Uncombable hair syndrome

Summary

Uncombable hair syndrome (MONDO:0008621) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• Phenotypes (HPO): 6

Clinical features

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0001595	Abnormality of the hair	Very frequent (80-99%)
HP:0002208	Coarse hair	Very frequent (80-99%)
HP:0002224	Woolly hair	Very frequent (80-99%)
HP:0002552	Trichodysplasia	Very frequent (80-99%)
HP:0011364	White hair	Very frequent (80-99%)
HP:0002232	Patchy alopecia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	uncombable hair syndrome
Mondo ID	MONDO:0008621
MeSH	C536939
Orphanet	1410
ICD-11	244892708
SNOMED CT	254230001
UMLS	C0432347
MedGen	96596
GARD	0005404
Is cancer (heuristic)	no

Also known as: cheveux incoiffables · pili trianguli et canaliculi · spun glass hair · uncombable hair syndrome · unmanageable hair syndrome

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › disorder of pilosebaceous unit › hair anomaly › uncombable hair syndrome

Related subtypes (7): alopecia, ringed hair disease, trichodysplasia-xeroderma syndrome, isolated familial wooly hair disorder, pili torti, pili bifurcati, pili gemini

Subtypes (3): uncombable hair syndrome 2, uncombable hair syndrome 3, uncombable hair 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
PADI3	Strong	Autosomal recessive	uncombable hair syndrome 1	6
TGM3	Moderate	Autosomal recessive	uncombable hair syndrome 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGM3	Orphanet:1410	Uncombable hair syndrome
PADI3	Orphanet:1410	Uncombable hair syndrome

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
TGM3	HGNC:11779	ENSG00000125780	Q08188	Protein-glutamine gamma-glutamyltransferase E	gencc
PADI3	HGNC:18337	ENSG00000142619	Q9ULW8	Protein-arginine deiminase type-3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGM3	Protein-glutamine gamma-glutamyltransferase E	Catalyzes the calcium-dependent formation of isopeptide cross-links between glutamine and lysine residues in various proteins, as well as the conjugation of polyamines to proteins.
PADI3	Protein-arginine deiminase type-3	Catalyzes the deimination of arginine residues of proteins.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGM3	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
PADI3	Enzyme (other)	yes	3.5.3.15	PAD, Cupredoxin, PAD_C

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
esophagus mucosa	2
lower esophagus mucosa	2
skin of leg	1
urinary bladder	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGM3	120	tissue_specific	marker	lower esophagus mucosa, esophagus mucosa, skin of leg
PADI3	43	tissue_specific	marker	lower esophagus mucosa, esophagus mucosa, urinary bladder

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGM3	1,279
PADI3	494

Intra-cohort edges

A	B	Sources
PADI3	TGM3	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGM3	Q08188	11
PADI3	Q9ULW8	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Chromatin modifying enzymes	1	72.3×	0.014	PADI3

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
peptide cross-linking	1	1404.3×	0.004	TGM3
hair follicle morphogenesis	1	495.6×	0.004	TGM3
keratinocyte differentiation	1	247.8×	0.004	TGM3
protein modification process	1	244.2×	0.004	TGM3
keratinization	1	234.1×	0.004	TGM3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
TGM3	1	2
PADI3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	TGM3
STREPTONIGRIN	2	PADI3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PADI3	27	Binding:27
TGM3	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM3	2.3.2.13	protein-glutamine gamma-glutamyltransferase
PADI3	3.5.3.15	protein-arginine deiminase

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

2 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)
MOLIBRESIB	2	TGM3
STREPTONIGRIN	2	PADI3

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	2	TGM3, PADI3
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.