorders. Integrating imaging pattern with neurological, systemic and molecular features may improve diagnostic stratification and support more rational genetic testing in patients presenting with intracranial calcification.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-architecture-of-intracranial-brain-calcification-a-systematic-review/