| First Author | Yap P | Year | 2023 |
| Journal | Eur J Hum Genet | PubMed ID | 37926713 |
| Mgi Jnum | J:343177 | Mgi Id | MGI:7564371 |
| Doi | 10.1038/s41431-023-01484-9 | Citation | Yap P, et al. (2023) Biallelic ATP2B1 variants as a likely cause of a novel neurodevelopmental malformation syndrome with primary hypoparathyroidism. Eur J Hum Genet |
| abstractText | ATP2B1 encodes plasma membrane calcium-transporting-ATPase1 and plays an essential role in maintaining intracellular calcium homeostasis that regulates diverse signaling pathways. Heterozygous de novo missense and truncating ATP2B1 variants are associated with a neurodevelopmental phenotype of variable expressivity. We describe a proband with distinctive craniofacial gestalt, Pierre-Robin sequence, neurodevelopmental and growth deficit, periventricular heterotopia, brachymesophalangy, cutaneous syndactyly, and persistent hypocalcemia from primary hypoparathyroidism. Proband-parent trio exome sequencing identified compound heterozygous ATP2B1 variants: a maternally inherited splice-site (c.3060+2 T > G) and paternally inherited missense c.2938 G > T; p.(Val980Leu). Reverse-transcription-PCR on the proband's fibroblast-derived mRNA showed aberrantly spliced ATP2B1 transcripts targeted for nonsense-mediated decay. All correctly-spliced ATP2B1 mRNA encoding p.(Val980Leu) functionally causes decreased cellular Ca(2+) extrusion. Immunoblotting showed reduced fibroblast ATP2B1. We conclude that biallelic ATP2B1 variants are the likely cause of the proband's phenotype, strengthening the association of ATP2B1 as a neurodevelopmental gene and expanding the phenotypic characterization of a biallelic loss-of-function genotype. |
