Tessadori-Van Haaften neurodevelopmental syndrome 4

Summary

Tessadori-Van Haaften neurodevelopmental syndrome 4 (MONDO:0031000) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Tessadori-Van Haaften neurodevelopmental syndrome 4
Mondo ID	MONDO:0031000
OMIM	619951
UMLS	C5677016
MedGen	1804234
Is cancer (heuristic)	no

Also known as: Tessadori-Van Haaften neurodevelopmental syndrome 4 · TEVANED4

Data availability: 4 ClinVar variants · 1 GenCC gene-disease record.

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 4

Related subtypes (3): Tessadori-van Haaften neurodevelopmental syndrome 1, Tessadori-van Haaften neurodevelopmental syndrome 2, Tessadori-Van Haaften neurodevelopmental 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

4 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2443865	NM_003495.3(H4C9):c.122G>T (p.Arg41Leu)	H2BC12	Pathogenic	no assertion criteria provided
2443866	NM_003495.3(H4C9):c.227A>G (p.His76Arg)	H2BC12	Pathogenic	no assertion criteria provided
4056785	NM_003495.3(H4C9):c.52C>T (p.Arg18Cys)	H2BC12	Uncertain significance	criteria provided, single submitter
4526388	NM_003495.3(H4C9):c.76A>G (p.Asn26Asp)	H2BC12	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
H4C9	Strong	Autosomal dominant	neurodevelopmental disorder	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
H4C9	Orphanet:528084	Non-specific syndromic intellectual disability

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
H4C9	HGNC:4793	ENSG00000276180	P62805	Histone H4	gencc
H2BC12	HGNC:13954	ENSG00000197903	O60814	Histone H2B type 1-K	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
H4C9	Histone H4	Core component of nucleosome.
H2BC12	Histone H2B type 1-K	Core component of nucleosome.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
H4C9	Other/Unknown	no		Histone_H4, TAF_TATA-bd_Histone-like_dom, Histone-fold
H2BC12	Other/Unknown	no		Histone_H2B, H2A/H2B/H3, Histone-fold

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory bulb	1
primordial germ cell in gonad	1
blood	1
bone marrow cell	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
H4C9	163	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, olfactory bulb
H2BC12	134	ubiquitous	marker	bone marrow cell, monocyte, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
H4C9	4,216
H2BC12	3,113

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
H4C9	P62805	626
H2BC12	O60814	85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 62. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	271.9×	1e-04	H2BC12, H4C9
Packaging Of Telomere Ends	2	219.6×	1e-04	H2BC12, H4C9
Recognition and association of DNA glycosylase with site containing an affected purine	2	203.9×	1e-04	H2BC12, H4C9
Cleavage of the damaged purine	2	203.9×	1e-04	H2BC12, H4C9
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	2	184.2×	1e-04	H2BC12, H4C9
Cleavage of the damaged pyrimidine	2	184.2×	1e-04	H2BC12, H4C9
RNA Polymerase I Promoter Opening	2	184.2×	1e-04	H2BC12, H4C9
ChAHP complex assembly	2	184.2×	1e-04	H2BC12, H4C9
DNA methylation	2	178.4×	1e-04	H2BC12, H4C9
FXIIa activates plasma kallikrein-kinin system	2	173.0×	1e-04	H2BC12, H4C9
SIRT1 negatively regulates rRNA expression	2	170.4×	1e-04	H2BC12, H4C9
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3	2	167.9×	1e-04	H2BC12, H4C9
Nonhomologous End-Joining (NHEJ)	2	167.9×	1e-04	H2BC12, H4C9
Inhibition of DNA recombination at telomere	2	167.9×	1e-04	H2BC12, H4C9
Assembly of the ORC complex at the origin of replication	2	165.5×	1e-04	H2BC12, H4C9
DNA Damage/Telomere Stress Induced Senescence	2	163.1×	1e-04	H2BC12, H4C9
Chromatin modifications during the maternal to zygotic transition (MZT)	2	163.1×	1e-04	H2BC12, H4C9
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	2	163.1×	1e-04	H2BC12, H4C9
Deposition of new CENPA-containing nucleosomes at the centromere	2	158.6×	1e-04	H2BC12, H4C9
Condensation of Prophase Chromosomes	2	156.4×	1e-04	H2BC12, H4C9
Defective pyroptosis	2	156.4×	1e-04	H2BC12, H4C9
PRC2 methylates histones and DNA	2	152.3×	1e-04	H2BC12, H4C9
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	2	152.3×	1e-04	H2BC12, H4C9
CHD6, CHD7, CHD8, CHD9 subfamily	2	148.3×	1e-04	H2BC12, H4C9
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	2	146.4×	1e-04	H2BC12, H4C9
Transcriptional regulation by small RNAs	2	144.6×	1e-04	H2BC12, H4C9
Meiotic synapsis	2	141.0×	1e-04	H2BC12, H4C9
NuRD complex assembly	2	141.0×	1e-04	H2BC12, H4C9
Meiotic recombination	2	129.8×	1e-04	H2BC12, H4C9
Interaction of NuRD complexes with transcription factors	2	126.9×	1e-04	H2BC12, H4C9

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
protein localization to CENP-A containing chromatin	1	468.1×	0.009	H4C9
negative regulation of megakaryocyte differentiation	1	443.5×	0.009	H4C9
innate immune response in mucosa	1	337.0×	0.009	H2BC12
telomere organization	1	312.1×	0.009	H4C9
antibacterial humoral response	1	165.2×	0.013	H2BC12
killing of cells of another organism	1	135.9×	0.013	H2BC12
defense response to Gram-negative bacterium	1	84.3×	0.017	H2BC12
antimicrobial humoral immune response mediated by antimicrobial peptide	1	81.0×	0.017	H2BC12
nucleosome assembly	1	70.2×	0.017	H4C9
defense response to Gram-positive bacterium	1	63.8×	0.017	H2BC12
chromatin organization	1	49.6×	0.020	H4C9

Therapeutics

Drug target analysis

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

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
H4C9	1	2
H2BC12	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMREDOBRESIB	2	H4C9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
H4C9	14	Binding:14

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

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	H4C9

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	H4C9
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	H2BC12

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)
H2BC12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.