Immunodeficiency-centromeric instability-facial anomalies syndrome 4

Summary

Immunodeficiency-centromeric instability-facial anomalies syndrome 4 (MONDO:0014829) is a disease caused by HELLS (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: HELLS (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 23

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency-centromeric instability-facial anomalies syndrome 4
Mondo ID	MONDO:0014829
OMIM	616911
DOID	DOID:0090011
UMLS	C4310798
MedGen	934765
GARD	0016169
Is cancer (heuristic)	no

Also known as: HELLS immunodeficiency-centromeric instability-facial anomalies syndrome · ICF4 · immunodeficiency-centromeric instability-Facial anomalies syndrome 4 · immunodeficiency-centromeric instability-facial anomalies syndrome caused by mutation in HELLS · immunodeficiency-centromeric instability-Facial anomalies syndrome type 4 · immunodeficiency-centromeric instability-facial anomalies syndrome type 4

Data availability: 23 ClinVar variants · 2 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 4

Related subtypes (3): immunodeficiency-centromeric instability-facial anomalies syndrome 1, immunodeficiency-centromeric instability-facial anomalies syndrome 2, immunodeficiency-centromeric instability-facial anomalies syndrome 3

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

23 retrieved; paginated sample, class counts are floors:

5 benign, 5 pathogenic, 3 uncertain significance, 3 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
225523	NM_018063.5(HELLS):c.2096A>G (p.Gln699Arg)	HELLS	Pathogenic	no assertion criteria provided
225524	NM_018063.5(HELLS):c.370+2T>A	HELLS	Pathogenic	criteria provided, multiple submitters, no conflicts
225525	NM_018063.5(HELLS):c.2283_2286del (p.Ser762fs)	HELLS	Pathogenic	no assertion criteria provided
225526	NM_018063.5(HELLS):c.610A>T (p.Lys204Ter)	HELLS	Pathogenic	no assertion criteria provided
225527	NM_018063.5(HELLS):c.374_381dup (p.Lys128Ter)	HELLS	Pathogenic	no assertion criteria provided
225528	NM_018063.5(HELLS):c.2394GTT[2] (p.Leu801del)	HELLS	Likely pathogenic	criteria provided, single submitter
3779727	NM_018063.5(HELLS):c.276+1G>A	HELLS	Likely pathogenic	criteria provided, single submitter
1032786	NM_018063.5(HELLS):c.360A>G (p.Glu120=)	HELLS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2969713	NM_018063.5(HELLS):c.1035T>C (p.His345=)	HELLS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
768380	NM_018063.5(HELLS):c.2182A>G (p.Ile728Val)	HELLS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028083	NM_018063.5(HELLS):c.1537A>G (p.Arg513Gly)	HELLS	Uncertain significance	criteria provided, multiple submitters, no conflicts
811038	NM_018063.5(HELLS):c.1258C>G (p.Leu420Val)	HELLS	Uncertain significance	criteria provided, multiple submitters, no conflicts
998163	NM_018063.5(HELLS):c.2077G>T (p.Asp693Tyr)	HELLS	Uncertain significance	criteria provided, single submitter
1166855	NM_018063.5(HELLS):c.31+20T>C	HELLS	Benign	criteria provided, multiple submitters, no conflicts
1168418	NM_018063.5(HELLS):c.231A>C (p.Ile77=)	HELLS	Benign	criteria provided, multiple submitters, no conflicts
1657241	NM_018063.5(HELLS):c.706-18A>G	HELLS	Likely benign	criteria provided, multiple submitters, no conflicts
709251	NM_018063.5(HELLS):c.1965A>G (p.Glu655=)	HELLS	Benign	criteria provided, multiple submitters, no conflicts
710853	NM_018063.5(HELLS):c.993G>A (p.Thr331=)	HELLS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
716400	NM_018063.5(HELLS):c.2T>C (p.Met1Thr)	HELLS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
739088	NM_018063.5(HELLS):c.913A>G (p.Thr305Ala)	HELLS	Likely benign	criteria provided, multiple submitters, no conflicts
776529	NM_018063.5(HELLS):c.270A>G (p.Gln90=)	HELLS	Benign	criteria provided, multiple submitters, no conflicts
779935	NM_018063.5(HELLS):c.153+10G>T	HELLS	Benign	criteria provided, multiple submitters, no conflicts
790454	NM_018063.5(HELLS):c.334G>A (p.Gly112Ser)	HELLS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
HELLS	Strong	Autosomal recessive	immunodeficiency-centromeric instability-facial anomalies syndrome 4	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HELLS	Orphanet:2268	ICF syndrome

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
HELLS	HGNC:4861	ENSG00000119969	Q9NRZ9	Lymphoid-specific helicase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HELLS	Lymphoid-specific helicase	ATP-dependent chromatin remodeler that regulates chromatin accessibility, DNA methylation, and histone modifications.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HELLS	Other/Unknown	no		SNF2_N, Helicase_C-like, Helicase_ATP-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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HELLS	221	ubiquitous	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HELLS	4,165

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HELLS	Q9NRZ9	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
TGFBR3 expression	1	456.8×	0.002	HELLS

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
chromosomal DNA methylation maintenance following DNA replication	1	4213.0×	0.002	HELLS
pericentric heterochromatin formation	1	3370.4×	0.002	HELLS
lymphocyte proliferation	1	2407.4×	0.002	HELLS
negative regulation of gene expression via chromosomal CpG island methylation	1	1053.2×	0.003	HELLS
urogenital system development	1	991.3×	0.003	HELLS
negative regulation of intrinsic apoptotic signaling pathway	1	766.0×	0.003	HELLS
DNA methylation-dependent constitutive heterochromatin formation	1	543.6×	0.003	HELLS
double-strand break repair	1	203.0×	0.008	HELLS
cellular response to leukemia inhibitory factor	1	159.0×	0.008	HELLS
double-strand break repair via homologous recombination	1	156.0×	0.008	HELLS
kidney development	1	140.4×	0.008	HELLS
cell division	1	46.2×	0.023	HELLS
apoptotic process	1	28.7×	0.035	HELLS

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
HELLS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HELLS	6	Binding:6

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HELLS

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)
HELLS	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.