Immunodeficiency-centromeric instability-facial anomalies syndrome 2

Summary

Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (MONDO:0013553) is a disease caused by ZBTB24 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ZBTB24 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 481

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency-centromeric instability-facial anomalies syndrome 2
Mondo ID	MONDO:0013553
OMIM	614069
DOID	DOID:0090009
UMLS	C3279748
MedGen	481378
GARD	0015751
Is cancer (heuristic)	no

Also known as: ICF2 · immunodeficiency-centromeric instability-facial anomalies syndrome 2 · immunodeficiency-centromeric instability-facial anomalies syndrome caused by mutation in ZBTB24 · immunodeficiency-centromeric instability-Facial anomalies syndrome type 2 · immunodeficiency-centromeric instability-facial anomalies syndrome type 2 · ZBTB24 immunodeficiency-centromeric instability-facial anomalies syndrome

Data availability: 481 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › immunodeficiency-centromeric instability-facial anomalies syndrome › immunodeficiency-centromeric instability-facial anomalies syndrome 2

Related subtypes (3): immunodeficiency-centromeric instability-facial anomalies syndrome 1, immunodeficiency-centromeric instability-facial anomalies syndrome 3, immunodeficiency-centromeric instability-facial anomalies syndrome 4

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

481 retrieved; paginated sample, class counts are floors:

245 likely benign, 155 uncertain significance, 42 pathogenic, 14 benign, 11 likely pathogenic, 6 conflicting classifications of pathogenicity, 6 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3246029	NC_000006.11:g.(?109765394)(109798153_?)del	MICAL1	Pathogenic	criteria provided, single submitter
1074302	NM_014797.3(ZBTB24):c.909dup (p.Lys304Ter)	ZBTB24	Pathogenic	criteria provided, single submitter
1353720	NM_014797.3(ZBTB24):c.1118C>G (p.Ser373Ter)	ZBTB24	Pathogenic	criteria provided, single submitter
1526123	NM_014797.3(ZBTB24):c.501dup (p.Val168fs)	ZBTB24	Pathogenic	criteria provided, multiple submitters, no conflicts
2028359	NM_014797.3(ZBTB24):c.389del (p.Asn130fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2071437	NM_014797.3(ZBTB24):c.1439dup (p.His480fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2429329	NM_014797.3(ZBTB24):c.953-2A>G	ZBTB24	Pathogenic	criteria provided, single submitter
2703195	NM_014797.3(ZBTB24):c.377_378del (p.Thr126fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2725726	NM_014797.3(ZBTB24):c.1161del (p.Phe387fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2734924	NM_014797.3(ZBTB24):c.787A>T (p.Lys263Ter)	ZBTB24	Pathogenic	criteria provided, single submitter
2750593	NM_014797.3(ZBTB24):c.1125_1135del (p.Gln375fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2793751	NM_014797.3(ZBTB24):c.993del (p.Phe331fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2809786	NM_014797.3(ZBTB24):c.868_875dup (p.Arg295fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2826131	NM_014797.3(ZBTB24):c.971_972delinsAA (p.Cys324Ter)	ZBTB24	Pathogenic	criteria provided, single submitter
2840471	NM_014797.3(ZBTB24):c.911_914del (p.Lys304fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2841373	NM_014797.3(ZBTB24):c.1272_1281del (p.Leu425fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2863511	NM_014797.3(ZBTB24):c.226_227del (p.Ile76fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2865191	NM_014797.3(ZBTB24):c.431del (p.Gly144fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2866507	NM_014797.3(ZBTB24):c.44_50del (p.His15fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2870778	NM_014797.3(ZBTB24):c.825_844del (p.His276fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2879709	NM_014797.3(ZBTB24):c.658G>T (p.Glu220Ter)	ZBTB24	Pathogenic	criteria provided, single submitter
2880060	NM_014797.3(ZBTB24):c.350_351del (p.Lys117fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2915423	NM_014797.3(ZBTB24):c.795dup (p.Asp266fs)	ZBTB24	Pathogenic	criteria provided, single submitter
2956344	NM_014797.3(ZBTB24):c.593_594del (p.Phe198fs)	ZBTB24	Pathogenic	criteria provided, single submitter
3004627	NM_014797.3(ZBTB24):c.997C>T (p.Gln333Ter)	ZBTB24	Pathogenic	criteria provided, single submitter
31093	NM_014797.3(ZBTB24):c.958C>T (p.Arg320Ter)	ZBTB24	Pathogenic	criteria provided, multiple submitters, no conflicts
31095	NM_014797.3(ZBTB24):c.833C>G (p.Ser278Ter)	ZBTB24	Pathogenic	criteria provided, single submitter
31096	NM_014797.3(ZBTB24):c.1222T>G (p.Cys408Gly)	ZBTB24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31097	NM_014797.3(ZBTB24):c.1369C>T (p.Arg457Ter)	ZBTB24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3246027	NC_000006.11:g.(?109787054)(109803229_?)del	ZBTB24	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
ZBTB24	Definitive	Autosomal recessive	immunodeficiency-centromeric instability-facial anomalies syndrome 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZBTB24	Orphanet:2268	ICF syndrome
MICAL1	Orphanet:101046	Epilepsy with auditory features

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZBTB24	HGNC:21143	ENSG00000112365	O43167	Zinc finger and BTB domain-containing protein 24	gencc,clinvar
MICAL1	HGNC:20619	ENSG00000135596	Q8TDZ2	[F-actin]-monooxygenase MICAL1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZBTB24	Zinc finger and BTB domain-containing protein 24	May be involved in BMP2-induced transcription.
MICAL1	[F-actin]-monooxygenase MICAL1	Monooxygenase that promotes depolymerization of F-actin by mediating oxidation of specific methionine residues on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZBTB24	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
MICAL1	Transcription factor	no	1.14.13.225	CH_dom, Znf_LIM, FAD-bd

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
tendon of biceps brachii	1
granulocyte	1
left coronary artery	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZBTB24	256	ubiquitous	yes	endothelial cell, Brodmann (1909) area 23, tendon of biceps brachii
MICAL1	234	ubiquitous	marker	right coronary artery, granulocyte, left coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZBTB24	1,685
MICAL1	1,045

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MICAL1	Q8TDZ2	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZBTB24	O43167	56.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.028	MICAL1
Hemostasis	1	36.0×	0.028	MICAL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sulfur oxidation	1	4213.0×	0.001	MICAL1
regulation of regulated secretory pathway	1	4213.0×	0.001	MICAL1
actin filament depolymerization	1	648.1×	0.005	MICAL1
actin filament bundle assembly	1	227.7×	0.010	MICAL1
hematopoietic progenitor cell differentiation	1	118.7×	0.015	ZBTB24
cytoskeleton organization	1	66.3×	0.023	MICAL1
negative regulation of apoptotic process	1	17.4×	0.073	MICAL1
signal transduction	1	8.0×	0.136	MICAL1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ZBTB24

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZBTB24	0	0
MICAL1	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
ZBTB24	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MICAL1	1.14.13.225	F-actin monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ZBTB24, MICAL1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZBTB24	3	—
MICAL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.