Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly

Summary

Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly (MONDO:0957999) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly
Mondo ID	MONDO:0957999
OMIM	620653
UMLS	C5882733
MedGen	1850178
GARD	0026905
Is cancer (heuristic)	no

Data availability: 4 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2499469	NM_032982.4(CASP2):c.1156del (p.Tyr386fs)	CASP2	Pathogenic	criteria provided, single submitter
2499470	NM_032982.4(CASP2):c.1174C>T (p.Gln392Ter)	CASP2	Pathogenic	criteria provided, single submitter
2499471	NM_032982.4(CASP2):c.130C>T (p.Arg44Ter)	CASP2	Pathogenic	criteria provided, single submitter
2499511	NM_032982.4(CASP2):c.876+1G>T	CASP2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CASP2	Moderate	Autosomal recessive	intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly	2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASP2	HGNC:1503	ENSG00000106144	P42575	Caspase-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASP2	Caspase-2	Is a regulator of the cascade of caspases responsible for apoptosis execution.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASP2	Enzyme (other)	yes	3.4.22.55	Pept_C14_p20, CARD, Pept_C14_p10

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
tendon of biceps brachii	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASP2	264	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, trabecular bone tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASP2	1,870

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASP2	P42575	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NADE modulates death signalling	1	1903.3×	0.008	CASP2
TP53 Regulates Transcription of Caspase Activators and Caspases	1	951.7×	0.008	CASP2
TP53 Regulates Transcription of Cell Death Genes	1	543.8×	0.009	CASP2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	356.9×	0.009	CASP2
NOD1/2 Signaling Pathway	1	317.2×	0.009	CASP2
Cell death signalling via NRAGE, NRIF and NADE	1	219.6×	0.011	CASP2
p75 NTR receptor-mediated signalling	1	187.2×	0.011	CASP2
Death Receptor Signaling	1	139.3×	0.013	CASP2
Transcriptional Regulation by TP53	1	62.1×	0.027	CASP2
Innate Immune System	1	25.5×	0.059	CASP2
RNA Polymerase II Transcription	1	22.5×	0.061	CASP2
Gene expression (Transcription)	1	17.8×	0.070	CASP2
Generic Transcription Pathway	1	15.1×	0.076	CASP2
Immune System	1	13.0×	0.083	CASP2
Signal Transduction	1	10.2×	0.098	CASP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
luteolysis	1	3370.4×	0.005	CASP2
neural retina development	1	936.2×	0.005	CASP2
ectopic germ cell programmed cell death	1	842.6×	0.005	CASP2
execution phase of apoptosis	1	766.0×	0.005	CASP2
positive regulation of apoptotic signaling pathway	1	581.1×	0.006	CASP2
extrinsic apoptotic signaling pathway in absence of ligand	1	468.1×	0.006	CASP2
DNA damage response, signal transduction by p53 class mediator	1	358.6×	0.006	CASP2
intrinsic apoptotic signaling pathway in response to DNA damage	1	324.1×	0.006	CASP2
positive regulation of neuron apoptotic process	1	271.8×	0.007	CASP2
apoptotic signaling pathway	1	224.7×	0.007	CASP2
cellular response to mechanical stimulus	1	216.1×	0.007	CASP2
protein processing	1	170.2×	0.008	CASP2
positive regulation of apoptotic process	1	56.7×	0.021	CASP2
DNA damage response	1	53.5×	0.021	CASP2
negative regulation of apoptotic process	1	34.8×	0.031	CASP2
apoptotic process	1	28.7×	0.035	CASP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CASP2	53	Binding:48, ADMET:2, Functional:2, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASP2	3.4.22.55	caspase-2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CASP2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CASP2	53	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.