Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features

• Published in: European journal of human genetics : EJHG Vol. 29; no. 8; pp. 1226 - 1234
• Main Authors: Zaki, Maha S., Accogli, Andrea, Mirzaa, Ghayda, Rahman, Fatima, Mohammed, Hiba, Porras-Hurtado, Gloria Liliana, Efthymiou, Stephanie, Maqbool, Shazia, Shukla, Anju, Vincent, John B., Hussain, Abrar, Mir, Asif, Beetz, Christian, Leubauer, Anika, Houlden, Henry, Gleeson, Joseph G., Maroofian, Reza
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.08.2021; Springer International Publishing
• Subjects: Adolescent; Adult; Apoptosis; Caspase-2; Child; Child, Preschool; Cognition; Death Domain Receptor Signaling Adaptor Proteins - genetics; Developmental Disabilities - genetics; Developmental Disabilities - pathology; DNA damage; Epilepsy; Female; Genes, Recessive; Hereditary diseases; Humans; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - pathology; Lissencephaly - genetics; Lissencephaly - pathology; Male; Megalencephaly; Mutation; Neocortex; Neurodevelopmental disorders; Neuroimaging; p53 Protein; Pedigree; Syndrome
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-021-00910-0

The PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outlin`e the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.