Homozygous Loss-of-Function Variant in SLC20A1 Coding for Ubiquitous Phosphate Transporter PiT1 Is Associated With Multiple Developmental Abnormalities

Homozygous SLC20A1 loss-of-function, ubiquitous phosphate transporter PiT1, dysregulation of cell proliferation/differentiation

The first human case of a homozygous loss-of-function variant in SLC20A1 is reported in a child with tetralogy of Fallot, unilateral renal agenesis, and polydactyly. SLC20A1 encodes PiT1, a ubiquitous phosphate transporter involved in regulation of cell proliferation, differentiation, and apoptosis. Heterozygous variants had been associated with urinary tract malformations, but the severe biallelic multisystemic phenotype had never been described in humans — homozygous murine models being embryonically lethal.

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This first biallelic case extends SLC20A1 pathogenicity to an autosomal recessive spectrum distinct from the known heterozygous urinary phenotype. Should be referenced in genotypic databases as a gene to consider for Fallot + renal agenesis + polydactyly malformation associations, to facilitate diagnosis of future cases.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 0/1 · Publication status: 1/1 → Total: 7/10