Biallelic SLC20A2 loss-of-function in severe early-onset neurodevelopmental disorder with brain calcification.

Biallelic SLC20A2 variants have recently been linked to a severe childhood-onset phenotype distinct from classical adult-onset primary brain calcification, but the molecular and radiologic consequences of homozygous truncating variants remain incompletely defined. We describe a child with severe early-onset neurodevelopmental disease caused by a homozygous SLC20A2 nonsense variant and provide clinical, neuroradiologic, segregation, and transcript-level characterization. The patient presented in early infancy with refractory seizures, severe hypotonia, left hemiplegia, profound developmental impairment, bilateral cataracts, and progressive intracranial calcification. Neuroimaging showed an unusual vascular and leptomeningeal calcification pattern with arterial narrowing, cytotoxic edema, subdural effusion, and rapid cerebral atrophy. Whole-exome sequencing identified a homozygous truncating variant, NM_001257180.2:c.1652 G > A, p.(Trp551Ter), in SLC20A2; both parents were heterozygous and showed radiologic findings consistent with SLC20A2-related primary brain calcification. RNA sequencing and RT-qPCR demonstrated marked reduction of SLC20A2 expression in patient-derived fibroblasts, supporting biallelic loss of function, whereas XPR1 expression was not significantly altered. Patient fibroblasts did not show overt Golgi fragmentation or ciliogenesis defects. These findings support a dose-dependent SLC20A2 disease spectrum and expand the phenotype associated with biallelic loss of function from primary brain calcification toward severe early-onset neurodevelopmental disorder with prominent vascular and leptomeningeal calcification.