Submission Details

PIDD1 was first reported in relation to autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly in 2018 (Harripaul et al., PMID: 28397838). This disorder is characterized by moderate to severe global developmental delay/intellectual disability, and variant lissencephaly with neuropsychiatric features. Nine variants (missense, nonsense, frameshift, and splicing) that have been reported in 11 probands in 4 publications (PMIDs: 28397838, 29302074, 33414379, 34163010) are included in this curation. All the reported probands were from consanguineous families and are homozygous. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is believed to be loss of function. This gene-disease relationship is also supported by in vitro functional assays (PMID: 33414379). Four different biallelic variants in PIDD1 (p.Gln863*, p.Arg637*, c.2275-1G>A and p.Arg815Trp ) were found to disrupt the Death Domain (DD), through which PIDD1 interacts with CRADD and RIP1. Nonsense variants Gln863* and Arg637* directly disrupt the DD, as does a missense variant, Arg815Trp. In HEK293 cells, both Gln863*and Arg815Trp mutants failed to co-localize with CRADD, leading to pidd1 aggregation, mis-localization, and failure to co-precipitate CRADD. All the three PIDD1 variants listed above caused loss of PIDDosome function in genome-edited cell lines. In summary, there is definitive evidence to support the relationship between PIDD1 and autosomal recessive intellectual developmental disorder-75 with neuropsychiatric features and variant lissencephaly. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen ID/Autism GCEP on the meeting date June 4th, 2024 (SOP Version 10).