Bryant-Li-Bhoj neurodevelopmental syndrome 2

Summary

Bryant-Li-Bhoj neurodevelopmental syndrome 2 (MONDO:0030607) is a disease caused by H3-3B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: H3-3B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Bryant-Li-Bhoj neurodevelopmental syndrome 2
Mondo ID	MONDO:0030607
OMIM	619721
DOID	DOID:0051012
UMLS	C5676906
MedGen	1811435
GARD	0027930
Is cancer (heuristic)	no

Also known as: BRYLIB2

Data availability: 19 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 › Bryant-Li-Bhoj neurodevelopmental syndrome › Bryant-Li-Bhoj neurodevelopmental syndrome 2

Related subtypes (1): Bryant-Li-Bhoj neurodevelopmental syndrome 1

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

19 retrieved; paginated sample, class counts are floors:

6 likely pathogenic, 4 uncertain significance, 3 pathogenic/likely pathogenic, 3 pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1183984	NM_005324.5(H3-3B):c.155T>A (p.Ile52Asn)	H3-3B	Pathogenic/Likely pathogenic	no assertion criteria provided
1339273	NM_005324.5(H3-3B):c.88G>C (p.Ala30Pro)	H3-3B	Pathogenic	no assertion criteria provided
1339274	NM_005324.5(H3-3B):c.365C>G (p.Pro122Arg)	H3-3B	Pathogenic	no assertion criteria provided
1339275	NM_005324.5(H3-3B):c.377A>G (p.Gln126Arg)	H3-3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2682274	NM_005324.5(H3-3B):c.52C>T (p.Arg18Cys)	H3-3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531680	NM_005324.5(H3-3B):c.29A>G (p.Lys10Arg)	H3-3B	Pathogenic	criteria provided, single submitter
1697246	NM_005324.5(H3-3B):c.68C>G (p.Thr23Arg)	H3-3B	Likely pathogenic	criteria provided, single submitter
1708061	NM_005324.5(H3-3B):c.35C>T (p.Thr12Ile)	H3-3B	Likely pathogenic	criteria provided, single submitter
2573076	NM_005324.5(H3-3B):c.376C>A (p.Gln126Lys)	H3-3B	Likely pathogenic	criteria provided, single submitter
3374710	NM_005324.5(H3-3B):c.11C>T (p.Thr4Ile)	H3-3B	Likely pathogenic	criteria provided, single submitter
3376158	NM_005324.5(H3-3B):c.91C>T (p.Pro31Ser)	H3-3B	Likely pathogenic	criteria provided, single submitter
4293548	NM_005324.5(H3-3B):c.365C>T (p.Pro122Leu)	H3-3B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
521247	NM_005324.5(H3-3B):c.23C>T (p.Ala8Val)	H3-3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
521569	NM_005324.5(H3-3B):c.119A>G (p.His40Arg)	H3-3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
985559	NM_005324.5(H3-3B):c.25C>T (p.Arg9Cys)	H3-3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2627565	NM_005324.5(H3-3B):c.328C>G (p.Leu110Val)	H3-3B	Uncertain significance	criteria provided, single submitter
3376745	NM_005324.5(H3-3B):c.50C>A (p.Pro17His)	H3-3B	Uncertain significance	criteria provided, single submitter
3907696	NM_005324.5(H3-3B):c.346A>G (p.Lys116Glu)	H3-3B	Uncertain significance	criteria provided, single submitter
4819845	NM_005324.5(H3-3B):c.271G>C (p.Gly91Arg)	H3-3B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · 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
H3-3B	Strong	Autosomal dominant	Bryant-Li-Bhoj neurodevelopmental syndrome 2	2

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
H3-3B	HGNC:4765	ENSG00000132475	P84243	Histone H3.3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
H3-3B	Histone H3.3	Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes.

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)
H3-3B	Other/Unknown	no		Histone_H3/CENP-A, H2A/H2B/H3, 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
oocyte	1
secondary oocyte	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
H3-3B	308	ubiquitous	marker	oocyte, secondary oocyte, trigeminal ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
H3-3B	1,595

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
H3-3B	P84243	103

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. 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	H3-3B
RNA Polymerase I Promoter Opening	1	184.2×	0.012	H3-3B
DNA methylation	1	178.4×	0.012	H3-3B
FXIIa activates plasma kallikrein-kinin system	1	173.0×	0.012	H3-3B
SIRT1 negatively regulates rRNA expression	1	170.4×	0.012	H3-3B
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3	1	167.9×	0.012	H3-3B
Inhibition of DNA recombination at telomere	1	167.9×	0.012	H3-3B
Assembly of the ORC complex at the origin of replication	1	165.5×	0.012	H3-3B
Chromatin modifications during the maternal to zygotic transition (MZT)	1	163.1×	0.012	H3-3B
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	1	163.1×	0.012	H3-3B
Condensation of Prophase Chromosomes	1	156.4×	0.012	H3-3B
Defective pyroptosis	1	156.4×	0.012	H3-3B
PRC2 methylates histones and DNA	1	152.3×	0.012	H3-3B
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	1	152.3×	0.012	H3-3B
CHD6, CHD7, CHD8, CHD9 subfamily	1	148.3×	0.012	H3-3B
Transcriptional regulation by small RNAs	1	144.6×	0.012	H3-3B
NuRD complex assembly	1	141.0×	0.012	H3-3B
Meiotic recombination	1	129.8×	0.012	H3-3B
Interaction of NuRD complexes with transcription factors	1	126.9×	0.012	H3-3B
Transcriptional regulation of granulopoiesis	1	125.5×	0.012	H3-3B
Pre-NOTCH Transcription and Translation	1	122.8×	0.012	H3-3B
B-WICH complex positively regulates rRNA expression	1	121.5×	0.012	H3-3B
RNA Polymerase I Promoter Escape	1	121.5×	0.012	H3-3B
Formation of the beta-catenin:TCF transactivating complex	1	120.2×	0.012	H3-3B
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	120.2×	0.012	H3-3B
Negative Regulation of CDH1 Gene Transcription	1	120.2×	0.012	H3-3B
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	117.7×	0.012	H3-3B
Regulation of PD-L1(CD274) transcription	1	108.8×	0.012	H3-3B
CHD1 and CHD2 subfamily	1	108.8×	0.012	H3-3B
Regulation of endogenous retroelements by KRAB-ZFP proteins	1	106.7×	0.012	H3-3B

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
negative regulation of chromosome condensation	1	4213.0×	0.002	H3-3B
pericentric heterochromatin formation	1	3370.4×	0.002	H3-3B
subtelomeric heterochromatin formation	1	1532.0×	0.003	H3-3B
muscle cell differentiation	1	842.6×	0.004	H3-3B
telomere organization	1	624.1×	0.004	H3-3B
oocyte maturation	1	601.9×	0.004	H3-3B
nucleus organization	1	561.7×	0.004	H3-3B
embryo implantation	1	351.1×	0.006	H3-3B
single fertilization	1	183.2×	0.008	H3-3B
positive regulation of cell growth	1	183.2×	0.008	H3-3B
male gonad development	1	156.0×	0.008	H3-3B
spermatid development	1	145.3×	0.008	H3-3B
nucleosome assembly	1	140.4×	0.008	H3-3B
multicellular organism growth	1	137.0×	0.008	H3-3B
osteoblast differentiation	1	121.2×	0.009	H3-3B
cell population proliferation	1	102.8×	0.010	H3-3B

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
H3-3B	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
H3-3B	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	H3-3B

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)
H3-3B	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.