CRADD

protein-coding

CASP2 and RIPK1 domain containing adaptor with death domain, the group of Caspase recruitment domain containing

Gene summary

This gene encodes a protein containing a death domain (DD) motif. This protein recruits caspase 2/ICH1 to the cell death signal transduction complex, which includes tumor necrosis factor receptor 1 (TNFR1A) and RIPK1/RIP kinase, and acts in promoting apoptosis. A mutation in this gene was associated with cognitive disability. A related pseudogene is found on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

MANE transcript

NM_003805.5

Inheritance

ClinVar variants

P:9U:35B:27

Top phenotype

Intellectual developmental disorder, autosomal recessive 34, with variant lissencephaly

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr12:93,677,375-93,894,840

External References & Databases

Ensembl (ENSG00000169372)

Transcript & Mutation Effects

hg38 • Region Span ~217.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: ClinGen

Variants in CRADD were initially reported in relation to autosomal recessive non-syndromic intellectual disability in 2012 in a Mennonite family with five individuals with developmental delay and intellectual disability (PMID: 22279524). Later, in 2016, variants in this gene were observed in individuals with lissencephaly and megalencephaly; this publication also reports MRI findings from the original Mennonite family reported in 2012, demonstrating that they also had lissencephaly (PMID: 27773430). Given the findings of developmental delay, intellectual disability, and lissencephaly, we chose to curate this gene for its relationship with autosomal recessive syndromic intellectual disability. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Biallelic frameshift, missense, and start-loss variants in CRADD have been reported in at least 47 probands in 6 publications (PMIDs: 22279524, 27773430, 28686357, 30167849, 33647455, 30914828); loss of function is the purported disease mechanism (PMIDs: 27773430, 28686357). Two founder variants have been identified in Mennonite and Finnish populations (PMIDs: 22279524, 27773430, 30914828). This gene-disease relationship is further supported by in vitro functional assays and a mouse model (PMID: 27773430). In summary, CRADD is definitively associated with autosomal recessive syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 06/16/2021 (SOP Version 8). Please note that while the genetic evidence score is tallied at 15 points, it should actually be 16 points to reflect scoring recommendations for autosomal recessive missense variants described in SOP version 8; at the time of this curation, the Gene Curation Interface was unable to accurately reflect these upgrades.

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 34, with variant lissencephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013785

Submitter: G2P

intellectual developmental disorder, autosomal recessive 34, with variant lissencephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013785

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 34, with variant lissencephalyAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22279524; 27773430

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRADD variants in ClinVar

10 Conditions Cataloged

not providedTotal: 49

Inborn genetic diseasesTotal: 25

Intellectual disability, autosomal recessive 34Total: 12

not specifiedTotal: 8

CRADD-related disorderTotal: 7

Intellectual disabilityTotal: 3

Moderate intellectual disabilityTotal: 1

Familial isolated arrhythmogenic right ventricular dysplasiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003805.5. 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			1 clinvar	20 clinvar	1 clinvar	22
missense	1 clinvar	2 clinvar	33 clinvar	5 clinvar	1 clinvar	42
nonsense		1 clinvar	1 clinvar			2
start loss	2 clinvar					2
frameshift	1 clinvar	2 clinvar				3
splice donor/acceptor (+/-2bp)						0
Total	4	5	35	25	2	71

Highest pathogenic variant AF is 0.00027390267

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003805.5	RefSeq	NP_003796.1	2	MANE Select
ENST00000332896.8	Ensembl	ENSP00000327647.3	2	MANE Select
NM_001320099.2	RefSeq	NP_001307028.1	2	Standard
NM_001320100.2	RefSeq	NP_001307029.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Apoptosis Modulation and Signaling
Apoptosis
Apoptotic Signaling Pathway
Gene expression (Transcription)
tnfr1 signaling pathway

Biological Process

activation of cysteine-type endopeptidase activity involved in apoptotic process
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
extrinsic apoptotic signaling pathway via death domain receptors
regulation of apoptotic process
positive regulation of apoptotic process

Molecular Function

protease binding
protein binding
protein binding, bridging
death domain binding

Cellular Component

nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000542893
Coding exons: 2
Length: 217466
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125747
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0968	118	121	0.975	0.00000736	1280
Missense (PolyPhen)		44	49.448	0.88983		549
Synonymous	-1.55	67	52.7	1.27	0.00000306	422
Loss of Function	2.43	0	6.87	0.00	2.94e-7	75

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Apoptotic adaptor molecule specific for caspase-2 and FASL/TNF receptor-interacting protein RIP. In the presence of RIP and TRADD, CRADD recruits caspase-2 to the TNFR-1 signalling complex.;
Disease: DISEASE: Mental retardation, autosomal recessive 34, with variant lissencephaly (MRT34) [MIM:614499]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT34 is a non-syndromic form. Affected individuals have mildly delayed development and significantly impaired cognitive function, precluding independent living and self-care. Speech is rudimentary, but articulate; autism is not present. {ECO:0000269|PubMed:22279524}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.146

Intolerance Scores

LoFtool: 0.215
RVIS EVS: -0.01
RVIS percentile EVS: 53.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.326

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium