Neonatal hemochromatosis

Summary

Neonatal hemochromatosis (MONDO:0009275) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 4
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000448	Prominent nose	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000581	Blepharophimosis	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0002612	Congenital hepatic fibrosis	Very frequent (80-99%)
HP:0003281	Increased circulating ferritin concentration	Very frequent (80-99%)
HP:0003452	Increased serum iron	Very frequent (80-99%)
HP:0006579	Prolonged neonatal jaundice	Very frequent (80-99%)
HP:0006709	Aplasia/Hypoplasia of the nipples	Very frequent (80-99%)
HP:0100542	Abnormal localization of kidney	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neonatal hemochromatosis
Mondo ID	MONDO:0009275
MeSH	C536394
OMIM	231100
Orphanet	446
NCIT	C129980
UMLS	C0268059
MedGen	82768
GARD	0007172
NORD	1494
Is cancer (heuristic)	no

Also known as: giant cell Hepatitis · giant cell Hepatitis (formerly) · hemochromatosis neonatal · idiopathic neonatal hemochromatosis · neonatal Hepatitis · neonatal hepatitis (formerly)

Data availability: 4 ClinVar variants · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › iron metabolism disease › hemosiderosis › hereditary hemochromatosis › neonatal hemochromatosis

Related subtypes (7): African iron overload, hemochromatosis type 3, hemochromatosis type 4, hemochromatosis type 5, hemochromatosis type 2, hemochromatosis type 1, digenic hemochromatosis

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 uncertain significance, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2498185	NC_000006.12:g.7673126T>C	BMP6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2498183	NC_000006.12:g.7427051ACAA[1]	BMP6	Uncertain significance	criteria provided, single submitter
2498186	NC_000016.10:g.30989361dup	HSD3B7	Uncertain significance	criteria provided, single submitter
2498187	NC_000016.10:g.30989573T>C	HSD3B7	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMP6	Orphanet:465508	Symptomatic form of HFE-related hemochromatosis
HSD3B7	Orphanet:79301	Congenital bile acid synthesis defect type 1

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
BMP6	HGNC:1073	ENSG00000153162	P22004	Bone morphogenetic protein 6	clinvar
HSD3B7	HGNC:18324	ENSG00000099377	Q9H2F3	3 beta-hydroxysteroid dehydrogenase type 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMP6	Bone morphogenetic protein 6	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes including cartilage and bone formation.
HSD3B7	3 beta-hydroxysteroid dehydrogenase type 7	The 3-beta-HSD enzymatic system plays a crucial role in the biosynthesis of all classes of hormonal steroids.

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)
BMP6	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
HSD3B7	Other/Unknown	no		3Beta_OHSteriod_DH/Estase, NAD(P)-bd_dom_sf, NAD(P)_dehydrat-like

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
cartilage tissue	1
oocyte	1
secondary oocyte	1
left adrenal gland	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMP6	197	ubiquitous	marker	secondary oocyte, cartilage tissue, oocyte
HSD3B7	177	ubiquitous	marker	right lobe of liver, liver, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSD3B7	3,327
BMP6	1,739

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BMP6	P22004	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HSD3B7	Q9H2F3	94.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 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
Synthesis of bile acids and bile salts via 24-hydroxycholesterol	1	878.5×	0.004	HSD3B7
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	761.3×	0.004	HSD3B7
Bile acid and bile salt metabolism	1	496.5×	0.004	HSD3B7
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	456.8×	0.004	HSD3B7
Synthesis of bile acids and bile salts	1	407.9×	0.004	HSD3B7
Metabolism of steroids	1	137.6×	0.010	HSD3B7
Metabolism of lipids	1	31.6×	0.036	HSD3B7
Metabolism	1	11.6×	0.086	HSD3B7

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
negative regulation of adherens junction organization	1	4213.0×	0.006	BMP6
positive regulation of aldosterone biosynthetic process	1	2808.7×	0.006	BMP6
positive regulation of aldosterone secretion	1	2106.5×	0.006	BMP6
B cell chemotaxis	1	1404.3×	0.006	HSD3B7
cellular response to iron ion	1	1203.7×	0.006	BMP6
positive regulation of lipopolysaccharide-mediated signaling pathway	1	766.0×	0.006	BMP6
positive regulation of endothelial cell differentiation	1	766.0×	0.006	BMP6
negative regulation of cell-cell adhesion mediated by cadherin	1	766.0×	0.006	BMP6
response to magnesium ion	1	702.2×	0.006	BMP6
type B pancreatic cell development	1	648.1×	0.006	BMP6
positive regulation of vascular permeability	1	648.1×	0.006	BMP6
male genitalia development	1	443.5×	0.009	BMP6
positive regulation of chondrocyte differentiation	1	401.2×	0.009	BMP6
positive regulation of intracellular signal transduction	1	324.1×	0.009	BMP6
bile acid biosynthetic process	1	312.1×	0.009	HSD3B7
steroid biosynthetic process	1	300.9×	0.009	HSD3B7
multicellular organismal-level iron ion homeostasis	1	290.6×	0.009	BMP6
cellular response to BMP stimulus	1	280.9×	0.009	BMP6
endochondral ossification	1	271.8×	0.009	BMP6
positive regulation of bone mineralization	1	195.9×	0.011	BMP6
response to retinoic acid	1	191.5×	0.011	BMP6
positive regulation of SMAD protein signal transduction	1	191.5×	0.011	BMP6
eye development	1	175.5×	0.011	BMP6
positive regulation of protein secretion	1	172.0×	0.011	BMP6
response to activity	1	162.0×	0.011	BMP6
response to glucocorticoid	1	162.0×	0.011	BMP6
bone development	1	138.1×	0.012	BMP6
cartilage development	1	125.8×	0.013	BMP6
intracellular iron ion homeostasis	1	122.1×	0.013	BMP6
positive regulation of epithelial cell proliferation	1	122.1×	0.013	BMP6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
BMP6	0	0
HSD3B7	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
BMP6	1	Binding:1

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

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	2	BMP6, HSD3B7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BMP6	1	—
HSD3B7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.