distal myopathy, Welander type

Summary

distal myopathy, Welander type (MONDO:0011466) is a disease caused by TIA1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: >1 / 1000 (Sweden) [Orphanet-validated]
• Causal gene: TIA1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 267
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	>1 / 1000	100	Sweden	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0003458	EMG: myopathic abnormalities	Very frequent (80-99%)
HP:0008954	Intrinsic hand muscle atrophy	Very frequent (80-99%)
HP:0008959	Distal upper limb muscle weakness	Very frequent (80-99%)
HP:0009027	Foot dorsiflexor weakness	Very frequent (80-99%)
HP:0009077	Weakness of long finger extensor muscles	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0003376	Steppage gait	Frequent (30-79%)
HP:0003805	Rimmed vacuoles	Frequent (30-79%)
HP:0007149	Distal upper limb amyotrophy	Frequent (30-79%)
HP:0008180	Mildly elevated creatine kinase	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	distal myopathy, Welander type
Mondo ID	MONDO:0011466
OMIM	604454
Orphanet	603
UMLS	C0221054
MedGen	67441
GARD	0005552
Is cancer (heuristic)	no

Also known as: distal myopathy, Swedish type · WDM · Welander distal myopathy · Welander distal myopathy, Swedish type

Data availability: 267 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant distal myopathy › distal myopathy, Welander type

Related subtypes (14): tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure, myofibrillar myopathy 2, myofibrillar myopathy 3, myofibrillar myopathy 4, Finnish upper limb-onset distal myopathy, distal myopathy with posterior leg and anterior hand involvement, distal myopathy, Tateyama type, adult-onset distal myopathy due to VCP mutation, KLHL9-related early-onset distal myopathy, distal myopathy with vocal cord weakness, TARDBP-related predominantly upper-limb distal myopathy, asymetric thumb-handgrip weakness-distal myopathy, calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy

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

267 retrieved; paginated sample, class counts are floors:

131 uncertain significance, 114 likely benign, 11 benign, 5 conflicting classifications of pathogenicity, 5 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
41480	NM_022173.4(TIA1):c.1150G>A (p.Glu384Lys)	TIA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1045764	NM_022173.4(TIA1):c.1006G>A (p.Gly336Ser)	TIA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1081184	NM_022173.4(TIA1):c.283A>T (p.Thr95Ser)	TIA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1592491	NM_022173.4(TIA1):c.474+15_474+17dup	TIA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
261567	NM_022173.4(TIA1):c.1070A>G (p.Asn357Ser)	TIA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
992595	NM_022173.4(TIA1):c.1085C>T (p.Pro362Leu)	TIA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1004185	NM_022173.4(TIA1):c.154G>A (p.Glu52Lys)	TIA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1004639	NM_022173.4(TIA1):c.167A>G (p.His56Arg)	TIA1	Uncertain significance	criteria provided, single submitter
1006176	NM_022173.4(TIA1):c.805G>A (p.Val269Ile)	TIA1	Uncertain significance	criteria provided, single submitter
1019780	NM_022173.4(TIA1):c.1118A>G (p.Asn373Ser)	TIA1	Uncertain significance	criteria provided, single submitter
1028743	NM_022173.4(TIA1):c.775C>A (p.His259Asn)	TIA1	Uncertain significance	criteria provided, single submitter
1036305	NM_022173.4(TIA1):c.562G>T (p.Ala188Ser)	TIA1	Uncertain significance	criteria provided, single submitter
1037062	NM_022173.4(TIA1):c.277+6T>G	TIA1	Uncertain significance	criteria provided, single submitter
1043578	NM_022173.4(TIA1):c.683A>T (p.Gln228Leu)	TIA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1058761	NM_022173.4(TIA1):c.913C>T (p.Pro305Ser)	TIA1	Uncertain significance	criteria provided, single submitter
1059725	NM_022173.4(TIA1):c.597G>C (p.Gln199His)	TIA1	Uncertain significance	criteria provided, single submitter
1352602	NM_022173.4(TIA1):c.155A>C (p.Glu52Ala)	TIA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1354819	NM_022173.4(TIA1):c.188T>C (p.Leu63Ser)	TIA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1363922	NM_022173.4(TIA1):c.434A>C (p.Lys145Thr)	TIA1	Uncertain significance	criteria provided, single submitter
1369300	NM_022173.4(TIA1):c.507C>T (p.Gly169=)	TIA1	Uncertain significance	criteria provided, single submitter
1382266	NM_022173.4(TIA1):c.41T>G (p.Leu14Arg)	TIA1	Uncertain significance	criteria provided, single submitter
1387073	NM_022173.4(TIA1):c.802T>A (p.Ser268Thr)	TIA1	Uncertain significance	criteria provided, single submitter
1388878	NM_022173.4(TIA1):c.467A>C (p.Asn156Thr)	TIA1	Uncertain significance	criteria provided, single submitter
1395636	NM_022173.4(TIA1):c.820A>T (p.Ile274Phe)	TIA1	Uncertain significance	criteria provided, single submitter
1404868	NM_022173.4(TIA1):c.172C>A (p.His58Asn)	TIA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1406976	NM_022173.4(TIA1):c.1157A>C (p.Gln386Pro)	TIA1	Uncertain significance	criteria provided, single submitter
1411686	NM_022173.4(TIA1):c.928G>A (p.Gly310Ser)	TIA1	Uncertain significance	criteria provided, single submitter
1412010	NM_022173.4(TIA1):c.583+1G>A	TIA1	Uncertain significance	criteria provided, single submitter
1412333	NC_000002.11:g.(?70439851)(70458006_?)dup	TIA1	Uncertain significance	criteria provided, single submitter
1413240	NM_022173.4(TIA1):c.1059G>T (p.Trp353Cys)	TIA1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
TIA1	Strong	Autosomal dominant	distal myopathy, Welander type	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TIA1	Orphanet:603	Distal myopathy, Welander type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TIA1	HGNC:11802	ENSG00000116001	P31483	Cytotoxic granule associated RNA binding protein TIA1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TIA1	Cytotoxic granule associated RNA binding protein TIA1	RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to uridine-rich (U-rich) RNA sequences.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TIA1	Other/Unknown	no		RRM_dom, RRM_euk-type, Nucleotide-bd_a/b_plait_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	1
right ovary	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TIA1	297	ubiquitous	marker	right uterine tube, right ovary, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TIA1	3,482

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TIA1	P31483	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 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
FGFR2 alternative splicing	1	423.0×	0.005	TIA1
Signaling by FGFR2	1	407.9×	0.005	TIA1
Signaling by FGFR	1	346.1×	0.005	TIA1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.024	TIA1
Signal Transduction	1	10.2×	0.098	TIA1

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
protein localization to cytoplasmic stress granule	1	2106.5×	0.004	TIA1
positive regulation of epithelial cell apoptotic process	1	1296.3×	0.004	TIA1
regulation of mRNA splicing, via spliceosome	1	887.0×	0.004	TIA1
stress granule assembly	1	601.9×	0.004	TIA1
negative regulation of cytokine production	1	510.7×	0.004	TIA1
regulation of alternative mRNA splicing, via spliceosome	1	244.2×	0.007	TIA1
negative regulation of translation	1	195.9×	0.007	TIA1
RNA splicing	1	88.2×	0.014	TIA1
mRNA processing	1	78.8×	0.014	TIA1
apoptotic process	1	28.7×	0.035	TIA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
TIA1	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
TIA1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TIA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TIA1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.