CHD7-related CHARGE syndrome

Summary

CHD7-related CHARGE syndrome (MONDO:1010178) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 62

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	CHD7-related CHARGE syndrome
Mondo ID	MONDO:1010178
OMIM	214800
GARD	0028139
Is cancer (heuristic)	no

Also known as: CHARGE syndrome due to CHD7 deficiency · CHD7-related CHARGE syndrome

Data availability: 62 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › CHARGE syndrome › CHD7-related CHARGE syndrome

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

62 retrieved; paginated sample, class counts are floors:

36 pathogenic, 9 likely pathogenic, 7 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 4 uncertain significance, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028060	NM_017780.4(CHD7):c.6193C>T (p.Arg2065Cys)	CHD7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185684	NM_017780.4(CHD7):c.6217C>T (p.Gln2073Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
195978	NM_017780.4(CHD7):c.5405-17G>A	CHD7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235889	NM_017780.4(CHD7):c.6955C>T (p.Arg2319Cys)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
265403	NM_017780.4(CHD7):c.550C>T (p.Gln184Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
2664742	NM_017780.4(CHD7):c.487C>T (p.Gln163Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
267436	NM_017780.4(CHD7):c.6148C>T (p.Arg2050Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
279762	NM_017780.4(CHD7):c.5029C>T (p.Arg1677Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
4532101	NM_017780.4(CHD7):c.1979del (p.Lys660fs)	CHD7	Pathogenic	criteria provided, single submitter
4537433	NM_017780.4(CHD7):c.4953dup (p.Asn1652Ter)	CHD7	Pathogenic	criteria provided, single submitter
459547	NM_017780.4(CHD7):c.3937del (p.Ser1313fs)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
4685511	NM_017780.4(CHD7):c.5627C>G (p.Ser1876Ter)	CHD7	Pathogenic	criteria provided, single submitter
4685555	NM_017780.4(CHD7):c.7536del (p.Arg2512fs)	CHD7	Pathogenic	criteria provided, single submitter
4813445	NM_017780.4(CHD7):c.5653dup (p.Ile1885fs)	CHD7	Pathogenic	criteria provided, single submitter
4813777	NM_017780.4(CHD7):c.1319del (p.Pro440fs)	CHD7	Pathogenic	criteria provided, single submitter
4813790	NM_017780.4(CHD7):c.2429del (p.Arg809_Ser810insTer)	CHD7	Pathogenic	criteria provided, single submitter
4813793	NM_017780.4(CHD7):c.2605del (p.Leu869fs)	CHD7	Pathogenic	criteria provided, single submitter
4813799	NM_017780.4(CHD7):c.3062T>G (p.Val1021Gly)	CHD7	Pathogenic	criteria provided, single submitter
4813807	NM_017780.4(CHD7):c.3867del (p.Gly1290fs)	CHD7	Pathogenic	criteria provided, single submitter
4813810	NM_017780.4(CHD7):c.3961del (p.Ile1321fs)	CHD7	Pathogenic	criteria provided, single submitter
4813824	NM_017780.4(CHD7):c.5058del (p.Ala1687fs)	CHD7	Pathogenic	criteria provided, single submitter
4813825	NM_017780.4(CHD7):c.5451del (p.Leu1818fs)	CHD7	Pathogenic	criteria provided, single submitter
4813830	NM_017780.4(CHD7):c.6229_6230del (p.Arg2077fs)	CHD7	Pathogenic	criteria provided, single submitter
4819028	NM_017780.4(CHD7):c.4850+2_4850+9del	CHD7	Pathogenic	criteria provided, single submitter
4819309	NM_017780.4(CHD7):c.3801dup (p.Glu1268fs)	CHD7	Pathogenic	criteria provided, single submitter
4819310	NM_017780.4(CHD7):c.5435A>G (p.Asp1812Gly)	CHD7	Pathogenic	criteria provided, single submitter
4819312	NM_017780.4(CHD7):c.3971_3974dup (p.Tyr1325Ter)	CHD7	Pathogenic	criteria provided, single submitter
4819313	NM_017780.4(CHD7):c.8678dup (p.Leu2894fs)	CHD7	Pathogenic	criteria provided, single submitter
4819315	NM_017780.4(CHD7):c.5978_5981del (p.Asp1993fs)	CHD7	Pathogenic	criteria provided, single submitter
4819316	NM_017780.4(CHD7):c.7400del (p.Leu2467fs)	CHD7	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 8 · 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
SEMA3E	Moderate	Autosomal dominant	CHD7-related CHARGE syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEMA3E	Orphanet:138	CHARGE syndrome
TTPA	Orphanet:96	Ataxia with vitamin E deficiency
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
CYP7B1	Orphanet:100986	Autosomal recessive spastic paraplegia type 5A
CYP7B1	Orphanet:79302	Congenital bile acid synthesis defect type 3

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SEMA3E	HGNC:10727	ENSG00000170381	O15041	Semaphorin-3E	gencc
TTPA	HGNC:12404	ENSG00000137561	P49638	Alpha-tocopherol transfer protein	clinvar
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
CYP7B1	HGNC:2652	ENSG00000172817	O75881	Cytochrome P450 7B1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEMA3E	Semaphorin-3E	Plays an important role in signaling via the cell surface receptor PLXND1.
TTPA	Alpha-tocopherol transfer protein	Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
CYP7B1	Cytochrome P450 7B1	A cytochrome P450 monooxygenase involved in the metabolism of endogenous oxysterols and steroid hormones, including neurosteroids.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	7.3×	0.390
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEMA3E	Antibody/Immunoglobulin	yes		Semap_dom, Ig-like_dom, Immunoglobulin_dom
TTPA	Other/Unknown	no		CRAL-TRIO_dom, CRAL/TRIO_N_dom, CRAL/TRIO_N_dom_sf
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
CYP7B1	Enzyme (other)	yes	1.14.14.29	Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CYP7A1-type

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood vessel layer	1
calcaneal tendon	1
cortical plate	1
buccal mucosa cell	1
liver	1
right lobe of liver	1
cerebellar vermis	1
secondary oocyte	1
sural nerve	1
esophagus squamous epithelium	1
oral cavity	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEMA3E	197	broad	marker	cortical plate, calcaneal tendon, blood vessel layer
TTPA	135	broad	yes	right lobe of liver, liver, buccal mucosa cell
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
CYP7B1	239	broad	marker	seminal vesicle, oral cavity, esophagus squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHD7	4,819
CYP7B1	1,891
TTPA	1,060
SEMA3E	917

Intra-cohort edges

A	B	Sources
CHD7	SEMA3E	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTPA	P49638	6
CHD7	Q9P2D1	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP7B1	O75881	91.98
SEMA3E	O15041	84.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP7B1 causes SPG5A and CBAS3	1	2855.0×	0.002	CYP7B1
Vitamin E transport	1	2855.0×	0.002	TTPA
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	190.3×	0.015	CYP7B1
Other semaphorin interactions	1	150.3×	0.015	SEMA3E
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	114.2×	0.015	CYP7B1
Synthesis of bile acids and bile salts	1	102.0×	0.015	CYP7B1
Endogenous sterols	1	98.5×	0.015	CYP7B1
Semaphorin interactions	1	98.5×	0.015	SEMA3E
CHD6, CHD7, CHD8, CHD9 subfamily	1	37.1×	0.036	CHD7
Axon guidance	1	11.3×	0.098	SEMA3E
Nervous system development	1	10.7×	0.098	SEMA3E
Developmental Biology	1	3.6×	0.249	SEMA3E

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
right ventricular compact myocardium morphogenesis	1	4213.0×	0.009	CHD7
negative regulation of establishment of blood-brain barrier	1	4213.0×	0.009	TTPA
cranial nerve development	1	1404.3×	0.010	CHD7
olfactory nerve development	1	1404.3×	0.010	CHD7
regulation of growth hormone secretion	1	1404.3×	0.010	CHD7
vitamin E metabolic process	1	842.6×	0.010	TTPA
gonadotrophin-releasing hormone neuronal migration to the hypothalamus	1	702.2×	0.010	SEMA3E
B cell chemotaxis	1	702.2×	0.010	CYP7B1
chordate embryonic development	1	702.2×	0.010	CHD7
vitamin transport	1	702.2×	0.010	TTPA
female genitalia development	1	601.9×	0.010	CHD7
nose development	1	601.9×	0.010	CHD7
semicircular canal morphogenesis	1	601.9×	0.010	CHD7
epithelium development	1	526.6×	0.010	CHD7
positive regulation of amyloid-beta clearance	1	526.6×	0.010	TTPA
olfactory behavior	1	468.1×	0.010	CHD7
prostate gland epithelium morphogenesis	1	468.1×	0.010	CYP7B1
genitalia development	1	421.3×	0.010	CHD7
atrioventricular canal development	1	383.0×	0.011	CHD7
adult heart development	1	300.9×	0.011	CHD7
cardiac septum morphogenesis	1	300.9×	0.011	CHD7
secondary palate development	1	300.9×	0.011	CHD7
intermembrane lipid transfer	1	300.9×	0.011	TTPA
negative regulation of intracellular estrogen receptor signaling pathway	1	280.9×	0.011	CYP7B1
ventricular trabecula myocardium morphogenesis	1	263.3×	0.012	CHD7
negative regulation of cell-matrix adhesion	1	221.7×	0.012	SEMA3E
aorta morphogenesis	1	221.7×	0.012	CHD7
innervation	1	221.7×	0.012	CHD7
sterol metabolic process	1	210.7×	0.013	CYP7B1
face development	1	200.6×	0.013	CHD7

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
SEMA3E	0	0
TTPA	0	0
CHD7	0	0
CYP7B1	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
TTPA	5	Binding:5
CYP7B1	2	ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP7B1	1.14.14.29	25/26-hydroxycholesterol 7alpha-hydroxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	2	SEMA3E, CYP7B1
E	Difficult family or no structure, no drug	2	TTPA, CHD7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SEMA3E	0	—
TTPA	5	—
CHD7	0	—
CYP7B1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.