An in‐frame deletion affecting the critical acid loop of PPP2R5D is associated with a neonatal lethal form of PPP2R5D‐related neurodevelopmental disorder

Abstract

AbstractHeterozygous pathogenic variants in PPP2R5D gene are associated with PPP2R5D‐related neurodevelopmental disorder, a rare autosomal dominant condition, characterized by neurodevelopmental impairment in childhood, macrocephaly/megalencephaly, hypotonia, epilepsy, and dysmorphic features. Up‐to‐date, only approximately 100 cases have been published in the literature and the full phenotypic and genotypic spectrum have not yet been fully described. PPP2R5D gene encodes the B56δ subunit of the PP2A enzyme complex. We describe a neonatal form of PPP2R5D‐related disorder with early infantile death, caused by a novel in‐frame deletion causing loss of 8 amino acids and insertion of serine at position 201 (p.Phe194_Pro201delinsSer) of the B56δ subunit. This deletion is predicted to disrupt a critical acidic loop of amino acids important for binding other subunits of the PP2A enzyme complex, and harbors many of the residues previously reported to cause a mild–moderate form of this condition. This report describes a neonatal lethal presentation of the PPP2R5D‐related neurodevelopmental disorder and provides additional evidence that disruption of the acidic loop is an important pathomechanism underlying PPP2R5D‐related disorder.