Monilethrix

Summary

Monilethrix (MONDO:0008009) is a disease caused by variants in KRT83 and KRT86, with 4 cohort genes. The dominant Reactome pathway is Formation of the cornified envelope (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: KRT83 (GenCC Strong), KRT86 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 87
• Phenotypes (HPO): 14

Clinical features

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000499	Abnormal eyelash morphology	Very frequent (80-99%)
HP:0000534	Abnormal eyebrow morphology	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0002213	Fine hair	Very frequent (80-99%)
HP:0002217	Slow-growing hair	Very frequent (80-99%)
HP:0002232	Patchy alopecia	Very frequent (80-99%)
HP:0002299	Brittle hair	Very frequent (80-99%)
HP:0007502	Follicular hyperkeratosis	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	monilethrix
Mondo ID	MONDO:0008009
MeSH	D056734
OMIM	158000
Orphanet	573
DOID	DOID:0050472
ICD-11	415074833
NCIT	C84894
SNOMED CT	69488000
UMLS	C0546966
MedGen	108185
GARD	0000093
NORD	1454
Is cancer (heuristic)	no

Also known as: MNLIX · monilethrix · moniliform hair syndrome · nodose hair

Data availability: 87 ClinVar variants · 10 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › monilethrix

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (3): monilethrix-2, monilethrix-3, monilethrix-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

87 retrieved; paginated sample, class counts are floors:

37 benign, 22 uncertain significance, 11 conflicting classifications of pathogenicity, 8 benign/likely benign, 5 pathogenic, 2 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
7609	NM_001320198.2(KRT86):c.1237G>A (p.Glu413Lys)	KRT86	Pathogenic	criteria provided, single submitter
7610	NM_001320198.2(KRT86):c.1239G>T (p.Glu413Asp)	KRT86	Pathogenic	no assertion criteria provided
7612	NM_001320198.2(KRT86):c.340A>G (p.Asn114Asp)	KRT86	Pathogenic	no assertion criteria provided
7613	NM_001320198.2(KRT86):c.1204G>C (p.Glu402Gln)	KRT86	Pathogenic	no assertion criteria provided
7614	NM_001320198.2(KRT86):c.353C>A (p.Ala118Glu)	KRT86	Pathogenic	no assertion criteria provided
6837	NM_002282.3(KRT83):c.1219G>A (p.Glu407Lys)	KRT83	Likely pathogenic	criteria provided, multiple submitters, no conflicts
7611	NM_001320198.2(KRT86):c.1204G>A (p.Glu402Lys)	KRT86	Likely pathogenic	criteria provided, single submitter
561048	NM_002281.4(KRT81):c.846T>A (p.Tyr282Ter)	KRT81	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309495	NM_002282.3(KRT83):c.1423C>T (p.Pro475Ser)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309508	NM_002282.3(KRT83):c.1018G>A (p.Glu340Lys)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309513	NM_002282.3(KRT83):c.910A>T (p.Ser304Cys)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309515	NM_002282.3(KRT83):c.877C>T (p.Arg293Cys)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309524	NM_002282.3(KRT83):c.667G>A (p.Ala223Thr)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880709	NM_002282.3(KRT83):c.828G>A (p.Met276Ile)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880710	NM_002282.3(KRT83):c.790G>A (p.Val264Met)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882052	NM_002282.3(KRT83):c.1356G>A (p.Pro452=)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882054	NM_002282.3(KRT83):c.1302C>A (p.Ser434Arg)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884065	NM_002282.3(KRT83):c.389G>A (p.Arg130His)	KRT83	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
309487	NM_002282.3(KRT83):c.*225C>T	KRT83	Uncertain significance	criteria provided, single submitter
309491	NM_002282.3(KRT83):c.*107T>G	KRT83	Uncertain significance	criteria provided, single submitter
309492	NM_002282.3(KRT83):c.*44C>T	KRT83	Uncertain significance	criteria provided, single submitter
309497	NM_002282.3(KRT83):c.1398G>A (p.Leu466=)	KRT83	Uncertain significance	criteria provided, single submitter
309510	NM_002282.3(KRT83):c.1014A>G (p.Thr338=)	KRT83	Uncertain significance	criteria provided, single submitter
309514	NM_002282.3(KRT83):c.891G>C (p.Glu297Asp)	KRT83	Uncertain significance	criteria provided, single submitter
309518	NM_002282.3(KRT83):c.815G>A (p.Arg272Gln)	KRT83	Uncertain significance	criteria provided, multiple submitters, no conflicts
309531	NM_002282.3(KRT83):c.514G>A (p.Glu172Lys)	KRT83	Uncertain significance	criteria provided, multiple submitters, no conflicts
309532	NM_002282.3(KRT83):c.502C>T (p.Arg168Trp)	KRT83	Uncertain significance	criteria provided, multiple submitters, no conflicts
309534	NM_002282.3(KRT83):c.485G>T (p.Gly162Val)	KRT83	Uncertain significance	criteria provided, single submitter
309541	NM_002282.3(KRT83):c.184G>A (p.Gly62Ser)	KRT83	Uncertain significance	criteria provided, single submitter
309542	NM_002282.3(KRT83):c.183C>T (p.Ala61=)	KRT83	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 6 · 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
KRT81	Strong	Autosomal dominant	monilethrix-1	4
KRT83	Strong	Autosomal dominant	monilethrix	6
KRT86	Strong	Autosomal dominant	monilethrix	5
DSG4	Supportive	Autosomal dominant	monilethrix	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT81	Orphanet:573	Monilethrix
KRT83	Orphanet:316	Progressive symmetric erythrokeratodermia
KRT83	Orphanet:573	Monilethrix
KRT86	Orphanet:573	Monilethrix
DSG4	Orphanet:55654	Hypotrichosis simplex
DSG4	Orphanet:573	Monilethrix

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT81	HGNC:6458	ENSG00000205426	Q14533	Keratin, type II cuticular Hb1	gencc,clinvar
KRT83	HGNC:6460	ENSG00000170523	P78385	Keratin, type II cuticular Hb3	gencc,clinvar
KRT86	HGNC:6463	ENSG00000170442	O43790	Keratin, type II cuticular Hb6	gencc,clinvar
DSG4	HGNC:21307	ENSG00000175065	Q86SJ6	Desmoglein-4	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSG4	Desmoglein-4	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT81	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KRT83	Other/Unknown	no		Keratin_II, Growth_fac_rcpt_cys_sf, IF_conserved
KRT86	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
DSG4	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Desmosomal_cadherin

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	4
diaphragm	2
hair follicle	1
type B pancreatic cell	1
right coronary artery	1
sperm	1
esophagus mucosa	1
lower lobe of lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT81	131	tissue_specific	marker	diaphragm, male germ line stem cell (sensu Vertebrata) in testis, hair follicle
KRT83	73	tissue_specific	yes	diaphragm, type B pancreatic cell, male germ line stem cell (sensu Vertebrata) in testis
KRT86	160	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, sperm, right coronary artery
DSG4	24		marker	male germ line stem cell (sensu Vertebrata) in testis, esophagus mucosa, lower lobe of lung

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DSG4	1,636
KRT81	1,077
KRT83	1,053
KRT86	244

Intra-cohort edges

A	B	Sources
DSG4	KRT81	string_interaction
DSG4	KRT83	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 4 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT86	O43790	75.50
KRT83	P78385	74.81
KRT81	Q14533	74.40
DSG4	Q86SJ6	65.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	4	87.8×	5e-08	KRT81, KRT83, KRT86, DSG4
Keratinization	4	55.7×	2e-07	KRT81, KRT83, KRT86, DSG4
Developmental Biology	3	10.8×	0.001	KRT81, KRT83, KRT86

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermediate filament organization	3	180.6×	1e-06	KRT81, KRT83, KRT86
keratinization	3	175.5×	1e-06	KRT81, KRT83, KRT86
hair cycle	1	234.1×	0.013	KRT83
hair follicle development	1	95.8×	0.023	DSG4
keratinocyte differentiation	1	62.0×	0.025	DSG4
epidermis development	1	52.7×	0.025	KRT83
BMP signaling pathway	1	50.1×	0.025	DSG4
homophilic cell-cell adhesion	1	35.1×	0.032	DSG4
cell-cell adhesion	1	25.4×	0.039	DSG4

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRT81	0	0
KRT83	0	0
KRT86	0	0
DSG4	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
KRT81	1	Binding:1
KRT83	1	Binding:1
KRT86	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	KRT81, KRT83, KRT86, DSG4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT81	1	—
KRT83	1	—
KRT86	1	—
DSG4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.