A novel de novo ATP2B1 variant causes autosomal dominant intellectual developmental disorder 66 by disrupting calcium homeostasis via impaired membrane trafficking

Heterozygous pathogenic variants in ATP2B1 (encoding PMCA1) cause autosomal dominant intellectual developmental disorder 66 (MRD66; OMIM #619910). To date, only 12 pathogenic de novo ATP2B1 variants have been reported in MRD66. This study aimed to identify the genetic etiology in a Chinese infant with a neurodevelopmental disorder characterized by early-onset seizures and global developmental delay (GDD) and functionally characterize a novel ATP2B1 missense variant. Trio-based whole-exome sequencing revealed a heterozygous de novo ATP2B1 variant (c.2140A>C, p.Thr714Pro) in the proband. The proband presented with infantile spasms, GDD (Gesell Developmental Quotient: 65–74), and severe growth restriction (height/weight