CRADD-Related Thin Lissencephaly

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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic CRADD variants segregate with disease. Homozygous and compound heterozygous cases are reported. Clinical severity varies substantially, including an apparently healthy homozygous father whose MRI showed hypogyration; genotype does not predict a uniformly severe lissencephaly outcome.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:27773430 SUPPORT Human Clinical

"individuals with recessive CRADD mutations (n = 13) presented with TLIS, mild to moderate ID, epilepsy (3 of 13)"

The expanded founding cohort links the recessive genotype to cortical malformation and neurodevelopmental manifestations.

PMID:28686357 SUPPORT Human Clinical

"the allegedly healthy father was also found to be homozygous for the variant, prompting evaluation by brain MRI which revealed hypogyration."

A mildly affected adult illustrates variable expression and the limits of prenatal prognostication.

PMID:33710394 SUPPORT Human Clinical

"In family FIN38 a Finnish founder variant ... (Polla et al. 2019) and a novel start loss variant ... in CRADD were identified."

The later Finnish case extends the allelic spectrum beyond homozygous founder variants.

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Mechanistic Hypotheses

2

Reduced developmental cell death as the bridge to cortical malformation

cradd_developmental_apoptosis EMERGING

Evidence balance 1 support

Cell and mouse experiments motivate a developmental apoptosis model, but human cortical apoptosis and migration have not been directly distinguished. Synapse pruning and whole-cell death remain alternative or complementary intermediates.

Pathograph links

Reduced Caspase-2-Dependent Neuronal Apoptosis -> Abnormal Cortical Gyration INDIRECT UNKNOWN INTERMEDIATES Reduced developmental neuronal or synaptic elimination is proposed to disturb human cortical formation; the responsible cell population and process are unresolved.

Reduced Caspase-2-Dependent Neuronal Apoptosis -> Brain Overgrowth INDIRECT UNKNOWN INTERMEDIATES Reduced developmental cell death is a candidate explanation for variable brain enlargement, not a directly demonstrated human intermediate.

Show evidence (1 reference)

PMID:27773430 SUPPORT Other

"It is not clear whether the megalencephaly, undulating pachygyria, increased cortical thickness, and intellectual disability characteristic of CRADD-TLIS result from reduced pruning of synaptic connections, decreased programmed cell death of inappropriate neurons, or a combination of the two."

The authors leave the human developmental intermediate unresolved.

Assembly impairment as an allele-specific route to adaptor dysfunction

cradd_assembly_activity EMERGING

Evidence balance 2 support

Purified R170C/H proteins fail stable complex assembly, while cellular pairwise PIDD binding is retained. A functional connection between these assay-specific observations and lost adaptor activity remains proposed.

Pathograph links

Impaired PIDDosome Assembly -> Loss of CRADD Adaptor Activity INDIRECT UNKNOWN INTERMEDIATES Impaired stable assembly is a proposed allele-specific route to lost adaptor function for R170C/H. Purified-protein assembly and cellular binding/activation use different preparations, so this bridge is not directly established in developing human cortex.

Show evidence (2 references)

PMID:30281648 SUPPORT In Vitro

"The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution peaks after size exclusion chromatography"

Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation gives a different result.

PMID:27773430 SUPPORT In Vitro

"Immunoprecipitation of recombinant FLAG-CRADD overexpressed in Neuro2a (data not shown) and HEK293T cells co-precipitated V5-PIDD-DD for each of the CRADD-TLIS variants except p.Gly128Arg"

Cellular PIDD binding is retained for three variants, with G128R the exception.

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Discussions and Knowledge Gaps

3

Which developmental process connects impaired CRADD signaling to human cortical malformation, and which models can distinguish altered neuronal death from synaptic remodeling?

HUMAN MODEL MISMATCH OPEN gap_cradd_mouse_model_lamination_mismatch

Attached to

pathophysiology#Reduced Caspase-2-Dependent Neuronal Apoptosis pathophysiology#Abnormal Cortical Gyration

Cradd-null mice show brain enlargement and handling-induced seizures but normal cortical layering. Patient-variant experiments establish impaired caspase-2 activation and cell death in cultured cells. They do not directly distinguish altered neuronal death, synaptic remodeling or another developmental process in human cortex. Human cortical models and gyrencephalic organisms could test the proposed bridge without assuming it.

Proposed experiments

CRADD-null / CRADD-TLIS human cortical organoid apoptosis and lamination assay

iPSC organoid perturbation assay

exp_cradd_human_organoid_apoptosis

Generate CRADD-null and patient-variant (e.g., p.Gly128Arg) iPSC-derived cortical organoids and quantify caspase-2 activation, developmental neuronal apoptosis, neuron number, cortical-plate thickness, and lamination relative to isogenic controls, to test whether reduced caspase-2-mediated apoptosis produces a human cortical-architecture phenotype not seen in mouse.

Model systems

Human iPSC-derived cortical organoid

Cortical organoid differentiated from patient-derived or gene-edited human iPSCs carrying CRADD loss-of-function variants.

ORGANOID

CRADD loss in a gyrencephalic model

in vivo gene perturbation

exp_cradd_gyrencephalic_model

Evaluate cortical lamination, gyration, and brain size after CRADD loss-of-function in a gyrencephalic species (e.g., ferret) that, unlike the mouse, normally gyrifies, to test whether the human-like cortical phenotype emerges when a gyrencephalic developmental program is present.

Model systems

Gyrencephalic mammalian model

A gyrencephalic species with an outer subventricular zone and cortical folding, contrasting with the lissencephalic mouse.

OTHER

Show evidence (2 references)

PMID:27773430 SUPPORT Model Organism

"Morphological analysis of Cradd−/− cortex revealed normal layering indistinguishable from WT mice"

Normal layering in the knockout does not establish or reproduce the human MRI gyral pattern.

PMID:27773430 SUPPORT Other

"It is not clear whether the megalencephaly, undulating pachygyria, increased cortical thickness, and intellectual disability characteristic of CRADD-TLIS result from reduced pruning of synaptic connections, decreased programmed cell death of inappropriate neurons, or a combination of the two."

The authors leave the human developmental intermediate unresolved.

Why do R170C/H retain PIDD association in cellular coimmunoprecipitation but fail stable assembly in purified-protein assays?

KNOWLEDGE GAP OPEN gap_cradd_pidd_binding_assay_difference

Attached to

pathophysiology#Impaired PIDDosome Assembly

Pairwise association and higher-order stable assembly can differ, and the experiments use different protein preparations. Their relevance to developing human cortex is unresolved.

Show evidence (2 references)

PMID:27773430 SUPPORT In Vitro

"Immunoprecipitation of recombinant FLAG-CRADD overexpressed in Neuro2a (data not shown) and HEK293T cells co-precipitated V5-PIDD-DD for each of the CRADD-TLIS variants except p.Gly128Arg"

Cellular PIDD binding is retained for three variants, with G128R the exception.

PMID:30281648 SUPPORT In Vitro

"The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution peaks after size exclusion chromatography"

Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation gives a different result.

What explains the additional findings in the family carrying linked homozygous CRADD and USP44 variants?

KNOWLEDGE GAP OPEN gap_cradd_usp44_linked_variants

The reported adults have skeletal, facial and digestive findings whose attribution remains uncertain; cosegregation of linked variants cannot assign each manifestation to one gene.

Show evidence (1 reference)

PMID:33647455 SUPPORT Human Clinical

"whether the damaging USP44 variant contributed to the disease in the family we present is not clear."

The authors leave the contribution of the second gene unresolved.

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Pathophysiology

7

Loss of CRADD Adaptor Activity

Disease-associated alleles impair the adaptor pathway that recruits and activates caspase-2. Direct functional evidence is strongest for the four tested death-domain missense alleles; protein depletion, assembly defects and preserved pairwise interactions depend on the allele and assay.

Genetic context CRADD hgnc:2340 variant_origin: GERMLINE functional_impact: Loss of CRADD-dependent caspase-2 activation; allele-specific protein and interaction defects.

protein-macromolecule adaptor activity GO:0030674 ↓ DECREASED

Downstream

Reduced Caspase-2 Activation Directly tested missense proteins fail to activate caspase-2.

Intellectual Disability Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.

Delayed Speech and Language Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.

Global Developmental Delay Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.

Seizures Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.

Aggressive Behavior Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.

Show evidence (2 references)

PMID:27773430 SUPPORT Other

"CRADD (also known as RAIDD) is a death-domain-containing adaptor protein that oligomerizes with PIDD and caspase-2 to initiate apoptosis."

Normal molecular adaptor function, interpreted with the adjacent variant-activation assay.

PMID:27773430 SUPPORT In Vitro

"We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not."

Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.

Gly128Arg CRADD Protein Depletion

G128R patient fibroblasts contain very little CRADD; overexpressed G128R also shows reduced abundance and abnormal aggregates. This protein-depletion phenotype is not demonstrated for every disease allele.

Experimental models

G128R patient dermal fibroblasts PRIMARY CELL CULTURE Experimental observations inform this node within the stated preparation.

Downstream

Loss of CRADD Adaptor Activity Allele-specific loss of available adaptor protein.

Show evidence (1 reference)

PMID:27773430 SUPPORT In Vitro

"Dermal fibroblasts from p.Gly128Arg CRADD TLIS-affected subjects are essentially null for CRADD abundance"

Patient-derived fibroblasts demonstrate allele-specific protein depletion; other alleles were not tested in patient fibroblasts.

Impaired PIDDosome Assembly

Purified R170C/H CRADD death domains and full-length proteins show impaired stable assembly with PIDD-DD. F164C is unstable in the recombinant preparation and G128R could not be expressed. Cellular coimmunoprecipitation retains PIDD binding for F164C/R170C/R170H, so loss of all PIDD interactions is not a universal established mechanism.

Assembly impairment as an allele-specific route to adaptor dysfunction

Experimental models

Purified RAIDD–PIDD death-domain complexes OTHER Experimental observations inform this node within the stated preparation.

Downstream

Loss of CRADD Adaptor Activity Impaired stable assembly is a proposed allele-specific route to lost adaptor function for R170C/H. Purified-protein assembly and cellular binding/activation use different preparations, so this bridge is not directly established in developing human cortex.

Show evidence (2 references)

PMID:30281648 SUPPORT In Vitro

"The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution peaks after size exclusion chromatography"

Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation gives a different result.

PMID:27773430 SUPPORT In Vitro

"Immunoprecipitation of recombinant FLAG-CRADD overexpressed in Neuro2a (data not shown) and HEK293T cells co-precipitated V5-PIDD-DD for each of the CRADD-TLIS variants except p.Gly128Arg"

Cellular PIDD binding is retained for three variants, with G128R the exception.

Reduced Caspase-2 Activation

The four tested disease-associated missense proteins retain measurable caspase-2 binding when normalized for abundance but fail to activate caspase-2 in PC12 cells.

cysteine-type endopeptidase activator activity involved in apoptotic process GO:0008656 ↓ DECREASED

Experimental models

PC12 protein-import caspase and survival assays CELL LINE Experimental observations inform this node within the stated preparation.

Downstream

Reduced Caspase-2-Dependent Neuronal Apoptosis Loss of caspase-2 activation accompanies failure to induce cell death in the import assay.

Show evidence (1 reference)

PMID:27773430 SUPPORT In Vitro

"We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not."

Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.

Reduced Caspase-2-Dependent Neuronal Apoptosis

Imported wild-type CRADD induces PC12 cell death and death of cultured Cradd-null sympathetic neurons; disease-associated proteins fail in PC12 cells, and G128R fails in the sympathetic-neuron assay. Reduced apoptosis during human corticogenesis is a hypothesis extrapolated from these experiments.

Reduced developmental cell death as the bridge to cortical malformation

neuron CL:0000540

neuron apoptotic process GO:0051402 ↓ DECREASED

Experimental models

PC12 protein-import caspase and survival assays CELL LINE Experimental observations inform this node within the stated preparation.

Cradd-null sympathetic neuron cultures PRIMARY CELL CULTURE Experimental observations inform this node within the stated preparation.

Downstream

Abnormal Cortical Gyration Reduced developmental neuronal or synaptic elimination is proposed to disturb human cortical formation; the responsible cell population and process are unresolved.

Brain Overgrowth Reduced developmental cell death is a candidate explanation for variable brain enlargement, not a directly demonstrated human intermediate.

Show evidence (2 references)

PMID:27773430 SUPPORT In Vitro

"Transduction of PC12 cells with Pen1-linked CRADD-TLIS variants (p.Gly128Arg, p.Phe164Cys, p.Arg170Cys, and p.Arg170His) failed to induce cell death"

All four tested missense variants failed to reproduce the cell death induced by imported wild-type CRADD.

PMID:27773430 SUPPORT In Vitro

"CRADD WT resulted in significant cell death of primary sympathetic neurons from Cradd−/− mice 1 day after transduction, whereas cell survival after transduction of p.Gly128Arg CRADD was indistinguishable from that of non-transduced cells"

The neuronal culture experiment tested G128R against wild-type protein; it is not a measurement of human fetal apoptosis.

Abnormal Cortical Gyration

Frontotemporal predominant broad gyri and shallow sulci accompany a mildly thick cortex, usually 5–7 mm and up to 8 mm in the Finnish series. Imaging establishes cortical morphology, not a histological migration or apoptosis defect.

Animal models

Cradd-null mouse Mus musculus fails to recapitulate Experimental observations inform this node within the stated preparation.

Downstream

Thin Lissencephaly The cortical imaging pattern defines this manifestation.

Show evidence (2 references)

PMID:30914828 SUPPORT Human Clinical

"The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening."

The indexed primary report establishes the characteristic imaging phenotype.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"All patients whose brain imaging data was available (... = 19; 86%) showed frontotemporal predominant pachygyria."

All 19 imaged participants in the Finnish founder series showed the cortical pattern.

Brain Overgrowth

Brain/head enlargement occurs in some patients and in Cradd-null mice, but most Finnish founder cases have a normal head circumference. Enlarged endocast volume does not establish excess neuron number.

Animal models

Cradd-null mouse Mus musculus partially recapitulates Experimental observations inform this node within the stated preparation.

Downstream

Megalencephaly Brain enlargement manifests as megalencephaly in a subset.

Show evidence (3 references)

PMID:27773430 SUPPORT Model Organism

"all mutant mice had a statistically significant increase in endocast volume that corresponds to increased brain volume"

Micro-CT endocast measurements support mouse brain enlargement, not a direct neuronal-count assay.

PMID:30914828 SUPPORT Human Clinical

"Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients."

The abstract supports these variable clinical findings; body text supplies the exact denominators.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"absolute megalencephaly was found only in one patient and relative megalencephaly was found in two additional patients in our cohort."

Brain overgrowth is variable across cohorts.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

23

Cardiovascular 1

Dilated Perivascular Spaces Dilation of Virchow-Robin spaces HP:0012520

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Prominent perivascular spaces were seen in all the patients."

Published imaging finding in the founder cohort.

Digestive 1

Constipation HP:0002019

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"He has a tendency to have constipation."

Published supplementary case history; an individual observation rather than a universal disease feature.

Eye 3

Strabismus HP:0000486

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Strabismus and visual problems were observed in nine out of the 22 patients (... = 9/22, 41%)."

Combined ocular finding, not a strabismus-only prevalence estimate.

Amblyopia HP:0000646

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"In the ophthalmological examination at the age of 17 years left eye amblyopia was noted."

Published supplementary case history; an individual observation rather than a universal disease feature.

Esotropia HP:0000565

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"In the physical examination at the age of 14 years she has convergent esotropia."

Published supplementary case history; an individual observation rather than a universal disease feature.

Genitourinary 1

Enuresis HP:0000805

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"Enuresis nocturna continued until 16 years of age."

Published supplementary case history; an individual observation rather than a universal disease feature.

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"He had global developmental delay and mild hypotonia."

Published supplementary case history; an individual observation rather than a universal disease feature.

Nervous System 16

Thin Lissencephaly Anterior predominant pachygyria with 5-10 mm cortical thickness HP:0020188

Show evidence (2 references)

PMID:30914828 SUPPORT Human Clinical

"The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening."

The indexed primary report establishes the characteristic imaging phenotype.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"All patients whose brain imaging data was available (... = 19; 86%) showed frontotemporal predominant pachygyria."

All 19 imaged participants in the Finnish founder series showed the cortical pattern.

Intellectual Disability VERY_FREQUENT HP:0001249

Show evidence (4 references)

PMID:30914828 SUPPORT Human Clinical

"All patients show ID of variable severity."

The abstract summarizes intellectual impairment across the cohort; the body distinguishes 21 individuals with ID and one young child classified as global developmental delay.

PMID:27773430 SUPPORT Human Clinical

"9 (69%) had mild intellectual disability (ID), while three had mild to moderate ID and one had borderline ID (IQ = 70–75)"

Severity within the 13-person founding cohort.

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"She has moderate to severe intellectual disability (IQ 39/WAIS)."

FIN-1 IX/1 shows a broader severity range than the main cohort summary.

+ 1 more reference

Delayed Speech and Language Delayed speech and language development HP:0000750

Show evidence (2 references)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Language development was markedly delayed in young patients."

The founder cohort documents language delay.

PMID:22279524 SUPPORT Human Clinical

"Speech is rudimentary but articulate."

The earlier Mennonite cohort had limited articulate speech.

Global Developmental Delay HP:0001263

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"global developmental delay (... = 1/22, VIII/9, FIN-14, at the age of 4 years)"

Age-qualified global delay in the main founder-cohort report.

Megalencephaly HP:0001355

Show evidence (2 references)

PMID:30914828 SUPPORT Human Clinical

"Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients."

The abstract supports these variable clinical findings; body text supplies the exact denominators.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"absolute megalencephaly was found only in one patient and relative megalencephaly was found in two additional patients in our cohort."

Founder-series head growth varies from earlier reports.

Seizures OCCASIONAL HP:0001250

Show evidence (2 references)

PMID:27773430 SUPPORT Human Clinical

"individuals with recessive CRADD mutations (n = 13) presented with TLIS, mild to moderate ID, epilepsy (3 of 13)"

The expanded founding cohort links the recessive genotype to cortical malformation and neurodevelopmental manifestations.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"two individuals were diagnosed with epilepsy (... = 2/22, 9%)"

Epilepsy was a minority finding in the Finnish founder series. 3/13 (23%) and 2/22 (9%) lie within OCCASIONAL; these are separate clinical cohorts, not a pooled prevalence.

Aggressive Behavior FREQUENT HP:0000718

Show evidence (2 references)

PMID:30914828 SUPPORT Human Clinical

"Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients."

The abstract supports these variable clinical findings; body text supplies the exact denominators.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Neuropsychiatric problems characterized by aggressive bursts started usually at school age but also much later in adulthood requiring neuroleptic medication in 10 patients (... = 10/22, 45%)."

Cohort-specific behavioral manifestation and treatment use. 10/22 = 45%, supporting FREQUENT within the Finnish founder cohort.

Hyperactivity HP:0000752

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Distractability or hyperactive behavior at school-going age was present in seven patients (... = 7/22, 32%)."

The reported proportion combines distractibility and hyperactivity rather than proving each sign in all seven.

Short Attention Span HP:0000736

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"Her behavior is characterized by labile mood, short attention span, aggressive bursts and echolalia."

FIN-1 IX/1 clinical description.

EEG Abnormality OCCASIONAL HP:0002353

Show evidence (2 references)

PMID:30914828 SUPPORT Human Clinical

"Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients."

The abstract supports these variable clinical findings; body text supplies the exact denominators.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"EEG abnormalities, including photosensitivity and background slowing, were present in five (... = 5/17, 29%) patients."

Use the tested denominator, not all 22, for the EEG finding. 5/17 = 29% of tested Finnish patients, supporting OCCASIONAL; the denominator excludes untested patients.

Echolalia HP:0010529

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"Her behavior is characterized by labile mood, short attention span, aggressive bursts and echolalia."

Published supplementary case history; an individual observation rather than a universal disease feature.

Attention Deficit Hyperactivity Disorder HP:0007018

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"At the age of seven years ADHD was diagnosed and she used methylphenidate medication for two years to help her concentration on school."

Published supplementary case history; an individual observation rather than a universal disease feature.

Anxiety HP:0000739

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"She has been diagnosed with panic disorder and aggressive and impulsive behavior disorder at the age of 14 years old"

Published supplementary case history; an individual observation rather than a universal disease feature.

Hallucinations HP:0000738

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"Her disease is characterized by aggressive bursts and hallucinations."

Published supplementary case history; an individual observation rather than a universal disease feature.

Photoparoxysmal EEG Response EEG with photoparoxysmal response HP:0010852

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Five out of the 22 patients showed EEG abnormalities, such as photosensitivity (... = 3) and general background slowing (... = 2)"

The main results distinguish photosensitivity from background slowing; the discussion gives 17 tested patients.

Slow EEG Background EEG with abnormally slow frequencies HP:0011203

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Five out of the 22 patients showed EEG abnormalities, such as photosensitivity (... = 3) and general background slowing (... = 2)"

The finding is in the tested subset, not evidence of epilepsy by itself.

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Genetic Associations

1

CRADD (Causative biallelic variants)

Gene: CRADD hgnc:2340 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:27773430 SUPPORT Human Clinical

"individuals with recessive CRADD mutations (n = 13) presented with TLIS, mild to moderate ID, epilepsy (3 of 13)"

The expanded founding cohort links the recessive genotype to cortical malformation and neurodevelopmental manifestations.

PMID:30914828 SUPPORT Human Clinical

"The majority of the ancestors originated from Northeastern Finland indicating a founder effect."

The indexed primary paper identifies a Finnish founder effect.

CGGV:assertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z SUPPORT Other

"| CRADD | HGNC:2340 | syndromic intellectual disability | MONDO:0000508 | AR | Definitive | SOP8 | Intellectual Disability and Autism Gene Curation Expert Panel | 2021-06-16T18:00:00.000Z |"

ClinGen Intellectual Disability and Autism GCEP classified the broader CRADD–syndromic intellectual disability relationship as Definitive on 2021-06-16 (SOP8); this is not a validity tier assigned to the narrower entry.

Variants (9)

p.Gly128Arg

Gene: CRADD hgnc:2340 single nucleotide variant

Variant detail: missense

NM_003805.3:c.382G>C; Homozygous Mennonite allele; patient fibroblast protein depletion and reduced PIDD interaction.

Show evidence (2 references)

PMID:27773430 SUPPORT Human Clinical

"detected a homozygous mutation of CRADD ... c.382G>C"

The primary report identifies this missense allele; transcript NM_003805.3.

PMID:27773430 SUPPORT In Vitro

"We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not."

Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.

p.Phe164Cys

Gene: CRADD hgnc:2340 single nucleotide variant

Variant detail: missense

NM_003805.3:c.491T>G; In trans with a CRADD-containing 12q22 deletion; cellular abundance and PIDD co-IP retained, but purified protein is unstable.

Show evidence (2 references)

PMID:27773430 SUPPORT Human Clinical

"a fourth missense change (c.491T>G"

The primary report identifies this missense allele; transcript NM_003805.3.

PMID:27773430 SUPPORT In Vitro

"We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not."

Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.

p.Arg170Cys

Gene: CRADD hgnc:2340 single nucleotide variant

Variant detail: missense

NM_003805.3:c.508C>T; Homozygous in Turkish siblings; cellular co-IP retained but purified complex formation impaired.

Show evidence (2 references)

PMID:27773430 SUPPORT Human Clinical

"two other homozygous missense mutations in CRADD (c.508C>T"

The primary report identifies this missense allele; transcript NM_003805.3.

PMID:27773430 SUPPORT In Vitro

"We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not."

Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.

p.Arg170His

Gene: CRADD hgnc:2340 single nucleotide variant

Variant detail: missense

NM_003805.3:c.509G>A; Homozygous Finnish founder allele; also reported in trans with a start-loss allele.

Show evidence (2 references)

PMID:27773430 SUPPORT Human Clinical

"two other homozygous missense mutations in CRADD ... c.509G>A"

The primary report identifies this missense allele; transcript NM_003805.3.

PMID:27773430 SUPPORT In Vitro

"We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not."

Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.

CRADD-containing 12q22 deletion

Gene: CRADD hgnc:2340 deletion

A 3.07 Mb deletion (hg38 chr12:92443579–95515465) in trans with p.Phe164Cys; additional genes are deleted, so not every feature can be assigned to CRADD alone.

Show evidence (1 reference)

PMID:27773430 SUPPORT Human Clinical

"a 3.07 Mb deletion of chromosome 12q22 (chr12: 92,443,579–95,515,465; hg38) in this boy that includes the remaining CRADD allele"

Copy-number loss supplies the second allele; this is a multigene deletion.

p.Ala18IlefsTer47

Gene: CRADD hgnc:2340 deletion

NM_003805.5:c.52_59del, as recorded in the ClinGen case-level curation of the Harel family. The homozygous father and two fetuses illustrate variable expression.

Show evidence (2 references)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z SUPPORT Other

"NM_003805.5(CRADD):c.52_59del (p.Ala18IlefsTer47) ... Harel T, et al."

ClinGen case III-4 names the frameshift allele from Harel2017. The structured CGGV cache omits case-level allele rows; the linked report page supplies this exact allele.

PMID:28686357 SUPPORT Human Clinical

"revealed a homozygous frameshift variant in CRADD"

The primary abstract confirms a homozygous frameshift but does not give its exact HGVS.

p.Asp96ArgfsTer6

Gene: CRADD hgnc:2340 insertion

Variant detail: frameshift insertion

Reported as NM_003805.3:c.283_284insC in the 2018 MR123 family, with two mildly affected brothers. ClinGen represents the allele as NM_003805.5:c.285dup (p.Asp96fs). No focal functional assay was reported.

Show evidence (2 references)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z SUPPORT Other

"NM_003805.5(CRADD):c.285dup (p.Asp96fs) ... Santos-Cortez RLP, et al."

ClinGen case MR123-3 records the normalized allele and cites Santos-Cortez2018. The structured CGGV cache omits case-level allele rows; the linked report page supplies this exact allele.

PMID:30167849 SUPPORT Human Clinical

"MR123–3 | 10 | M | 50 | 55 ... | Mild | None | CRADD |"

The primary clinical table places mild ID in the CRADD family.

c.2T>C start loss

Gene: CRADD hgnc:2340 single nucleotide variant

Variant detail: start loss

NM_003805.5:c.2T>C p.Met1? in trans with p.Arg170His in FIN38; delayed speech, pachygyria and mild cognitive impairment. No patient protein assay was reported.

Show evidence (2 references)

PMID:33710394 SUPPORT Human Clinical

"a novel start loss variant ... in CRADD were identified"

The main report identifies the start-loss allele.

file:data/literature_supplements/CRADD_Jarvela_2021_Supplement.extracted.md SUPPORT Human Clinical

"in one allele a novel variant c.2T>C:p.(M1?) and on the other allele the Finnish founder variant c.509G>A:p.(R170H) were identified."

The supplementary case history specifies both alleles.

c.2T>G start loss

Gene: CRADD hgnc:2340 single nucleotide variant

Variant detail: start loss

Reported homozygously with a linked homozygous USP44 frameshift in Pakistani adults. The contribution of USP44 and the cause of additional skeletal features remain unresolved.

Show evidence (1 reference)

PMID:33647455 SUPPORT Human Clinical

"homozygous CRADD c.2T > G (p.Met1?) and USP44 c.873_886delinsT (p.Leu291Phefs*8)"

The two linked candidate variants co-segregate; they are not independent proof of two additive syndromes.

💊

Medical Actions

12

Speech therapy and communication support

Action: Speech Language Therapy NCIT:C159273

Speech therapy is used for language delay; gestures, signs and pictures can support communication. Spontaneous improvement also occurred, so treatment benefit cannot be quantified from these reports.

Show evidence (2 references)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"The patients in the younger generations received speech therapy."

Observed care in the Finnish founder cohort.

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"Gestures, signs and pictures are used to help communication."

Communication support in FIN-12 VII/1.

Occupational therapy and developmental follow-up

Action: Occupational Therapy NCIT:C121351

Occupational therapy and developmental assessment were reported for a child with global delay and hypotonia.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"He receives regular speech and occupational therapy and he has regular ophthalmological and developmental follow-up."

Reported care of FIN-12 VII/1; not a tested disease-specific protocol.

Special education and daily-living support

Action: Supportive Care NCIT:C15747

School support and assisted living are individualized to functional ability. Some affected adults work and live relatively independently.

Show evidence (2 references)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Special education was given for the younger generations of the patients."

Educational support in the founder series.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"Majority of adult patients have moved to assisted living facilities where they can get help in everyday tasks."

Observed adult support needs, not inevitable dependence.

Carbamazepine

Action: Pharmacotherapy NCIT:C15986

Agent: carbamazepine CHEBI:3387

Episodes interpreted as epilepsy in FIN-4 IX/8 reportedly improved with carbamazepine. This is a single-case observation, not comparative efficacy evidence.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"were interpreted as epileptic fits mitigated with carbamatsepin."

Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.

Methylphenidate

Action: Pharmacotherapy NCIT:C15986

Agent: methylphenidate CHEBI:6887

Used for diagnosed ADHD in selected founder cases and attention deficit in the compound heterozygous FIN38 child.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"ADHD has been diagnosed and she is regularly using methylphenidate medication."

Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.

Risperidone

Action: Pharmacotherapy NCIT:C15986

Agent: risperidone CHEBI:8871

Used for aggressive or impulsive behavior in individual Finnish cases.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"At the age of 11 years risperidone medication was started due to impulsive and aggressive behavior disorder."

Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.

Diazepam

Action: Pharmacotherapy NCIT:C15986

Agent: diazepam CHEBI:49575

Reported as an as-needed medication alongside risperidone in FIN-9 III/4 with panic and aggressive behavior.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"risperidone medication and diazepam medication on behalf."

Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.

Asenapine

Action: Pharmacotherapy NCIT:C15986

Agent: asenapine CHEBI:71253

Reported for treatment-resistant aggressive and impulsive behavior in FIN-11 III/1 after other neuroleptics.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"currently she is using asenapine regularly and alprazolame on behalf."

Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.

Alprazolam

Action: Pharmacotherapy NCIT:C15986

Agent: alprazolam CHEBI:2611

Reported as an as-needed adjunct in FIN-11 III/1; the source spells the agent alprazolame.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"currently she is using asenapine regularly and alprazolame on behalf."

Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.

Perazine

Action: Pharmacotherapy NCIT:C15986

Agent: perazine CHEBI:59118

Reported for impulsive and restless behavior in FIN-11 III/3.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"She has impulsive and restless behavior treated with perazine medication."

Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.

Ophthalmological care

Action: Supportive Care NCIT:C15747

Visual assessment and follow-up are relevant to documented strabismus and refractive problems. Strabismus surgery was performed in an individual case.

Show evidence (2 references)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"At the age of four years retroposition of the medial rectus muscle and resection of the lateral rectus muscle was performed."

Eye-muscle surgery in FIN-13 VIII/2.

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"He receives regular speech and occupational therapy and he has regular ophthalmological and developmental follow-up."

Follow-up in FIN-12 VII/1.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Discuss recessive inheritance and variable expressivity. Prenatal cortical imaging and a biallelic CRADD result cannot reliably predict severe disability; an apparently healthy homozygous father had hypogyration.

Show evidence (1 reference)

PMID:28686357 SUPPORT Human Clinical

"This study underscores the phenotypic variability of pathogenic variants in CRADD and the challenges of prenatal genetic counseling."

The primary family report emphasizes uncertainty of prenatal prognosis.

🔬

Diagnosis

4

Brain MRI

MRI identifies frontotemporal predominant pachygyria with mildly thick cortex. Mild abnormalities may be missed initially; normal head circumference does not exclude the diagnosis.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (1 reference)

PMID:30914828 SUPPORT Human Clinical

"brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant."

The primary report recommends imaging to support molecular diagnosis.

Molecular testing and segregation

Exome or targeted testing identifies CRADD alleles; segregation and copy-number evaluation are relevant when only one sequence allele is found. A multigene deletion has supplied a second allele.

Show evidence (2 references)

PMID:27773430 SUPPORT Human Clinical

"Trio-based whole-exome sequencing (WES) in two families with TLIS detected a homozygous mutation of CRADD"

Primary discovery approach.

PMID:27773430 SUPPORT Human Clinical

"a 3.07 Mb deletion of chromosome 12q22 (chr12: 92,443,579–95,515,465; hg38) in this boy that includes the remaining CRADD allele"

Copy-number loss supplies the second allele; this is a multigene deletion.

Developmental and cognitive assessment

Serial language, developmental and cognitive assessment defines support needs; severity can vary within one family and between summary tables and detailed case histories.

Show evidence (1 reference)

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md SUPPORT Human Clinical

"In the developmental assessment at the age of 16 years (WISC-IV) his cognitive skills correspond to moderate intellectual disability."

FIN-13 VIII/3 underwent standardized assessment.

EEG in clinical evaluation

EEG characterized seizures or background abnormalities in the reported cohorts. Photosensitivity and slowing can occur without a clinical epilepsy diagnosis.

Show evidence (2 references)

PMID:30914828 SUPPORT Human Clinical

"Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients."

The abstract supports these variable clinical findings; body text supplies the exact denominators.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/ SUPPORT Human Clinical

"EEG abnormalities, including photosensitivity and background slowing, were present in five (... = 5/17, 29%) patients."

Use the tested denominator, not all 22, for the EEG finding.

🧫

Experimental Models

5

G128R patient dermal fibroblasts PRIMARY_CELL_CULTURE

CRADD protein abundance was measured by immunoblotting; no patient cortical-neuron apoptosis was measured.

Cell source

Dermal fibroblasts from affected individuals, heterozygous parents and controls

Pathograph links

Gly128Arg CRADD Protein Depletion measures fidelity: unknown Experimental observations inform this node within the stated preparation.

Limitations: Peripheral cells and one allele; other patients did not supply fibroblasts.

Show evidence (1 reference)

PMID:27773430 SUPPORT In Vitro

"Dermal fibroblasts from p.Gly128Arg CRADD TLIS-affected subjects are essentially null for CRADD abundance"

Patient-derived fibroblasts demonstrate allele-specific protein depletion; other alleles were not tested in patient fibroblasts.

PC12 protein-import caspase and survival assays CELL_LINE

WT and four missense proteins were compared for binding, caspase-2 activation and survival.

Cell source

Rat PC12 cells transduced with Penetratin-linked human CRADD proteins

Pathograph links

Reduced Caspase-2 Activation measures fidelity: unknown Experimental observations inform this node within the stated preparation.

Limitations: Exogenous protein import into a cell line.

Show evidence (1 reference)

PMID:27773430 SUPPORT In Vitro

"We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not."

Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.

Reduced Caspase-2-Dependent Neuronal Apoptosis measures fidelity: unknown Experimental observations inform this node within the stated preparation.

Limitations: PC12 survival is not human developmental neuron elimination.

Show evidence (1 reference)

PMID:27773430 SUPPORT In Vitro

"Transduction of PC12 cells with Pen1-linked CRADD-TLIS variants (p.Gly128Arg, p.Phe164Cys, p.Arg170Cys, and p.Arg170His) failed to induce cell death"

All four tested missense variants failed to reproduce the cell death induced by imported wild-type CRADD.

Cradd-null sympathetic neuron cultures PRIMARY_CELL_CULTURE

Imported WT human CRADD induced death whereas G128R did not.

Cell source

Sympathetic neurons isolated from newborn Cradd-null mice

Pathograph links

Reduced Caspase-2-Dependent Neuronal Apoptosis measures fidelity: unknown Experimental observations inform this node within the stated preparation.

Limitations: Peripheral sympathetic neurons, one mutant allele and exogenous protein import.

Show evidence (1 reference)

PMID:27773430 SUPPORT In Vitro

"CRADD WT resulted in significant cell death of primary sympathetic neurons from Cradd−/− mice 1 day after transduction, whereas cell survival after transduction of p.Gly128Arg CRADD was indistinguishable from that of non-transduced cells"

The neuronal culture experiment tested G128R against wild-type protein; it is not a measurement of human fetal apoptosis.

Cellular CRADD interaction assays CELL_LINE

Coimmunoprecipitation retains PIDD association for F164C/R170C/R170H, unlike G128R; this differs from purified-protein results.

Cell source

HEK293T and Neuro2a cells expressing CRADD and PIDD-DD

Show evidence (1 reference)

PMID:27773430 SUPPORT In Vitro

"Immunoprecipitation of recombinant FLAG-CRADD overexpressed in Neuro2a (data not shown) and HEK293T cells co-precipitated V5-PIDD-DD for each of the CRADD-TLIS variants except p.Gly128Arg"

Cellular PIDD binding is retained for three variants, with G128R the exception.

Purified RAIDD–PIDD death-domain complexes OTHER

E. coli-expressed CRADD death domains or full-length protein were mixed with PIDD-DD and examined by size-exclusion chromatography and native PAGE.

Pathograph links

Impaired PIDDosome Assembly measures fidelity: unknown Experimental observations inform this node within the stated preparation.

Limitations: Purified recombinant proteins lack cellular context; co-IP results differ.

Show evidence (1 reference)

PMID:30281648 SUPPORT In Vitro

"The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution peaks after size exclusion chromatography"

Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation gives a different result.

🐁

Animal Models

1

Cradd-null mouse

Knockout mice have increased endocast volume and handling-induced seizures (8/31, versus 0/60 WT/heterozygous littermates), with normal cortical layering. Smaller body and limb size were also observed.

Species

Mus musculus

Genotype

Cradd−/− on C57BL/6 background

Pathograph links

Brain Overgrowth partially recapitulates fidelity: unknown Experimental observations inform this node within the stated preparation.

Limitations: Brain volume is inferred from endocast; neuron number was not counted.

Show evidence (1 reference)

PMID:27773430 SUPPORT Model Organism

"all mutant mice had a statistically significant increase in endocast volume that corresponds to increased brain volume"

Micro-CT endocast measurements support mouse brain enlargement, not a direct neuronal-count assay.

Abnormal Cortical Gyration fails to recapitulate fidelity: unknown Experimental observations inform this node within the stated preparation.

Limitations: Mouse cortex is normally lissencephalic and remained normally layered; the human cortical phenotype is not reproduced.

Divergences from the human mechanism

species mismatch

Mouse cortex is normally lissencephalic and remained normally layered; the human cortical phenotype is not reproduced.

Show evidence (1 reference)

PMID:27773430 SUPPORT Model Organism

"Morphological analysis of Cradd−/− cortex revealed normal layering indistinguishable from WT mice"

Normal layering in the knockout does not establish or reproduce the human MRI gyral pattern.

Show evidence (2 references)

PMID:27773430 SUPPORT Model Organism

"all mutant mice had a statistically significant increase in endocast volume that corresponds to increased brain volume"

Micro-CT endocast measurements support mouse brain enlargement, not a direct neuronal-count assay.

PMID:27773430 SUPPORT Model Organism

"8 of 31 (26%) Cradd−/− mice displayed handling-induced seizures; no WT or Cradd+/− littermates (0 of 60) had seizures."

Mouse seizure susceptibility is not the human cohort frequency.

{ }

Source YAML

click to show

name: CRADD-Related Thin Lissencephaly
creation_date: '2026-06-10T12:00:00Z'
category: Mendelian
disease_term:
  preferred_term: CRADD-related thin lissencephaly
  term:
    id: MONDO:0013785
    label: intellectual disability, autosomal recessive 34
parents:
- Lissencephaly Spectrum Disorders
synonyms:
- CRADD-related frontotemporal pachygyria
- CRADD-related intellectual developmental disorder
- MRT34
- Thin lissencephaly due to CRADD deficiency
- Autosomal recessive intellectual disability 34
description: >-
  An autosomal recessive neurodevelopmental disorder caused by biallelic CRADD variants, characterized
  by frontotemporal predominant pachygyria with mildly thickened cortex and variable intellectual and
  language impairment. Behavioral symptoms and strabismus are common in the Finnish founder series; seizures
  and megalencephaly are variable. Reported alleles include death-domain missense, frameshift, start-loss
  and a multigene deletion in trans with a missense allele. Experimental variants impair CRADD-dependent
  caspase-2 activation and cell death, but the exact developmental link to human cortical malformation
  remains unresolved. Cradd-null mice develop brain enlargement and handling-induced seizures without
  the human cortical pattern.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic CRADD variants segregate with disease. Homozygous and compound heterozygous cases are reported.
    Clinical severity varies substantially, including an apparently healthy homozygous father whose MRI
    showed hypogyration; genotype does not predict a uniformly severe lissencephaly outcome.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      individuals with recessive CRADD mutations (n = 13) presented with TLIS, mild to moderate ID, epilepsy
      (3 of 13)
    explanation: >-
      The expanded founding cohort links the recessive genotype to cortical malformation and neurodevelopmental
      manifestations.
  - reference: PMID:28686357
    reference_title: >-
      Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated
      with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the allegedly healthy father was also found to be homozygous for the variant, prompting evaluation
      by brain MRI which revealed hypogyration.
    explanation: A mildly affected adult illustrates variable expression and the limits of prenatal prognostication.
  - reference: PMID:33710394
    reference_title: >-
      Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability
      (ID) in the founder population of Finland.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In family FIN38 a Finnish founder variant ... (Polla et al. 2019) and a novel start loss variant
      ... in CRADD were identified.
    explanation: The later Finnish case extends the allelic spectrum beyond homozygous founder variants.
pathophysiology:
- name: Loss of CRADD Adaptor Activity
  role: trigger
  description: >-
    Disease-associated alleles impair the adaptor pathway that recruits and activates caspase-2. Direct
    functional evidence is strongest for the four tested death-domain missense alleles; protein depletion,
    assembly defects and preserved pairwise interactions depend on the allele and assay.
  genetic_context:
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    variant_origin: GERMLINE
    functional_impact: Loss of CRADD-dependent caspase-2 activation; allele-specific protein and interaction defects.
  molecular_functions:
  - preferred_term: protein-macromolecule adaptor activity
    term:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CRADD (also known as RAIDD) is a death-domain-containing adaptor protein that oligomerizes with
      PIDD and caspase-2 to initiate apoptosis.
    explanation: Normal molecular adaptor function, interpreted with the adjacent variant-activation assay.
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
    explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
  downstream:
  - target: Reduced Caspase-2 Activation
    causal_link_type: DIRECT
    description: Directly tested missense proteins fail to activate caspase-2.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
      explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        9 (69%) had mild intellectual disability (ID), while three had mild to moderate ID and one had
        borderline ID (IQ = 70–75)
      explanation: Severity within the 13-person founding cohort.
    - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
      reference_title: >-
        Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
        frontotemporal predominant pachygyria in the Finnish population
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: She has moderate to severe intellectual disability (IQ 39/WAIS).
      explanation: FIN-1 IX/1 shows a broader severity range than the main cohort summary.
  - target: Delayed Speech and Language
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Language development was markedly delayed in young patients.
      explanation: The founder cohort documents language delay.
    - reference: PMID:22279524
      reference_title: Genetic mapping and exome sequencing identify variants associated with five novel diseases.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Speech is rudimentary but articulate.
      explanation: The earlier Mennonite cohort had limited articulate speech.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: global developmental delay (... = 1/22, VIII/9, FIN-14, at the age of 4 years)
      explanation: Age-qualified global delay in the main founder-cohort report.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        individuals with recessive CRADD mutations (n = 13) presented with TLIS, mild to moderate ID,
        epilepsy (3 of 13)
      explanation: >-
        The expanded founding cohort links the recessive genotype to cortical malformation and neurodevelopmental
        manifestations.
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: two individuals were diagnosed with epilepsy (... = 2/22, 9%)
      explanation: Epilepsy was a minority finding in the Finnish founder series.
  - target: Aggressive Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical genotype–phenotype association; the intervening human cellular mechanism remains unresolved.
    evidence:
    - reference: PMID:30914828
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients
        and megalencephaly in three patients.
      explanation: The abstract supports these variable clinical findings; body text supplies the exact denominators.
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Neuropsychiatric problems characterized by aggressive bursts started usually at school age but
        also much later in adulthood requiring neuroleptic medication in 10 patients (... = 10/22, 45%).
      explanation: Cohort-specific behavioral manifestation and treatment use.
- name: Gly128Arg CRADD Protein Depletion
  description: >-
    G128R patient fibroblasts contain very little CRADD; overexpressed G128R also shows reduced abundance
    and abnormal aggregates. This protein-depletion phenotype is not demonstrated for every disease allele.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Dermal fibroblasts from p.Gly128Arg CRADD TLIS-affected subjects are essentially null for CRADD abundance
    explanation: >-
      Patient-derived fibroblasts demonstrate allele-specific protein depletion; other alleles were not
      tested in patient fibroblasts.
  downstream:
  - target: Loss of CRADD Adaptor Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Allele-specific loss of available adaptor protein.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Dermal fibroblasts from p.Gly128Arg CRADD TLIS-affected subjects are essentially null for CRADD abundance
      explanation: >-
        Patient-derived fibroblasts demonstrate allele-specific protein depletion; other alleles were
        not tested in patient fibroblasts.
- name: Impaired PIDDosome Assembly
  description: >-
    Purified R170C/H CRADD death domains and full-length proteins show impaired stable assembly with PIDD-DD.
    F164C is unstable in the recombinant preparation and G128R could not be expressed. Cellular coimmunoprecipitation
    retains PIDD binding for F164C/R170C/R170H, so loss of all PIDD interactions is not a universal established
    mechanism.
  evidence:
  - reference: PMID:30281648
    reference_title: RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution
      peaks after size exclusion chromatography
    explanation: >-
      Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation
      gives a different result.
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunoprecipitation of recombinant FLAG-CRADD overexpressed in Neuro2a (data not shown) and HEK293T
      cells co-precipitated V5-PIDD-DD for each of the CRADD-TLIS variants except p.Gly128Arg
    explanation: Cellular PIDD binding is retained for three variants, with G128R the exception.
  downstream:
  - target: Loss of CRADD Adaptor Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cradd_assembly_activity
    description: >-
      Impaired stable assembly is a proposed allele-specific route to lost adaptor function for R170C/H.
      Purified-protein assembly and cellular binding/activation use different preparations, so this bridge
      is not directly established in developing human cortex.
    evidence:
    - reference: PMID:30281648
      reference_title: RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS).
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution
        peaks after size exclusion chromatography
      explanation: >-
        Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation
        gives a different result.
- name: Reduced Caspase-2 Activation
  description: >-
    The four tested disease-associated missense proteins retain measurable caspase-2 binding when normalized
    for abundance but fail to activate caspase-2 in PC12 cells.
  molecular_functions:
  - preferred_term: cysteine-type endopeptidase activator activity involved in apoptotic process
    term:
      id: GO:0008656
      label: cysteine-type endopeptidase activator activity involved in apoptotic process
    modifier: DECREASED
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
    explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
  downstream:
  - target: Reduced Caspase-2-Dependent Neuronal Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of caspase-2 activation accompanies failure to induce cell death in the import assay.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
      explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transduction of PC12 cells with Pen1-linked CRADD-TLIS variants (p.Gly128Arg, p.Phe164Cys, p.Arg170Cys,
        and p.Arg170His) failed to induce cell death
      explanation: All four tested missense variants failed to reproduce the cell death induced by imported wild-type CRADD.
- name: Reduced Caspase-2-Dependent Neuronal Apoptosis
  conforms_to: "neural_progenitor_centrosome_spindle_dysfunction#Programmed Cell Death Imbalance Branch"
  description: >-
    Imported wild-type CRADD induces PC12 cell death and death of cultured Cradd-null sympathetic neurons;
    disease-associated proteins fail in PC12 cells, and G128R fails in the sympathetic-neuron assay. Reduced
    apoptosis during human corticogenesis is a hypothesis extrapolated from these experiments.
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transduction of PC12 cells with Pen1-linked CRADD-TLIS variants (p.Gly128Arg, p.Phe164Cys, p.Arg170Cys,
      and p.Arg170His) failed to induce cell death
    explanation: All four tested missense variants failed to reproduce the cell death induced by imported wild-type CRADD.
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CRADD WT resulted in significant cell death of primary sympathetic neurons from Cradd−/− mice 1
      day after transduction, whereas cell survival after transduction of p.Gly128Arg CRADD was indistinguishable
      from that of non-transduced cells
    explanation: >-
      The neuronal culture experiment tested G128R against wild-type protein; it is not a measurement
      of human fetal apoptosis.
  downstream:
  - target: Abnormal Cortical Gyration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced developmental neuronal or synaptic elimination is proposed to disturb human cortical formation;
      the responsible cell population and process are unresolved.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is not clear whether the megalencephaly, undulating pachygyria, increased cortical thickness,
        and intellectual disability characteristic of CRADD-TLIS result from reduced pruning of synaptic
        connections, decreased programmed cell death of inappropriate neurons, or a combination of the
        two.
      explanation: The authors leave the human developmental intermediate unresolved.
    hypothesis_groups:
    - cradd_developmental_apoptosis
  - target: Brain Overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced developmental cell death is a candidate explanation for variable brain enlargement, not
      a directly demonstrated human intermediate.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is not clear whether the megalencephaly, undulating pachygyria, increased cortical thickness,
        and intellectual disability characteristic of CRADD-TLIS result from reduced pruning of synaptic
        connections, decreased programmed cell death of inappropriate neurons, or a combination of the
        two.
      explanation: The authors leave the human developmental intermediate unresolved.
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        all mutant mice had a statistically significant increase in endocast volume that corresponds to
        increased brain volume
      explanation: Micro-CT endocast measurements support mouse brain enlargement, not a direct neuronal-count assay.
    hypothesis_groups:
    - cradd_developmental_apoptosis
- name: Abnormal Cortical Gyration
  description: >-
    Frontotemporal predominant broad gyri and shallow sulci accompany a mildly thick cortex, usually 5–7
    mm and up to 8 mm in the Finnish series. Imaging establishes cortical morphology, not a histological
    migration or apoptosis defect.
  evidence:
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening.
    explanation: The indexed primary report establishes the characteristic imaging phenotype.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients whose brain imaging data was available (... = 19; 86%) showed frontotemporal predominant
      pachygyria.
    explanation: All 19 imaged participants in the Finnish founder series showed the cortical pattern.
  downstream:
  - target: Thin Lissencephaly
    causal_link_type: DIRECT
    description: The cortical imaging pattern defines this manifestation.
    evidence:
    - reference: PMID:30914828
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening.
      explanation: The indexed primary report establishes the characteristic imaging phenotype.
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients whose brain imaging data was available (... = 19; 86%) showed frontotemporal predominant
        pachygyria.
      explanation: All 19 imaged participants in the Finnish founder series showed the cortical pattern.
- name: Brain Overgrowth
  description: >-
    Brain/head enlargement occurs in some patients and in Cradd-null mice, but most Finnish founder cases
    have a normal head circumference. Enlarged endocast volume does not establish excess neuron number.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      all mutant mice had a statistically significant increase in endocast volume that corresponds to
      increased brain volume
    explanation: Micro-CT endocast measurements support mouse brain enlargement, not a direct neuronal-count assay.
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients
      and megalencephaly in three patients.
    explanation: The abstract supports these variable clinical findings; body text supplies the exact denominators.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      absolute megalencephaly was found only in one patient and relative megalencephaly was found in two
      additional patients in our cohort.
    explanation: Brain overgrowth is variable across cohorts.
  downstream:
  - target: Megalencephaly
    causal_link_type: DIRECT
    description: Brain enlargement manifests as megalencephaly in a subset.
    evidence:
    - reference: PMID:30914828
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients
        and megalencephaly in three patients.
      explanation: The abstract supports these variable clinical findings; body text supplies the exact denominators.
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        absolute megalencephaly was found only in one patient and relative megalencephaly was found in
        two additional patients in our cohort.
      explanation: Founder-series head growth varies from earlier reports.
mechanistic_hypotheses:
- hypothesis_group_id: cradd_developmental_apoptosis
  hypothesis_label: Reduced developmental cell death as the bridge to cortical malformation
  status: EMERGING
  description: >-
    Cell and mouse experiments motivate a developmental apoptosis model, but human cortical apoptosis
    and migration have not been directly distinguished. Synapse pruning and whole-cell death remain alternative
    or complementary intermediates.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is not clear whether the megalencephaly, undulating pachygyria, increased cortical thickness,
      and intellectual disability characteristic of CRADD-TLIS result from reduced pruning of synaptic
      connections, decreased programmed cell death of inappropriate neurons, or a combination of the two.
    explanation: The authors leave the human developmental intermediate unresolved.
- hypothesis_group_id: cradd_assembly_activity
  hypothesis_label: Assembly impairment as an allele-specific route to adaptor dysfunction
  status: EMERGING
  description: >-
    Purified R170C/H proteins fail stable complex assembly, while cellular pairwise PIDD binding is retained.
    A functional connection between these assay-specific observations and lost adaptor activity remains
    proposed.
  evidence:
  - reference: PMID:30281648
    reference_title: RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution
      peaks after size exclusion chromatography
    explanation: >-
      Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation
      gives a different result.
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunoprecipitation of recombinant FLAG-CRADD overexpressed in Neuro2a (data not shown) and HEK293T
      cells co-precipitated V5-PIDD-DD for each of the CRADD-TLIS variants except p.Gly128Arg
    explanation: Cellular PIDD binding is retained for three variants, with G128R the exception.
phenotypes:
- name: Thin Lissencephaly
  category: Neurological
  description: >-
    Frontotemporal predominant pachygyria with mild cortical thickening; all 19 imaged Finnish founder
    cases showed this pattern. Earlier images were sometimes interpreted as normal before re-review.
  phenotype_term:
    preferred_term: Anterior predominant pachygyria with 5-10 mm cortical thickness
    term:
      id: HP:0020188
      label: Anterior predominant pachygyria with 5-10 mm cortical thickness
  evidence:
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening.
    explanation: The indexed primary report establishes the characteristic imaging phenotype.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients whose brain imaging data was available (... = 19; 86%) showed frontotemporal predominant
      pachygyria.
    explanation: All 19 imaged participants in the Finnish founder series showed the cortical pattern.
- name: Intellectual Disability
  category: Neurological
  description: >-
    Often mild to moderate in clinical summaries, with borderline cognition in one founding case and moderate-to-severe
    impairment in an individual Finnish case. Some adults work or live relatively independently, while
    others require assistance.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients show ID of variable severity.
    explanation: >-
      The abstract summarizes intellectual impairment across the cohort; the body distinguishes 21 individuals
      with ID and one young child classified as global developmental delay.
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      9 (69%) had mild intellectual disability (ID), while three had mild to moderate ID and one had borderline
      ID (IQ = 70–75)
    explanation: Severity within the 13-person founding cohort.
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She has moderate to severe intellectual disability (IQ 39/WAIS).
    explanation: FIN-1 IX/1 shows a broader severity range than the main cohort summary.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patients were characterized by either mild to moderate ID (... = 21/22) or global developmental delay
    explanation: >-
      21/22 = 95.5% with ID in the main clinical description supports VERY_FREQUENT; the remaining four-year-old
      had GDD.
  frequency: VERY_FREQUENT
- name: Delayed Speech and Language
  category: Neurological
  description: >-
    Marked language delay can follow apparently normal early development. Speech may improve by school
    age; severity remains variable.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Language development was markedly delayed in young patients.
    explanation: The founder cohort documents language delay.
  - reference: PMID:22279524
    reference_title: Genetic mapping and exome sequencing identify variants associated with five novel diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Speech is rudimentary but articulate.
    explanation: The earlier Mennonite cohort had limited articulate speech.
- name: Global Developmental Delay
  category: Neurological
  description: Documented in young Finnish children before definitive cognitive classification.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: global developmental delay (... = 1/22, VIII/9, FIN-14, at the age of 4 years)
    explanation: Age-qualified global delay in the main founder-cohort report.
- name: Megalencephaly
  category: Neurological
  description: >-
    Variable brain/head enlargement, prominent in the founding report but only one absolute and two relative
    cases in the 22-person Finnish cohort; it is not required for diagnosis.
  phenotype_term:
    preferred_term: Megalencephaly
    term:
      id: HP:0001355
      label: Megalencephaly
  evidence:
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients
      and megalencephaly in three patients.
    explanation: The abstract supports these variable clinical findings; body text supplies the exact denominators.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      absolute megalencephaly was found only in one patient and relative megalencephaly was found in two
      additional patients in our cohort.
    explanation: Founder-series head growth varies from earlier reports.
- name: Seizures
  category: Neurological
  description: >-
    Epilepsy affected 3/13 in the expanded founding cohort and 2/22 in the Finnish series. Photosensitive
    EEG abnormalities alone should not be equated with epilepsy.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      individuals with recessive CRADD mutations (n = 13) presented with TLIS, mild to moderate ID, epilepsy
      (3 of 13)
    explanation: >-
      The expanded founding cohort links the recessive genotype to cortical malformation and neurodevelopmental
      manifestations.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: two individuals were diagnosed with epilepsy (... = 2/22, 9%)
    explanation: >-
      Epilepsy was a minority finding in the Finnish founder series. 3/13 (23%) and 2/22 (9%) lie within
      OCCASIONAL; these are separate clinical cohorts, not a pooled prevalence.
  frequency: OCCASIONAL
- name: Aggressive Behavior
  category: Behavioral
  description: >-
    Aggressive bursts occurred in 10/22 Finnish patients and could require neuroleptic medication. Onset
    varied from school age to adulthood.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients
      and megalencephaly in three patients.
    explanation: The abstract supports these variable clinical findings; body text supplies the exact denominators.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuropsychiatric problems characterized by aggressive bursts started usually at school age but also
      much later in adulthood requiring neuroleptic medication in 10 patients (... = 10/22, 45%).
    explanation: >-
      Cohort-specific behavioral manifestation and treatment use. 10/22 = 45%, supporting FREQUENT within
      the Finnish founder cohort.
  frequency: FREQUENT
- name: Hyperactivity
  category: Behavioral
  description: Distractibility or hyperactive behavior occurred in 7/22 Finnish patients.
  phenotype_term:
    preferred_term: Hyperactivity
    term:
      id: HP:0000752
      label: Hyperactivity
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Distractability or hyperactive behavior at school-going age was present in seven patients (... = 7/22, 32%).
    explanation: The reported proportion combines distractibility and hyperactivity rather than proving each sign in all seven.
- name: Short Attention Span
  category: Behavioral
  description: Short attention span is described in several founder cases.
  phenotype_term:
    preferred_term: Short attention span
    term:
      id: HP:0000736
      label: Short attention span
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her behavior is characterized by labile mood, short attention span, aggressive bursts and echolalia.
    explanation: FIN-1 IX/1 clinical description.
- name: Strabismus
  category: Ophthalmological
  description: >-
    Strabismus and visual problems together affected 9/22 Finnish patients. Esotropia and exotropia are
    described in individual cases.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Strabismus and visual problems were observed in nine out of the 22 patients (... = 9/22, 41%).
    explanation: Combined ocular finding, not a strabismus-only prevalence estimate.
- name: EEG Abnormality
  category: Neurological
  description: >-
    Five of 17 tested Finnish patients had EEG abnormalities, including photosensitivity in three and
    generalized background slowing in two. Some had no clinical epilepsy.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients
      and megalencephaly in three patients.
    explanation: The abstract supports these variable clinical findings; body text supplies the exact denominators.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EEG abnormalities, including photosensitivity and background slowing, were present in five (...
      = 5/17, 29%) patients.
    explanation: >-
      Use the tested denominator, not all 22, for the EEG finding. 5/17 = 29% of tested Finnish patients,
      supporting OCCASIONAL; the denominator excludes untested patients.
  frequency: OCCASIONAL
- name: Echolalia
  category: Behavioral
  description: Reported in multiple Finnish founder cases.
  phenotype_term:
    preferred_term: Echolalia
    term:
      id: HP:0010529
      label: Echolalia
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her behavior is characterized by labile mood, short attention span, aggressive bursts and echolalia.
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Hypotonia
  category: Neurological
  description: Mild hypotonia in FIN-12 VII/1; not universal.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had global developmental delay and mild hypotonia.
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Enuresis
  category: Genitourinary
  description: Persistent enuresis in individual founder cases.
  phenotype_term:
    preferred_term: Enuresis
    term:
      id: HP:0000805
      label: Enuresis
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Enuresis nocturna continued until 16 years of age.
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Constipation
  category: Gastrointestinal
  description: Constipation in individual founder cases; megacolon requiring surgery was reported in FIN-4 IX/8.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has a tendency to have constipation.
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  description: Formal ADHD diagnoses and methylphenidate treatment are reported in selected cases.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of seven years ADHD was diagnosed and she used methylphenidate medication for two years
      to help her concentration on school.
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Anxiety
  category: Behavioral
  description: Panic disorder was diagnosed in FIN-9 III/4 alongside aggressive and impulsive behavior.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has been diagnosed with panic disorder and aggressive and impulsive behavior disorder at the
      age of 14 years old
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Hallucinations
  category: Behavioral
  description: Hallucinations were described in FIN-7 II/1; an isolated report.
  phenotype_term:
    preferred_term: Hallucinations
    term:
      id: HP:0000738
      label: Hallucinations
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her disease is characterized by aggressive bursts and hallucinations.
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Amblyopia
  category: Ophthalmological
  description: Left-eye amblyopia in FIN-9 III/4.
  phenotype_term:
    preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the ophthalmological examination at the age of 17 years left eye amblyopia was noted.
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Esotropia
  category: Ophthalmological
  description: Esotropia and other strabismus patterns occur in selected cases.
  phenotype_term:
    preferred_term: Esotropia
    term:
      id: HP:0000565
      label: Esotropia
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the physical examination at the age of 14 years she has convergent esotropia.
    explanation: Published supplementary case history; an individual observation rather than a universal disease feature.
- name: Dilated Perivascular Spaces
  category: Neurological
  description: >-
    Prominent perivascular spaces were reported in all imaged patients in the Finnish founder series;
    this is an associated imaging observation, without an established CRADD-specific mechanism.
  phenotype_term:
    preferred_term: Dilation of Virchow-Robin spaces
    term:
      id: HP:0012520
      label: Dilation of Virchow-Robin spaces
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Prominent perivascular spaces were seen in all the patients.
    explanation: Published imaging finding in the founder cohort.
- name: Photoparoxysmal EEG Response
  category: Neurological
  description: >-
    EEG photosensitivity occurred in three Finnish patients; it is not equivalent to photosensitive clinical
    seizures.
  phenotype_term:
    preferred_term: EEG with photoparoxysmal response
    term:
      id: HP:0010852
      label: EEG with photoparoxysmal response
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five out of the 22 patients showed EEG abnormalities, such as photosensitivity (... = 3) and general
      background slowing (... = 2)
    explanation: >-
      The main results distinguish photosensitivity from background slowing; the discussion gives 17 tested
      patients.
- name: Slow EEG Background
  category: Neurological
  description: General background slowing occurred in two Finnish patients.
  phenotype_term:
    preferred_term: EEG with abnormally slow frequencies
    term:
      id: HP:0011203
      label: EEG with abnormally slow frequencies
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five out of the 22 patients showed EEG abnormalities, such as photosensitivity (... = 3) and general
      background slowing (... = 2)
    explanation: The finding is in the tested subset, not evidence of epilepsy by itself.
genetic:
- name: CRADD
  gene_term:
    preferred_term: CRADD
    term:
      id: hgnc:2340
      label: CRADD
  association: Causative biallelic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Missense, frameshift, start-loss and copy-number alleles are reported. Founder enrichment is documented
    in Finnish and Mennonite cohorts; published population frequencies are historical and are not disease-prevalence
    estimates. ClinGen classified the broader CRADD–syndromic intellectual disability relationship as
    definitive in 2021; that assertion uses MONDO:0000508 rather than the narrower identifier of this
    entry.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      individuals with recessive CRADD mutations (n = 13) presented with TLIS, mild to moderate ID, epilepsy
      (3 of 13)
    explanation: >-
      The expanded founding cohort links the recessive genotype to cortical malformation and neurodevelopmental
      manifestations.
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The majority of the ancestors originated from Northeastern Finland indicating a founder effect.
    explanation: The indexed primary paper identifies a Finnish founder effect.
  - reference: CGGV:assertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z
    reference_title: CRADD / syndromic intellectual disability (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | CRADD | HGNC:2340 | syndromic intellectual disability | MONDO:0000508 | AR | Definitive | SOP8
      | Intellectual Disability and Autism Gene Curation Expert Panel | 2021-06-16T18:00:00.000Z |
    explanation: >-
      ClinGen Intellectual Disability and Autism GCEP classified the broader CRADD–syndromic intellectual
      disability relationship as Definitive on 2021-06-16 (SOP8); this is not a validity tier assigned
      to the narrower entry.
  variants:
  - name: p.Gly128Arg
    variant_type: single nucleotide variant
    type: missense
    description: >-
      NM_003805.3:c.382G>C; Homozygous Mennonite allele; patient fibroblast protein depletion and reduced
      PIDD interaction.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: detected a homozygous mutation of CRADD ... c.382G>C
      explanation: The primary report identifies this missense allele; transcript NM_003805.3.
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
      explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
  - name: p.Phe164Cys
    variant_type: single nucleotide variant
    type: missense
    description: >-
      NM_003805.3:c.491T>G; In trans with a CRADD-containing 12q22 deletion; cellular abundance and PIDD
      co-IP retained, but purified protein is unstable.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a fourth missense change (c.491T>G
      explanation: The primary report identifies this missense allele; transcript NM_003805.3.
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
      explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
  - name: p.Arg170Cys
    variant_type: single nucleotide variant
    type: missense
    description: >-
      NM_003805.3:c.508C>T; Homozygous in Turkish siblings; cellular co-IP retained but purified complex
      formation impaired.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: two other homozygous missense mutations in CRADD (c.508C>T
      explanation: The primary report identifies this missense allele; transcript NM_003805.3.
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
      explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
  - name: p.Arg170His
    variant_type: single nucleotide variant
    type: missense
    description: NM_003805.3:c.509G>A; Homozygous Finnish founder allele; also reported in trans with a start-loss allele.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: two other homozygous missense mutations in CRADD ... c.509G>A
      explanation: The primary report identifies this missense allele; transcript NM_003805.3.
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
      explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
  - name: CRADD-containing 12q22 deletion
    variant_type: deletion
    type: deletion
    description: >-
      A 3.07 Mb deletion (hg38 chr12:92443579–95515465) in trans with p.Phe164Cys; additional genes are
      deleted, so not every feature can be assigned to CRADD alone.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a 3.07 Mb deletion of chromosome 12q22 (chr12: 92,443,579–95,515,465; hg38) in this boy that includes
        the remaining CRADD allele
      explanation: Copy-number loss supplies the second allele; this is a multigene deletion.
  - name: p.Ala18IlefsTer47
    variant_type: deletion
    type: deletion
    description: >-
      NM_003805.5:c.52_59del, as recorded in the ClinGen case-level curation of the Harel family. The
      homozygous father and two fetuses illustrate variable expression.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: >-
        url:https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: OTHER
      snippet: NM_003805.5(CRADD):c.52_59del (p.Ala18IlefsTer47) ... Harel T, et al.
      explanation: >-
        ClinGen case III-4 names the frameshift allele from Harel2017. The structured CGGV cache omits
        case-level allele rows; the linked report page supplies this exact allele.
    - reference: PMID:28686357
      reference_title: >-
        Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated
        with lissencephaly.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: revealed a homozygous frameshift variant in CRADD
      explanation: The primary abstract confirms a homozygous frameshift but does not give its exact HGVS.
  - name: p.Asp96ArgfsTer6
    variant_type: insertion
    type: frameshift insertion
    description: >-
      Reported as NM_003805.3:c.283_284insC in the 2018 MR123 family, with two mildly affected brothers.
      ClinGen represents the allele as NM_003805.5:c.285dup (p.Asp96fs). No focal functional assay was
      reported.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: >-
        url:https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: OTHER
      snippet: NM_003805.5(CRADD):c.285dup (p.Asp96fs) ... Santos-Cortez RLP, et al.
      explanation: >-
        ClinGen case MR123-3 records the normalized allele and cites Santos-Cortez2018. The structured
        CGGV cache omits case-level allele rows; the linked report page supplies this exact allele.
    - reference: PMID:30167849
      reference_title: >-
        Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders
        with intellectual disability.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: MR123–3 | 10 | M | 50 | 55 ... | Mild | None | CRADD |
      explanation: The primary clinical table places mild ID in the CRADD family.
  - name: c.2T>C start loss
    variant_type: single nucleotide variant
    type: start loss
    description: >-
      NM_003805.5:c.2T>C p.Met1? in trans with p.Arg170His in FIN38; delayed speech, pachygyria and mild
      cognitive impairment. No patient protein assay was reported.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: PMID:33710394
      reference_title: >-
        Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability
        (ID) in the founder population of Finland.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a novel start loss variant ... in CRADD were identified
      explanation: The main report identifies the start-loss allele.
    - reference: file:data/literature_supplements/CRADD_Jarvela_2021_Supplement.extracted.md
      reference_title: >-
        Supplementary information: Exome sequencing reveals predominantly de novo variants in disorders
        with intellectual disability (ID) in the founder population of Finland
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in one allele a novel variant c.2T>C:p.(M1?) and on the other allele the Finnish founder variant
        c.509G>A:p.(R170H) were identified.
      explanation: The supplementary case history specifies both alleles.
  - name: c.2T>G start loss
    variant_type: single nucleotide variant
    type: start loss
    description: >-
      Reported homozygously with a linked homozygous USP44 frameshift in Pakistani adults. The contribution
      of USP44 and the cause of additional skeletal features remain unresolved.
    gene:
      preferred_term: CRADD
      term:
        id: hgnc:2340
        label: CRADD
    evidence:
    - reference: PMID:33647455
      reference_title: >-
        CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental
        delay, strabismus, behavioural problems and skeletal anomalies.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: homozygous CRADD c.2T > G (p.Met1?) and USP44 c.873_886delinsT (p.Leu291Phefs*8)
      explanation: The two linked candidate variants co-segregate; they are not independent proof of two additive syndromes.
diagnosis:
- name: Brain MRI
  description: >-
    MRI identifies frontotemporal predominant pachygyria with mildly thick cortex. Mild abnormalities
    may be missed initially; normal head circumference does not exclude the diagnosis.
  evidence:
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain imaging studies are essential to support the molecular diagnosis for individuals with ID and
      a CRADD variant.
    explanation: The primary report recommends imaging to support molecular diagnosis.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
- name: Molecular testing and segregation
  description: >-
    Exome or targeted testing identifies CRADD alleles; segregation and copy-number evaluation are relevant
    when only one sequence allele is found. A multigene deletion has supplied a second allele.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Trio-based whole-exome sequencing (WES) in two families with TLIS detected a homozygous mutation of CRADD
    explanation: Primary discovery approach.
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 3.07 Mb deletion of chromosome 12q22 (chr12: 92,443,579–95,515,465; hg38) in this boy that includes
      the remaining CRADD allele
    explanation: Copy-number loss supplies the second allele; this is a multigene deletion.
- name: Developmental and cognitive assessment
  description: >-
    Serial language, developmental and cognitive assessment defines support needs; severity can vary within
    one family and between summary tables and detailed case histories.
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the developmental assessment at the age of 16 years (WISC-IV) his cognitive skills correspond
      to moderate intellectual disability.
    explanation: FIN-13 VIII/3 underwent standardized assessment.
- name: EEG in clinical evaluation
  description: >-
    EEG characterized seizures or background abnormalities in the reported cohorts. Photosensitivity and
    slowing can occur without a clinical epilepsy diagnosis.
  evidence:
  - reference: PMID:30914828
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients
      and megalencephaly in three patients.
    explanation: The abstract supports these variable clinical findings; body text supplies the exact denominators.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EEG abnormalities, including photosensitivity and background slowing, were present in five (...
      = 5/17, 29%) patients.
    explanation: Use the tested denominator, not all 22, for the EEG finding.
treatments:
- name: Speech therapy and communication support
  description: >-
    Speech therapy is used for language delay; gestures, signs and pictures can support communication.
    Spontaneous improvement also occurred, so treatment benefit cannot be quantified from these reports.
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patients in the younger generations received speech therapy.
    explanation: Observed care in the Finnish founder cohort.
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gestures, signs and pictures are used to help communication.
    explanation: Communication support in FIN-12 VII/1.
- name: Occupational therapy and developmental follow-up
  description: Occupational therapy and developmental assessment were reported for a child with global delay and hypotonia.
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He receives regular speech and occupational therapy and he has regular ophthalmological and developmental
      follow-up.
    explanation: Reported care of FIN-12 VII/1; not a tested disease-specific protocol.
- name: Special education and daily-living support
  description: >-
    School support and assisted living are individualized to functional ability. Some affected adults
    work and live relatively independently.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Special education was given for the younger generations of the patients.
    explanation: Educational support in the founder series.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
    reference_title: >-
      Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
      pachygyria in the Finnish population - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Majority of adult patients have moved to assisted living facilities where they can get help in everyday tasks.
    explanation: Observed adult support needs, not inevitable dependence.
- name: Carbamazepine
  description: >-
    Episodes interpreted as epilepsy in FIN-4 IX/8 reportedly improved with carbamazepine. This is a single-case
    observation, not comparative efficacy evidence.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: were interpreted as epileptic fits mitigated with carbamatsepin.
    explanation: Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.
- name: Methylphenidate
  description: >-
    Used for diagnosed ADHD in selected founder cases and attention deficit in the compound heterozygous
    FIN38 child.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylphenidate
      term:
        id: CHEBI:6887
        label: methylphenidate
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ADHD has been diagnosed and she is regularly using methylphenidate medication.
    explanation: Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.
- name: Risperidone
  description: Used for aggressive or impulsive behavior in individual Finnish cases.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: risperidone
      term:
        id: CHEBI:8871
        label: risperidone
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 11 years risperidone medication was started due to impulsive and aggressive behavior disorder.
    explanation: Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.
- name: Diazepam
  description: Reported as an as-needed medication alongside risperidone in FIN-9 III/4 with panic and aggressive behavior.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diazepam
      term:
        id: CHEBI:49575
        label: diazepam
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: risperidone medication and diazepam medication on behalf.
    explanation: Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.
- name: Asenapine
  description: Reported for treatment-resistant aggressive and impulsive behavior in FIN-11 III/1 after other neuroleptics.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: asenapine
      term:
        id: CHEBI:71253
        label: asenapine
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: currently she is using asenapine regularly and alprazolame on behalf.
    explanation: Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.
- name: Alprazolam
  description: Reported as an as-needed adjunct in FIN-11 III/1; the source spells the agent alprazolame.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alprazolam
      term:
        id: CHEBI:2611
        label: alprazolam
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: currently she is using asenapine regularly and alprazolame on behalf.
    explanation: Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.
- name: Perazine
  description: Reported for impulsive and restless behavior in FIN-11 III/3.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: perazine
      term:
        id: CHEBI:59118
        label: perazine
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She has impulsive and restless behavior treated with perazine medication.
    explanation: Published case-level use; no controlled CRADD treatment trial or disease-modifying effect is established.
- name: Ophthalmological care
  description: >-
    Visual assessment and follow-up are relevant to documented strabismus and refractive problems. Strabismus
    surgery was performed in an individual case.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of four years retroposition of the medial rectus muscle and resection of the lateral
      rectus muscle was performed.
    explanation: Eye-muscle surgery in FIN-13 VIII/2.
  - reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
    reference_title: >-
      Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
      frontotemporal predominant pachygyria in the Finnish population
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He receives regular speech and occupational therapy and he has regular ophthalmological and developmental
      follow-up.
    explanation: Follow-up in FIN-12 VII/1.
- name: Genetic counseling
  description: >-
    Discuss recessive inheritance and variable expressivity. Prenatal cortical imaging and a biallelic
    CRADD result cannot reliably predict severe disability; an apparently healthy homozygous father had
    hypogyration.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:28686357
    reference_title: >-
      Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated
      with lissencephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study underscores the phenotypic variability of pathogenic variants in CRADD and the challenges
      of prenatal genetic counseling.
    explanation: The primary family report emphasizes uncertainty of prenatal prognosis.
experimental_models:
- name: G128R patient dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Dermal fibroblasts from affected individuals, heterozygous parents and controls
  description: CRADD protein abundance was measured by immunoblotting; no patient cortical-neuron apoptosis was measured.
  modeled_mechanisms:
  - target: Gly128Arg CRADD Protein Depletion
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Experimental observations inform this node within the stated preparation.
    limitations: Peripheral cells and one allele; other patients did not supply fibroblasts.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Dermal fibroblasts from p.Gly128Arg CRADD TLIS-affected subjects are essentially null for CRADD abundance
      explanation: >-
        Patient-derived fibroblasts demonstrate allele-specific protein depletion; other alleles were
        not tested in patient fibroblasts.
- name: PC12 protein-import caspase and survival assays
  experimental_model_type: CELL_LINE
  cell_source: Rat PC12 cells transduced with Penetratin-linked human CRADD proteins
  description: WT and four missense proteins were compared for binding, caspase-2 activation and survival.
  modeled_mechanisms:
  - target: Reduced Caspase-2 Activation
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Experimental observations inform this node within the stated preparation.
    limitations: Exogenous protein import into a cell line.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We found that only WT CRADD induces caspase-2 activity; the CRADD-TLIS variants do not.
      explanation: Penetratin-linked proteins were imported into PC12 cells and active caspase-2 was captured with bVAD-fmk.
  - target: Reduced Caspase-2-Dependent Neuronal Apoptosis
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Experimental observations inform this node within the stated preparation.
    limitations: PC12 survival is not human developmental neuron elimination.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transduction of PC12 cells with Pen1-linked CRADD-TLIS variants (p.Gly128Arg, p.Phe164Cys, p.Arg170Cys,
        and p.Arg170His) failed to induce cell death
      explanation: All four tested missense variants failed to reproduce the cell death induced by imported wild-type CRADD.
- name: Cradd-null sympathetic neuron cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Sympathetic neurons isolated from newborn Cradd-null mice
  description: Imported WT human CRADD induced death whereas G128R did not.
  modeled_mechanisms:
  - target: Reduced Caspase-2-Dependent Neuronal Apoptosis
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Experimental observations inform this node within the stated preparation.
    limitations: Peripheral sympathetic neurons, one mutant allele and exogenous protein import.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        CRADD WT resulted in significant cell death of primary sympathetic neurons from Cradd−/− mice
        1 day after transduction, whereas cell survival after transduction of p.Gly128Arg CRADD was indistinguishable
        from that of non-transduced cells
      explanation: >-
        The neuronal culture experiment tested G128R against wild-type protein; it is not a measurement
        of human fetal apoptosis.
- name: Cellular CRADD interaction assays
  experimental_model_type: CELL_LINE
  cell_source: HEK293T and Neuro2a cells expressing CRADD and PIDD-DD
  description: >-
    Coimmunoprecipitation retains PIDD association for F164C/R170C/R170H, unlike G128R; this differs from
    purified-protein results.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunoprecipitation of recombinant FLAG-CRADD overexpressed in Neuro2a (data not shown) and HEK293T
      cells co-precipitated V5-PIDD-DD for each of the CRADD-TLIS variants except p.Gly128Arg
    explanation: Cellular PIDD binding is retained for three variants, with G128R the exception.
- name: Purified RAIDD–PIDD death-domain complexes
  experimental_model_type: OTHER
  description: >-
    E. coli-expressed CRADD death domains or full-length protein were mixed with PIDD-DD and examined
    by size-exclusion chromatography and native PAGE.
  modeled_mechanisms:
  - target: Impaired PIDDosome Assembly
    relationship: MEASURES
    fidelity: UNKNOWN
    description: Experimental observations inform this node within the stated preparation.
    limitations: Purified recombinant proteins lack cellular context; co-IP results differ.
    evidence:
    - reference: PMID:30281648
      reference_title: RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS).
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution
        peaks after size exclusion chromatography
      explanation: >-
        Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation
        gives a different result.
animal_models:
- name: Cradd-null mouse
  species: Mus musculus
  genotype: Cradd−/− on C57BL/6 background
  description: >-
    Knockout mice have increased endocast volume and handling-induced seizures (8/31, versus 0/60 WT/heterozygous
    littermates), with normal cortical layering. Smaller body and limb size were also observed.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      all mutant mice had a statistically significant increase in endocast volume that corresponds to
      increased brain volume
    explanation: Micro-CT endocast measurements support mouse brain enlargement, not a direct neuronal-count assay.
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      8 of 31 (26%) Cradd−/− mice displayed handling-induced seizures; no WT or Cradd+/− littermates (0
      of 60) had seizures.
    explanation: Mouse seizure susceptibility is not the human cohort frequency.
  modeled_mechanisms:
  - target: Brain Overgrowth
    relationship: PARTIALLY_RECAPITULATES
    fidelity: UNKNOWN
    description: Experimental observations inform this node within the stated preparation.
    limitations: Brain volume is inferred from endocast; neuron number was not counted.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        all mutant mice had a statistically significant increase in endocast volume that corresponds to
        increased brain volume
      explanation: Micro-CT endocast measurements support mouse brain enlargement, not a direct neuronal-count assay.
  - target: Abnormal Cortical Gyration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: UNKNOWN
    description: Experimental observations inform this node within the stated preparation.
    limitations: >-
      Mouse cortex is normally lissencephalic and remained normally layered; the human cortical phenotype
      is not reproduced.
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Morphological analysis of Cradd−/− cortex revealed normal layering indistinguishable from WT mice
      explanation: Normal layering in the knockout does not establish or reproduce the human MRI gyral pattern.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      description: >-
        Mouse cortex is normally lissencephalic and remained normally layered; the human cortical phenotype
        is not reproduced.
discussions:
- discussion_id: gap_cradd_mouse_model_lamination_mismatch
  prompt: >-
    Which developmental process connects impaired CRADD signaling to human cortical malformation, and
    which models can distinguish altered neuronal death from synaptic remodeling?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Caspase-2-Dependent Neuronal Apoptosis
  - pathophysiology#Abnormal Cortical Gyration
  rationale: >-
    Cradd-null mice show brain enlargement and handling-induced seizures but normal cortical layering.
    Patient-variant experiments establish impaired caspase-2 activation and cell death in cultured cells.
    They do not directly distinguish altered neuronal death, synaptic remodeling or another developmental
    process in human cortex. Human cortical models and gyrencephalic organisms could test the proposed
    bridge without assuming it.
  proposed_experiments:
  - experiment_id: exp_cradd_human_organoid_apoptosis
    name: CRADD-null / CRADD-TLIS human cortical organoid apoptosis and lamination assay
    description: >-
      Generate CRADD-null and patient-variant (e.g., p.Gly128Arg) iPSC-derived cortical organoids and
      quantify caspase-2 activation, developmental neuronal apoptosis, neuron number, cortical-plate thickness,
      and lamination relative to isogenic controls, to test whether reduced caspase-2-mediated apoptosis
      produces a human cortical-architecture phenotype not seen in mouse.
    experiment_type:
      preferred_term: iPSC organoid perturbation assay
    model_systems:
    - name: Human iPSC-derived cortical organoid
      description: >-
        Cortical organoid differentiated from patient-derived or gene-edited human iPSCs carrying CRADD
        loss-of-function variants.
      experimental_model_type: ORGANOID
  - experiment_id: exp_cradd_gyrencephalic_model
    name: CRADD loss in a gyrencephalic model
    description: >-
      Evaluate cortical lamination, gyration, and brain size after CRADD loss-of-function in a gyrencephalic
      species (e.g., ferret) that, unlike the mouse, normally gyrifies, to test whether the human-like
      cortical phenotype emerges when a gyrencephalic developmental program is present.
    experiment_type:
      preferred_term: in vivo gene perturbation
    model_systems:
    - name: Gyrencephalic mammalian model
      description: >-
        A gyrencephalic species with an outer subventricular zone and cortical folding, contrasting with
        the lissencephalic mouse.
      experimental_model_type: OTHER
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Morphological analysis of Cradd−/− cortex revealed normal layering indistinguishable from WT mice
    explanation: Normal layering in the knockout does not establish or reproduce the human MRI gyral pattern.
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is not clear whether the megalencephaly, undulating pachygyria, increased cortical thickness,
      and intellectual disability characteristic of CRADD-TLIS result from reduced pruning of synaptic
      connections, decreased programmed cell death of inappropriate neurons, or a combination of the two.
    explanation: The authors leave the human developmental intermediate unresolved.
- discussion_id: gap_cradd_pidd_binding_assay_difference
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do R170C/H retain PIDD association in cellular coimmunoprecipitation but fail stable assembly
    in purified-protein assays?
  attaches_to:
  - pathophysiology#Impaired PIDDosome Assembly
  rationale: >-
    Pairwise association and higher-order stable assembly can differ, and the experiments use different
    protein preparations. Their relevance to developing human cortex is unresolved.
  evidence:
  - reference: PMID:27773430
    reference_title: >-
      Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
      with a Rare Lissencephaly Variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunoprecipitation of recombinant FLAG-CRADD overexpressed in Neuro2a (data not shown) and HEK293T
      cells co-precipitated V5-PIDD-DD for each of the CRADD-TLIS variants except p.Gly128Arg
    explanation: Cellular PIDD binding is retained for three variants, with G128R the exception.
  - reference: PMID:30281648
    reference_title: RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mixture of PIDD DD with RD-DD R170C or RD-DD R170H did not produce distinct complex elution
      peaks after size exclusion chromatography
    explanation: >-
      Purified death-domain complexes fail to assemble stably in this assay; cellular coimmunoprecipitation
      gives a different result.
- discussion_id: gap_cradd_usp44_linked_variants
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What explains the additional findings in the family carrying linked homozygous CRADD and USP44 variants?
  rationale: >-
    The reported adults have skeletal, facial and digestive findings whose attribution remains uncertain;
    cosegregation of linked variants cannot assign each manifestation to one gene.
  evidence:
  - reference: PMID:33647455
    reference_title: >-
      CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental
      delay, strabismus, behavioural problems and skeletal anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: whether the damaging USP44 variant contributed to the disease in the family we present is not clear.
    explanation: The authors leave the contribution of the second gene unresolved.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:30914828
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening.
      explanation: The indexed primary report establishes the characteristic imaging phenotype.
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
      reference_title: >-
        Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
        pachygyria in the Finnish population - PMC
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients whose brain imaging data was available (... = 19; 86%) showed frontotemporal predominant
        pachygyria.
      explanation: All 19 imaged participants in the Finnish founder series showed the cortical pattern.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:27773430
      reference_title: >-
        Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
        with a Rare Lissencephaly Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        individuals with recessive CRADD mutations (n = 13) presented with TLIS, mild to moderate ID,
        epilepsy (3 of 13)
      explanation: >-
        The expanded founding cohort links the recessive genotype to cortical malformation and neurodevelopmental
        manifestations.
notes: >-
  The cortical imaging pattern can be subtle and head size normal. Finnish founder, Mennonite and other
  families differ in clinical severity; published cohort counts overlap between discovery and follow-up
  reports. The clinical phenotype is generally milder than classical thick lissencephaly, but individual
  support needs vary. Adult medical comorbidities in case histories are not established CRADD manifestations.
  No validated mechanistic subtypes or disease-modifying treatment are established by these reports.
references:
- reference: CGGV:assertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z
  title: CRADD / syndromic intellectual disability (Definitive)
- reference: PMID:22279524
  title: Genetic mapping and exome sequencing identify variants associated with five novel diseases.
- reference: PMID:27773430
  title: >-
    Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly
    with a Rare Lissencephaly Variant.
- reference: PMID:28686357
  title: >-
    Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated
    with lissencephaly.
- reference: PMID:30167849
  title: >-
    Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with
    intellectual disability.
- reference: PMID:30281648
  title: RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS).
- reference: PMID:30914828
  title: >-
    Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
    pachygyria in the Finnish population.
- reference: PMID:33647455
  title: >-
    CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental
    delay, strabismus, behavioural problems and skeletal anomalies.
- reference: PMID:33710394
  title: >-
    Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability
    (ID) in the founder population of Finland.
- reference: file:data/literature_supplements/CRADD_Jarvela_2021_Supplement.extracted.md
  title: >-
    Supplementary information: Exome sequencing reveals predominantly de novo variants in disorders with
    intellectual disability (ID) in the founder population of Finland
- reference: file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md
  title: >-
    Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying
    frontotemporal predominant pachygyria in the Finnish population
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/
  title: >-
    Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant
    pachygyria in the Finnish population - PMC
- reference: >-
    url:https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z
  title: curation results for Gene-Disease Validity

📚

References & Deep Research

References

13

CGGV:assertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z

CRADD / syndromic intellectual disability (Definitive)

No top-level findings curated for this source.

PMID:22279524

Genetic mapping and exome sequencing identify variants associated with five novel diseases.

No top-level findings curated for this source.

PMID:27773430

Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant.

No top-level findings curated for this source.

PMID:28686357

Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly.

No top-level findings curated for this source.

PMID:30167849

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.

No top-level findings curated for this source.

PMID:30281648

RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS).

No top-level findings curated for this source.

PMID:30914828

Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population.

No top-level findings curated for this source.

PMID:33647455

CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies.

No top-level findings curated for this source.

PMID:33710394

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.

No top-level findings curated for this source.

file:data/literature_supplements/CRADD_Jarvela_2021_Supplement.extracted.md

Supplementary information: Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

No top-level findings curated for this source.

file:data/literature_supplements/CRADD_Polla_2019_Supplement.extracted.md

Supplementary information: Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population

No top-level findings curated for this source.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6777631/

Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population - PMC

No top-level findings curated for this source.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_7f64ee7f-13a7-4a2d-b1a2-ad6c9e63cab3-2021-06-16T180000.000Z

curation results for Gene-Disease Validity

No top-level findings curated for this source.

CRADD-Related Thin Lissencephaly

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