Biallelic XPR1 Variants Are Linked to Brain Calcifications, Developmental Delay, Hypophosphatemia, and...

XPR1 encodes the only known phosphate exporter in human cells and regulates the export of inorganic phosphate (Pi). To date, heterozygous pathogenic variants have been reported to be associated with autosomal-dominant idiopathic basal ganglia calcification-6 (IBGC6; MIM: 616413). We collate clinical information on individuals with biallelic XPR1 variants and use in silico and cell-based studies to evaluate pathogenicity. Four consanguineous families have been documented, with a severe neonatal phenotype presenting with persistent pulmonary hypertension, chronic lung disease, cardiomyopathy, and hypophosphatemia. Affected individuals exhibit microcephaly, intracranial calcifications, and profound neurodevelopmental impairment; the prognosis is generally poor. Exome and Sanger sequencing confirmed segregation with homozygosity for a rare, likely deleterious, biallelic XPR1 variant NM_004736.4: c.1811G>A: p.Arg604Gln. Analysis of primary cell lines showed stable expression of the XPR1 protein. In silico structural analysis supported the variant's deleterious nature. Published mutagenesis studies demonstrate that mutations at the arginine residue (Arg604) within the second putative Pi coordination site substantially impair Pi export in functional flux assays. This study establishes a link between a novel severe neonatal disease and specific biallelic variants in XPR1 that result in a loss-of-function phenotype.