Tessadori-van Haaften neurodevelopmental syndrome 1

Summary

Tessadori-van Haaften neurodevelopmental syndrome 1 (MONDO:0030729) is a disease caused by H4C3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: H4C3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Tessadori-van Haaften neurodevelopmental syndrome 1
Mondo ID	MONDO:0030729
OMIM	619758
UMLS	C5676922
MedGen	1810348
Is cancer (heuristic)	no

Also known as: Tessadori-van Haaften neurodevelopmental syndrome 1 · TEVANED1

Data availability: 7 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 › Tessadori-Van-Haaften neurodevelopmental syndrome › Tessadori-van Haaften neurodevelopmental syndrome 1

Related subtypes (3): Tessadori-van Haaften neurodevelopmental syndrome 2, Tessadori-Van Haaften neurodevelopmental syndrome 3, Tessadori-Van Haaften neurodevelopmental 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

7 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699322	NM_003542.4(H4C3):c.274A>G (p.Lys92Glu)	H4C3	Pathogenic	criteria provided, single submitter
976699	NM_003542.4(H4C3):c.274A>C (p.Lys92Gln)	H4C3	Pathogenic	criteria provided, single submitter
1342161	NM_003542.4(H4C3):c.275A>G (p.Lys92Arg)	H4C3	Likely pathogenic	criteria provided, single submitter
2443610	NM_003542.4(H4C3):c.98C>G (p.Pro33Arg)	H4C3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2689193	NM_003542.4(H4C3):c.133A>T (p.Lys45Ter)	H4C3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065146	NM_003542.4(H4C3):c.221C>A (p.Thr74Lys)	H4C3	Uncertain significance	criteria provided, single submitter
3103994	NM_003542.4(H4C3):c.268G>T (p.Ala90Ser)	H4C3	Uncertain significance	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
H4C3	Strong	Autosomal dominant	Tessadori-van Haaften neurodevelopmental syndrome 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
H4C3	Orphanet:528084	Non-specific syndromic intellectual disability

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
H4C3	HGNC:4787	ENSG00000197061	P62805	Histone H4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
H4C3	Histone H4	Core component of nucleosome.

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)
H4C3	Other/Unknown	no		Histone_H4, TAF_TATA-bd_Histone-like_dom, Histone-fold

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
cervix squamous epithelium	1
endothelial cell	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
H4C3	244	ubiquitous	marker	endothelial cell, trabecular bone tissue, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
H4C3	4,216

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
H4C3	P62805	626

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. 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
Replacement of protamines by nucleosomes in the male pronucleus	1	271.9×	0.012	H4C3
HDMs demethylate histones	1	228.4×	0.012	H4C3
Packaging Of Telomere Ends	1	219.6×	0.012	H4C3
Recognition and association of DNA glycosylase with site containing an affected purine	1	203.9×	0.012	H4C3
Cleavage of the damaged purine	1	203.9×	0.012	H4C3
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	184.2×	0.012	H4C3
Cleavage of the damaged pyrimidine	1	184.2×	0.012	H4C3
RNA Polymerase I Promoter Opening	1	184.2×	0.012	H4C3
ChAHP complex assembly	1	184.2×	0.012	H4C3
DNA methylation	1	178.4×	0.012	H4C3
FXIIa activates plasma kallikrein-kinin system	1	173.0×	0.012	H4C3
SIRT1 negatively regulates rRNA expression	1	170.4×	0.012	H4C3
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3	1	167.9×	0.012	H4C3
Nonhomologous End-Joining (NHEJ)	1	167.9×	0.012	H4C3
Inhibition of DNA recombination at telomere	1	167.9×	0.012	H4C3
Assembly of the ORC complex at the origin of replication	1	165.5×	0.012	H4C3
DNA Damage/Telomere Stress Induced Senescence	1	163.1×	0.012	H4C3
Chromatin modifications during the maternal to zygotic transition (MZT)	1	163.1×	0.012	H4C3
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	1	163.1×	0.012	H4C3
PKMTs methylate histone lysines	1	160.8×	0.012	H4C3
SUMOylation of chromatin organization proteins	1	158.6×	0.012	H4C3
Deposition of new CENPA-containing nucleosomes at the centromere	1	158.6×	0.012	H4C3
Condensation of Prophase Chromosomes	1	156.4×	0.012	H4C3
Defective pyroptosis	1	156.4×	0.012	H4C3
PRC2 methylates histones and DNA	1	152.3×	0.012	H4C3
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	1	152.3×	0.012	H4C3
CHD6, CHD7, CHD8, CHD9 subfamily	1	148.3×	0.012	H4C3
RMTs methylate histone arginines	1	146.4×	0.012	H4C3
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	146.4×	0.012	H4C3
Transcriptional regulation by small RNAs	1	144.6×	0.012	H4C3

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
protein localization to CENP-A containing chromatin	1	936.2×	0.003	H4C3
negative regulation of megakaryocyte differentiation	1	887.0×	0.003	H4C3
telomere organization	1	624.1×	0.003	H4C3
nucleosome assembly	1	140.4×	0.009	H4C3
chromatin organization	1	99.1×	0.010	H4C3

Therapeutics

Drug target analysis

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

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
H4C3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMREDOBRESIB	2	H4C3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
H4C3	14	Binding:14

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
AMREDOBRESIB	2	H4C3

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	1	H4C3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.