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

Area of Science:

• Neurogenetics
• Molecular Neurology
• Radiology

Background:

• Primary brain calcification (PBC) is a rare neurological disorder characterized by abnormal calcium deposition in the brain.
• Genetic factors play a significant role in the pathogenesis of PBC, but the mutational spectrum is not fully elucidated.

Purpose of the Study:

• To identify the genetic cause of primary brain calcification in a patient presenting with speech impairment and intracranial calcifications.
• To characterize a novel variant in the SLC20A2 gene and assess its pathogenicity and familial segregation.

Main Methods:

• Brain computed tomography (CT) for radiological assessment of intracranial calcifications.
• Whole-genome sequencing (WGS) for identifying genetic variants.
• Segregation analysis within the affected family.
• Variant classification according to American College of Medical Genetics and Genomics (ACMG) guidelines.

Main Results:

• A novel frameshift variant (c.1089del, p.Ile363MetfsTer92) in the SLC20A2 gene was identified in the proband.
• The SLC20A2 variant was found to segregate with the disease phenotype in the patient's son and eldest daughter, both exhibiting intracranial calcifications.
• The second daughter, negative for the variant, showed no signs of calcification, supporting the variant's role in PBC.
• The identified variant was classified as likely pathogenic based on ACMG criteria.

Conclusions:

• This case report describes a novel loss-of-function variant in SLC20A2, expanding the known mutational spectrum for primary brain calcification.
• Genetic testing, particularly WGS, is crucial for accurate diagnosis and effective genetic counseling in families affected by PBC.
• The findings underscore the importance of SLC20A2 in brain calcification pathogenesis and highlight its clinical utility in diagnosing rare neurological disorders.