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

Biallelic SLC20A2 loss of function through a homozygous truncating variant with markedly reduced transcript levels, supporting a dose-dependent spectrum from adult heterozygous primary brain calcification to severe infantile disease.

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 remained poorly defined. The authors report a child carrying a homozygous nonsense variant, NM_001257180.2:c.1652G>A, p.(Trp551Ter), identified by whole-exome sequencing, presenting 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, while both heterozygous parents had radiologic findings consistent with SLC20A2-related primary brain calcification. RNA sequencing and RT-qPCR in patient fibroblasts showed markedly reduced SLC20A2 expression with no significant change in XPR1, and no overt Golgi fragmentation or ciliogenesis defect.

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The practical interest lies less in the variant than in the demonstration of a dosage gradient within one family: pauci-symptomatic but radiologically affected heterozygous parents, and a homozygous child with an encephalopathic course. Faced with a severe neurodevelopmental disorder plus calcification, this argues for imaging carrier relatives rather than declaring them unaffected, and for counselling that covers both recessive and late-penetrance dominant scenarios. The limitation must be stated plainly: a single index case, with an unusual imaging pattern whose specificity to the biallelic truncating genotype remains unproven.

Analysis by Dr Thibaut Benquey