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

SLC20A1 encodes the ubiquitously expressed phosphate transporter PiT1, a protein with roles extending beyond phosphate homeostasis to include regulation of proliferation, differentiation, apoptosis, and embryonic development. While heterozygous SLC20A1 variants have been associated with urinary tract malformations, the impact of biallelic loss-of-function was unknown. We report the first human case of a biallelic homozygous predicted loss of function variant in SLC20A1 (c.674_675delAA; p.K225TfsX34) in a child with multiple congenital anomalies including tetralogy of Fallot, unilateral renal agenesis, postaxial polydactyly, growth impairment, and developmental delay. PiT1 expression was decreased in fibroblasts of the proband. Transcriptome analysis of patient-derived fibroblasts suggests significant dysregulation of pathways critical for organogenesis, including PI3K-Akt, Wnt, MAPK, and BMP signaling. Population screening identified a carrier frequency of 1:432 among Ashkenazi Jewish individuals. Our findings expand the phenotypic spectrum of SLC20A1-related disease and provide evidence that biallelic PiT1 deficiency causes a previously unrecognized multisystem developmental disorder.