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

Maha S Zaki,Reza Maroofian,Andrea Accogli,Shazia Maqbool,John B Vincent,Henry Houlden,Stephanie Efthymiou,Anika Leubauer,Ghayda Mirzaa,Asif Mir,Christian Beetz,Joseph G Gleeson,Anju Shukla,Hiba Mohammed,Fatima Rahman,Abrar Hussain,Gloria Liliana Porras-Hurtado

doi:10.1038/s41431-021-00910-0

Abstract

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.

Highlights

The PIDDosome is a multiprotein complex that drives activation of the endopeptidase caspase-2 upon genotoxic stress to induce apoptosis [1, 2]
In the last few years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) described as “thin” lissencephaly (TLIS) variant and characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability (ID) [4]
We report 11 new patients with 5 novel homozygous variants in PIDD1, delineating the main phenotype associated with PIDD1-related disorder, previously described as part of large cohort studies with limited clinical information (Supplementary Table 2)

Summary

Introduction

The PIDDosome is a multiprotein complex that drives activation of the endopeptidase caspase-2 upon genotoxic stress to induce apoptosis [1, 2] It is composed by the p53induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD ( known as RAIDD) and the. In the last few years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) described as “thin” lissencephaly (TLIS) variant and characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability (ID) [4] This finding has raised attention on the PIDDosome complex, revealing additional biological functions aside the DNA-damage induced apoptosis [5]. The CRADDinteracting protein PIDD1 can function as a sensor surveilling centrosome numbers, critically regulating cellular

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