PIDD1

protein-coding

p53-induced death domain protein 1

Gene summary

The protein encoded by this gene contains a leucine-rich repeat and a death domain. This protein has been shown to interact with other death domain proteins, such as Fas (TNFRSF6)-associated via death domain (FADD) and MAP-kinase activating death domain-containing protein (MADD), and thus may function as an adaptor protein in cell death-related signaling processes. The expression of the mouse counterpart of this gene has been found to be positively regulated by the tumor suppressor p53 and to induce cell apoptosis in response to DNA damage, which suggests a role for this gene as an effector of p53-dependent apoptosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

Previous symbols:

LRDD
PIDD

MANE transcript

NM_145886.4

Inheritance

ClinVar variants

P:23U:242B:71

Top phenotype

intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr11:799,179-809,753

External References & Databases

Ensembl (ENSG00000177595)

Transcript & Mutation Effects

hg38 • Region Span ~10.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030785

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephalyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030785

Submitter: ClinGen

*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).

intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030785

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PIDD1 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 233

not providedTotal: 54

Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephalyTotal: 34

not specifiedTotal: 32

PIDD1-related disorderTotal: 29

PIDD1-associated neurodevelopmental disorderTotal: 2

Intellectual disabilityTotal: 2

Developmental and epileptic encephalopathy, 3Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145886.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	34 clinvar	6 clinvar	44
missense	2 clinvar		233 clinvar	27 clinvar	4 clinvar	266
nonsense	1 clinvar	2 clinvar	2 clinvar			5
start loss						0
frameshift	5 clinvar	7 clinvar	1 clinvar			13
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	2 clinvar			8
Total	10	13	242	61	10	336

Highest pathogenic variant AF is 0.0000882716

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 76 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_145886.4	RefSeq	NP_665893.2	15	MANE Select
ENST00000347755.10	Ensembl	ENSP00000337797.5	15	MANE Select
NM_145887.4	RefSeq	NP_665894.2	15	Standard
ENST00000411829.6	Ensembl	ENSP00000416801.2	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

p53 signaling pathway - Homo sapiens (human)
Apoptosis - Homo sapiens (human)
NF-kappa B signaling pathway - Homo sapiens (human)
miRNA Regulation of DNA Damage Response
Apoptosis Modulation and Signaling

Biological Process

apoptotic process
activation of cysteine-type endopeptidase activity involved in apoptotic process
cellular response to DNA damage stimulus
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
signal transduction

Molecular Function

endopeptidase activity
death receptor binding
volume-sensitive anion channel activity
protein binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
Golgi apparatus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000347755
Coding exons: 15
Length: 10575
Individuals with no LoFs: 125445
Homozygous LoFs: 0
Heterozygous LoFs: 108
Defined: 125553
p: 0.000430

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.838	634	577	1.10	0.0000396	5617
Missense (PolyPhen)		223	210.35	1.0601		2282
Synonymous	-1.74	287	252	1.14	0.0000158	2098
Loss of Function	1.07	29	35.9	0.807	0.00000190	362

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00083	0.00074	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.0017	0.0017	notable
East Asian	0.00077	0.00076	rare
Finnish	0.00025	0.00023	rare
European (Non-Finnish)	0.00035	0.00034	rare
South Asian	0.00063	0.00059	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes apoptosis downstream of the tumor suppressor as component of the DNA damage/stress response pathway that connects p53/TP53 to apoptosis. Associates with NEMO/IKBKG and RIP1 and enhances sumoylation and ubiquitination of NEMO/IKBKG which is important for activation of the transcription factor NF-kappa-B. Associates with CASP2/caspase-2 and CRADD/RAIDD, and induces activation of CASP2 which an important regulator in apoptotic pathways. {ECO:0000269|PubMed:10973264, ECO:0000269|PubMed:15073321, ECO:0000269|PubMed:16360037}.;

Recessive Scores

pRec: 0.106

Intolerance Scores

RVIS EVS: -1.38
RVIS percentile EVS: 4.36

Essentials

Essential (gene trap): N