Sheldon-hall syndrome

Summary

Sheldon-hall syndrome (MONDO:0011128) is a disease with 5 cohort genes and 2 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 5
• ClinVar variants: 2
• Phenotypes (HPO): 20
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000465	Webbed neck	Very frequent (80-99%)
HP:0001181	Adducted thumb	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0006501	Aplasia/Hypoplasia of the radius	Very frequent (80-99%)
HP:0007598	Bilateral single transverse palmar creases	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000275	Narrow face	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000411	Protruding ear	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0003049	Ulnar deviation of the wrist	Frequent (30-79%)
HP:0003272	Abnormality of the hip bone	Frequent (30-79%)
HP:0003422	Vertebral segmentation defect	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008368	Tarsal synostosis	Frequent (30-79%)
HP:0009465	Ulnar deviation of finger	Frequent (30-79%)
HP:0010557	Overlapping fingers	Frequent (30-79%)
HP:0100830	Round ear	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Sheldon-hall syndrome
Mondo ID	MONDO:0011128
Orphanet	1147
DOID	DOID:0111599
ICD-11	1206883656
UMLS	C1834523
MedGen	320374
GARD	0016556
Is cancer (heuristic)	no

Also known as: arthrogryposis multiplex congenita distal type 2B · arthrogryposis multiplex congenita distal type II with craniofacial abnormalities · arthrogryposis, distal, type 2B · DA2B · distal arthrogryposis type 2B · Freeman Sheldon syndrome, variant · Freeman Sheldon variant · Freeman-Sheldon syndrome variant · Sheldon-Hall syndrome

Data availability: 2 ClinVar variants · 5 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 › distal arthrogryposis › Sheldon-hall syndrome

Related subtypes (22): arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome, arthrogryposis-like hand anomaly-sensorineural deafness syndrome, Gordon syndrome, congenital contractural arachnodactyly, arthrogryposis, distal, type 2E, trismus-pseudocamptodactyly syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, Freeman-Sheldon syndrome, Ehlers-Danlos syndrome, musculocontractural type, arthrogryposis-severe scoliosis syndrome, distal arthrogryposis type 5D, autism spectrum disorder - epilepsy - arthrogryposis syndrome, arthrogryposis, distal, with impaired proprioception and touch, digitotalar dysmorphism, distal arthrogryposis type 10, distal arthrogryposis Moore weaver type, arthrogryposis, distal, type 1C, arthrogryposis, distal, IIa 11, arthrogryposis-ectodermal dysplasia-other anomalies syndrome, ACTC1-related distal arthrogryposis with congenital heart disease, arthrogryposis, distal, type 2B4, arthrogryposis, distal, type 12

Subtypes (3): distal arthrogryposis type 2B1, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3

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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
31874	NM_006757.4(TNNT3):c.187C>T (p.Arg63Cys)	TNNT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8913	NM_006757.4(TNNT3):c.188G>A (p.Arg63His)	TNNT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 49 · Orphanet: 21 · 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
MYH3	Definitive	Autosomal dominant	Freeman-Sheldon syndrome	14
NALCN	Supportive	Autosomal dominant	Sheldon-hall syndrome	11
TNNI2	Supportive	Autosomal dominant	Sheldon-hall syndrome	5
TNNT3	Supportive	Autosomal dominant	Sheldon-hall syndrome	7
TPM2	Supportive	Autosomal dominant	Sheldon-hall syndrome	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNT3	Orphanet:1146	Distal arthrogryposis type 1
TNNT3	Orphanet:1147	Sheldon-Hall syndrome
TNNI2	Orphanet:1146	Distal arthrogryposis type 1
TNNI2	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
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

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

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

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.
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.
MYH3	Myosin-3	Muscle contraction.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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	22.3×	0.132
Scaffold/PPI	1	3.5×	0.386
Other/Unknown	3	1.1×	0.608

Per-gene assignment

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

Expression context

Cohort genes with no expression data: 0.

4 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)	5
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
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNT3	135	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, gastrocnemius
TNNI2	134	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
MYH3	203	tissue_specific	yes	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

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

Intra-cohort edges

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

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
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 5 evidence-associated genes (5 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 5 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	4	246.9×	3e-09	TNNT3, TNNI2, TPM2, MYH3
Smooth Muscle Contraction	1	53.1×	0.056	TPM2
Stimuli-sensing channels	1	27.2×	0.072	NALCN
Ion channel transport	1	19.2×	0.076	NALCN
Muscle contraction	1	15.4×	0.076	MYH3
Transport of small molecules	1	5.0×	0.184	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 5 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	3370.4×	8e-07	TNNT3, TPM2
skeletal muscle contraction	3	306.4×	8e-07	TNNT3, TNNI2, MYH3
sarcomere organization	2	153.2×	5e-04	TNNT3, MYH3
muscle contraction	2	83.2×	0.001	TPM2, MYH3
positive regulation of calcium-dependent ATPase activity	1	3370.4×	0.001	TNNT3
positive regulation of synaptic transmission, cholinergic	1	674.1×	0.005	NALCN
regulation of striated muscle contraction	1	421.3×	0.007	TNNT3
regulation of resting membrane potential	1	259.3×	0.011	NALCN
muscle filament sliding	1	210.7×	0.011	MYH3
positive regulation of synaptic transmission, GABAergic	1	198.3×	0.011	NALCN
actin filament-based movement	1	160.5×	0.012	MYH3
face morphogenesis	1	99.1×	0.018	MYH3
ATP metabolic process	1	93.6×	0.018	MYH3
embryonic limb morphogenesis	1	80.2×	0.018	MYH3
cardiac muscle contraction	1	80.2×	0.018	TNNI2
calcium ion transmembrane transport	1	42.1×	0.030	NALCN
monoatomic ion transmembrane transport	1	41.6×	0.030	NALCN
sodium ion transmembrane transport	1	40.6×	0.030	NALCN
muscle organ development	1	33.4×	0.034	MYH3
potassium ion transmembrane transport	1	27.2×	0.040	NALCN
actin filament organization	1	23.7×	0.043	TPM2
positive regulation of DNA-templated transcription	1	5.6×	0.167	TNNI2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	NALCN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TNNT3, TNNI2, TPM2, MYH3

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01144741	Not specified	TERMINATED	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT05419245	Not specified	UNKNOWN	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome