Digitotalar dysmorphism

Summary

Digitotalar dysmorphism (MONDO:0015240) is a disease with 6 cohort genes. The dominant Reactome pathway is Striated Muscle Contraction (5 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 6
• Phenotypes (HPO): 9

Clinical features

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0001181	Adducted thumb	Very frequent (80-99%)
HP:0010557	Overlapping fingers	Very frequent (80-99%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0001883	Talipes	Frequent (30-79%)
HP:0009465	Ulnar deviation of finger	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0001838	Rocker bottom foot	Occasional (5-29%)
HP:0003272	Abnormality of the hip bone	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	digitotalar dysmorphism
Mondo ID	MONDO:0015240
MeSH	C565097
Orphanet	1146
DOID	DOID:0111596
ICD-11	1679749810
GARD	0000787
Is cancer (heuristic)	no

Also known as: AMCD1 · arthrogryposis multiplex congenita distal type 1 · DA1 · digitotalar dysmorphism · distal arthrogryposis type 1 · distal arthrogryposis type 1A (sub-type) · distal arthrogryposis type 1B (sub-type)

Data availability: 6 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome without intellectual disability › digitotalar dysmorphism

Related subtypes (167): Treacher-Collins syndrome, branchio-oto-renal syndrome, acrorenal syndrome, Townes-Brocks syndrome, Ascher syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, branchiooculofacial syndrome, Gordon syndrome, cataract-aberrant oral frenula-growth delay syndrome, cherubism, Alagille syndrome, cleft palate-lateral synechia syndrome, blepharocheilodontic syndrome, craniofacial-deafness-hand syndrome, cryptomicrotia-brachydactyly-excess fingertip arch syndrome, Beare-Stevenson cutis gyrata syndrome, Cyprus facial-neuromusculoskeletal syndrome, deafness-craniofacial syndrome, short stature-valvular heart disease-characteristic facies syndrome, 3-M syndrome, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, multinodular goiter-cystic kidney-polydactyly syndrome, hand-foot-genital syndrome, Bencze syndrome, oculoauriculovertebral spectrum with radial defects, Holt-Oram syndrome, mullerian duct anomalies-limb anomalies syndrome, Aase-Smith syndrome, LADD syndrome, Noonan syndrome with multiple lentigines, median nodule of the upper lip, Nager acrofacial dysostosis, Marshall syndrome, Binder syndrome, Schilbach-Rott syndrome, nasopalpebral lipoma-coloboma syndrome, autosomal dominant prognathism, short stature-craniofacial anomalies-genital hypoplasia syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, scalp-ear-nipple syndrome, flat face-microstomia-ear anomaly syndrome, Czeizel-Losonci syndrome, otospondylomegaepiphyseal dysplasia, autosomal dominant, ventricular extrasystoles with syncopal episodes-perodactyly-robin sequence syndrome, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, acrofacial dysostosis, Weyers type, Freeman-Sheldon syndrome, Ackerman syndrome, acro-renal-mandibular syndrome, acrocraniofacial dysostosis, PAGOD syndrome, alar cartilages hypoplasia-coloboma-telecanthus syndrome, microcephaly-albinism-digital anomalies syndrome, fetal akinesia deformation sequence, Cooper-Jabs syndrome, Barber-Say syndrome, Beemer-Ertbruggen syndrome, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, camptodactyly syndrome, Guadalajara type 1, camptodactyly syndrome, Guadalajara type 2, heart defects-limb shortening syndrome, Verloove Vanhorick-Brubakk syndrome, Juberg-Hayward syndrome, heart defect - tongue hamartoma - polysyndactyly syndrome, Fraser syndrome, split hand-foot malformation 1 with sensorineural hearing loss, von Voss-Cherstvoy syndrome, autosomal recessive faciodigitogenital syndrome, gingival fibromatosis-facial dysmorphism syndrome, Fibulo-ulnar hypoplasia-renal anomalies syndrome, frontofacionasal dysplasia, genito-palato-cardiac syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Holzgreve-Wagner-Rehder syndrome, hydrocephaly-tall stature-joint laxity syndrome, McKusick-Kaufman syndrome, acrofrontofacionasal dysostosis 2, Vici syndrome, Donohue syndrome, Dahlberg-Borer-Newcomer syndrome, macrosomia-microphthalmia-cleft palate syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, Nijmegen breakage syndrome, lethal congenital contracture syndrome 1, Richieri Costa-da Silva syndrome, Keipert syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, ichthyosis-oral and digital anomalies syndrome, otoonychoperoneal syndrome, PHAVER syndrome, polysyndactyly-cardiac malformation syndrome, postaxial acrofacial dysostosis, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, renal-genital-middle ear anomalies, Richieri Costa-Pereira syndrome, SHORT syndrome, tetraamelia-multiple malformations syndrome, thymic-renal-anal-lung dysplasia, trigonocephaly-bifid nose-acral anomalies syndrome, white forelock with malformations, syndactyly-telecanthus-anogenital and renal malformations syndrome, Abruzzo-Erickson syndrome, CHILD syndrome, pentalogy of Cantrell, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, short tarsus-absence of lower eyelashes syndrome, PARC syndrome, CODAS syndrome, pectus excavatum-macrocephaly-dysplastic nails syndrome, velo-facial-skeletal syndrome, anophthalmia plus syndrome, van den Ende-Gupta syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, diaphragmatic defect-limb deficiency-skull defect syndrome, cleft lip/palate-intestinal malrotation-cardiopathy syndrome, Matthew-Wood syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, dislocation of the hip-dysmorphism syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, grange syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, arhinia, choanal atresia, and microphthalmia, anonychia-microcephaly syndrome, developmental malformations-deafness-dystonia syndrome, lethal congenital contracture syndrome 2, craniolenticulosutural dysplasia, 8q22.1 microdeletion syndrome, Braddock syndrome, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, BNAR syndrome, Frias syndrome, lethal congenital contracture syndrome 3, Fontaine progeroid syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, Nijmegen breakage syndrome-like disorder, Warsaw breakage syndrome, even-plus syndrome, split-foot malformation-mesoaxial polydactyly syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, heart-hand syndrome type 2, night blindness-skeletal anomalies-dysmorphism syndrome, Charlie M syndrome, facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome, cleft lip-retinopathy syndrome, Cole-Carpenter syndrome, progressive non-infectious anterior vertebral fusion, dysmorphism-pectus carinatum-joint laxity syndrome, Hirschsprung disease-type D brachydactyly syndrome, mandibuloacral dysplasia, contractures - webbed neck - micrognathia - hypoplastic nipples syndrome, Thomas syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, branchiootic syndrome, auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome, Axenfeld-Rieger syndrome, macrostomia-preauricular tags-external ophthalmoplegia syndrome, pelvis syndrome, Fanconi anemia, van der Woude syndrome, hypertrichosis-acromegaloid facial appearance syndrome, 49,XYYYY syndrome, congenital vertebral-cardiac-renal anomalies syndrome, structural heart defects and renal anomalies syndrome, Greig cephalopolysyndactyly-contiguous gene syndrome

Subtypes (3): arthrogryposis, distal, type 1A, digitotalar dysmorphism; ulnar drift, hereditary, arthrogryposis, distal, type 1B

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: 60 · Orphanet: 24 · 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
MYBPC1	Supportive	Autosomal dominant	digitotalar dysmorphism	11
MYH3	Supportive	Autosomal dominant	digitotalar dysmorphism	14
NALCN	Supportive	Autosomal dominant	digitotalar dysmorphism	11
TNNI2	Supportive	Autosomal dominant	digitotalar dysmorphism	5
TNNT3	Supportive	Autosomal dominant	digitotalar dysmorphism	7
TPM2	Supportive	Autosomal dominant	digitotalar dysmorphism	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNI2	Orphanet:1146	Distal arthrogryposis type 1
TNNI2	Orphanet:1147	Sheldon-Hall syndrome
TNNT3	Orphanet:1146	Distal arthrogryposis type 1
TNNT3	Orphanet:1147	Sheldon-Hall syndrome
TPM2	Orphanet:1146	Distal arthrogryposis type 1
TPM2	Orphanet:1147	Sheldon-Hall syndrome
TPM2	Orphanet:171436	Typical nemaline myopathy
TPM2	Orphanet:171439	Childhood-onset nemaline myopathy
TPM2	Orphanet:171881	Cap myopathy
TPM2	Orphanet:2020	Congenital fiber-type disproportion myopathy
NALCN	Orphanet:1146	Distal arthrogryposis type 1
NALCN	Orphanet:1147	Sheldon-Hall syndrome
NALCN	Orphanet:2053	Freeman-Sheldon syndrome
NALCN	Orphanet:562528	Congenital limbs-face contractures-hypotonia-developmental delay syndrome
NALCN	Orphanet:700336	Hypotonia-speech impairment-severe cognitive delay syndrome due to NALCN deficiency
MYBPC1	Orphanet:1146	Distal arthrogryposis type 1
MYBPC1	Orphanet:137783	Lethal congenital contracture syndrome type 3
MYBPC1	Orphanet:498693	MYBPC1-related autosomal recessive non-lethal arthrogryposis multiplex congenita syndrome
MYH3	Orphanet:1146	Distal arthrogryposis type 1
MYH3	Orphanet:1147	Sheldon-Hall syndrome
MYH3	Orphanet:2053	Freeman-Sheldon syndrome
MYH3	Orphanet:2990	Autosomal recessive multiple pterygium syndrome
MYH3	Orphanet:3275	Spondylocarpotarsal synostosis
MYH3	Orphanet:65743	Autosomal dominant multiple pterygium syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNI2	HGNC:11946	ENSG00000130598	P48788	Troponin I, fast skeletal muscle	gencc
TNNT3	HGNC:11950	ENSG00000130595	P45378	Troponin T, fast skeletal muscle	gencc
TPM2	HGNC:12011	ENSG00000198467	P07951	Tropomyosin beta chain	gencc
NALCN	HGNC:19082	ENSG00000102452	Q8IZF0	Sodium leak channel NALCN	gencc
MYBPC1	HGNC:7549	ENSG00000196091	Q00872	Myosin-binding protein C, slow-type	gencc
MYH3	HGNC:7573	ENSG00000109063	P11055	Myosin-3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNI2	Troponin I, fast skeletal muscle	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TNNT3	Troponin T, fast skeletal muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TPM2	Tropomyosin beta chain	Binds to actin filaments in muscle and non-muscle cells.
NALCN	Sodium leak channel NALCN	Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.
MYBPC1	Myosin-binding protein C, slow-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.
MYH3	Myosin-3	Muscle contraction.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.33

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
Ion channel	1	18.6×	0.210
Antibody/Immunoglobulin	1	4.9×	0.377
Scaffold/PPI	1	2.9×	0.401
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNI2	Other/Unknown	no		Troponin, Troponin_sf, Troponin_I
TNNT3	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TPM2	Other/Unknown	no		Tropomyosin
NALCN	Ion channel	yes		Ion_trans_dom, Volt_channel_dom_sf, NALCN
MYBPC1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
MYH3	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
hindlimb stylopod muscle	2
skeletal muscle tissue	2
blood vessel layer	1
popliteal artery	1
saphenous vein	1
Brodmann (1909) area 23	1
corpus callosum	1
middle temporal gyrus	1
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNI2	134	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, gastrocnemius
TNNT3	135	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, gastrocnemius
TPM2	283	ubiquitous	marker	saphenous vein, popliteal artery, blood vessel layer
NALCN	201	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, corpus callosum
MYBPC1	225	broad	marker	biceps brachii, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii
MYH3	203	tissue_specific	yes	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NALCN	1,860
MYBPC1	1,816
MYH3	1,795
TNNI2	1,255
TNNT3	1,197
TPM2	357

Intra-cohort edges

A	B	Sources
MYBPC1	MYH3	string_interaction
MYBPC1	TNNI2	string_interaction
MYBPC1	TNNT3	string_interaction
MYH3	TNNI2	string_interaction
MYH3	TNNT3	string_interaction
MYH3	TPM2	biogrid_interaction
TNNI2	TNNT3	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYBPC1	Q00872	8
NALCN	Q8IZF0	5
TNNI2	P48788	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TPM2	P07951	91.51
TNNT3	P45378	77.99
MYH3	P11055	74.35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	5	257.2×	1e-11	TNNI2, TNNT3, TPM2, MYBPC1, MYH3
Muscle contraction	2	25.7×	0.007	MYBPC1, MYH3
Smooth Muscle Contraction	1	44.3×	0.045	TPM2
Stimuli-sensing channels	1	22.7×	0.065	NALCN
Ion channel transport	1	16.0×	0.073	NALCN
Transport of small molecules	1	4.2×	0.216	NALCN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of ATP-dependent activity	2	2808.7×	2e-06	TNNT3, TPM2
skeletal muscle contraction	3	255.3×	2e-06	TNNI2, TNNT3, MYH3
sarcomere organization	3	191.5×	3e-06	TNNT3, MYBPC1, MYH3
positive regulation of calcium-dependent ATPase activity	1	2808.7×	0.002	TNNT3
muscle contraction	2	69.3×	0.002	TPM2, MYH3
positive regulation of synaptic transmission, cholinergic	1	561.7×	0.007	NALCN
regulation of striated muscle contraction	1	351.1×	0.009	TNNT3
regulation of resting membrane potential	1	216.1×	0.013	NALCN
muscle filament sliding	1	175.5×	0.014	MYH3
positive regulation of synaptic transmission, GABAergic	1	165.2×	0.014	NALCN
actin filament-based movement	1	133.8×	0.016	MYH3
face morphogenesis	1	82.6×	0.023	MYH3
ATP metabolic process	1	78.0×	0.023	MYH3
embryonic limb morphogenesis	1	66.9×	0.023	MYH3
cardiac muscle contraction	1	66.9×	0.023	TNNI2
calcium ion transmembrane transport	1	35.1×	0.037	NALCN
monoatomic ion transmembrane transport	1	34.7×	0.037	NALCN
sodium ion transmembrane transport	1	33.8×	0.037	NALCN
muscle organ development	1	27.8×	0.043	MYH3
potassium ion transmembrane transport	1	22.6×	0.050	NALCN
actin filament organization	1	19.8×	0.054	TPM2
cell adhesion	1	6.2×	0.157	MYBPC1
positive regulation of DNA-templated transcription	1	4.7×	0.196	TNNI2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNNI2	0	0
TNNT3	0	0
TPM2	0	0
NALCN	0	0
MYBPC1	0	0
MYH3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	2	NALCN, MYBPC1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TNNI2, TNNT3, TPM2, MYH3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNNI2	0	—
TNNT3	0	—
TPM2	0	—
NALCN	0	—
MYBPC1	0	—
MYH3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.