autosomal recessive limb-girdle muscular dystrophy type 2H

Summary

autosomal recessive limb-girdle muscular dystrophy type 2H (MONDO:0009683) is a disease caused by TRIM32 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: TRIM32 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 222
• 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:0000298	Mask-like facies	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0002515	Waddling gait	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0003557	Increased variability in muscle fiber diameter	Very frequent (80-99%)
HP:0008994	Proximal muscle weakness in lower limbs	Very frequent (80-99%)
HP:0000098	Tall stature	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy type 2H
Mondo ID	MONDO:0009683
MeSH	C535897
OMIM	254110
Orphanet	1878
DOID	DOID:0110282
SNOMED CT	43226001
UMLS	C0270968
MedGen	78750
GARD	0003844
Is cancer (heuristic)	no

Also known as: autosomal recessive limb-girdle muscular dystrophy caused by mutation in TRIM32 · autosomal recessive limb-girdle muscular dystrophy type 2H · LGMD2H · limb-girdle muscular dystrophy due to TRIM32 deficiency · limb-girdle muscular dystrophy type 2H · muscular dystrophy limb-girdle type 2H · muscular dystrophy, limb-girdle, autosomal recessive 8 · muscular dystrophy, limb-girdle, type 2H · Sarcotubular myopathy · sarcotubular myopathy · TRIM32 autosomal recessive limb-girdle muscular dystrophy

Data availability: 222 ClinVar variants · 4 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 recessive disease › autosomal recessive limb-girdle muscular dystrophy › autosomal recessive limb-girdle muscular dystrophy type 2H

Related subtypes (31): epidermolysis bullosa simplex 5B, with muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, autosomal recessive limb-girdle muscular dystrophy type 2B, autosomal recessive limb-girdle muscular dystrophy type 2C, autosomal recessive limb-girdle muscular dystrophy type 2F, autosomal recessive limb-girdle muscular dystrophy type 2G, autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy type 2I, autosomal recessive limb-girdle muscular dystrophy type 2D, autosomal recessive limb-girdle muscular dystrophy type 2J, autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2L, autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2Q, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, autosomal recessive limb-girdle muscular dystrophy type R18, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, autosomal recessive limb-girdle muscular dystrophy type 2X, autosomal recessive limb-girdle muscular dystrophy type 2W, autosomal recessive limb-girdle muscular dystrophy type 2Y, autosomal recessive limb-girdle muscular dystrophy type 2R1, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, muscular dystrophy, limb-girdle, autosomal recessive 23, muscular dystrophy, limb-girdle, autosomal recessive 26, muscular dystrophy, limb-girdle, autosomal recessive 27, muscular dystrophy, limb-girdle, autosomal recessive 28, muscular dystrophy, limb-girdle, autosomal recessive 29

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

222 retrieved; paginated sample, class counts are floors:

155 uncertain significance, 28 conflicting classifications of pathogenicity, 14 likely pathogenic, 7 pathogenic/likely pathogenic, 6 likely benign, 6 benign, 4 pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1451474	NM_012210.4(TRIM32):c.606_607del (p.Arg203fs)	ASTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2780044	NM_012210.4(TRIM32):c.232_235del (p.Asp78fs)	ASTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3769251	NC_000009.11:g.(?119449583)(119463579_?)del	ASTN2	Pathogenic	criteria provided, single submitter
462946	NM_012210.4(TRIM32):c.1108del (p.Met370fs)	ASTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
498076	NM_012210.4(TRIM32):c.691del (p.Ala231fs)	ASTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7350	NM_012210.4(TRIM32):c.1459G>A (p.Asp487Asn)	ASTN2	Pathogenic	criteria provided, multiple submitters, no conflicts
7352	NM_012210.4(TRIM32):c.1560del (p.Cys521fs)	ASTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802505	NM_012210.4(TRIM32):c.1201A>T (p.Lys401Ter)	ASTN2	Pathogenic	criteria provided, multiple submitters, no conflicts
972625	NM_012210.4(TRIM32):c.458_465del (p.Leu153fs)	ASTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343785	NM_012210.4(TRIM32):c.1603del (p.Leu535fs)	TRIM32	Pathogenic	no assertion criteria provided
597209	NM_012210.4(TRIM32):c.1131_1132del (p.Tyr378fs)	TRIM32	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2434245	NM_012210.4(TRIM32):c.1584C>G (p.Tyr528Ter)	ASTN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3596355	NM_012210.4(TRIM32):c.430G>T (p.Glu144Ter)	ASTN2	Likely pathogenic	criteria provided, single submitter
3596357	NM_012210.4(TRIM32):c.495del (p.Arg166fs)	ASTN2	Likely pathogenic	criteria provided, single submitter
3596363	NM_012210.4(TRIM32):c.775_794del (p.Asp259fs)	ASTN2	Likely pathogenic	criteria provided, single submitter
3596369	NM_012210.4(TRIM32):c.1012del (p.Ala338fs)	ASTN2	Likely pathogenic	criteria provided, single submitter
3596380	NM_012210.4(TRIM32):c.1824del (p.Gly607_Tyr608insTer)	ASTN2	Likely pathogenic	criteria provided, single submitter
3897045	NM_012210.4(TRIM32):c.1506del (p.Val504fs)	ASTN2	Likely pathogenic	criteria provided, single submitter
4845925	NM_012210.4(TRIM32):c.650_657del (p.Asn217fs)	ASTN2	Likely pathogenic	criteria provided, single submitter
3596359	NM_012210.4(TRIM32):c.577_581del (p.Arg193fs)	TRIM32	Likely pathogenic	criteria provided, single submitter
3596361	NM_012210.4(TRIM32):c.697_721dup (p.Tyr241delinsCysAlaGlyCysValSerLeuTer)	TRIM32	Likely pathogenic	criteria provided, single submitter
3596372	NM_012210.4(TRIM32):c.1297_1298del (p.Val434fs)	TRIM32	Likely pathogenic	criteria provided, single submitter
3596373	NM_012210.4(TRIM32):c.1448_1449dup (p.Val484fs)	TRIM32	Likely pathogenic	criteria provided, single submitter
3596374	NM_012210.4(TRIM32):c.1481G>A (p.Trp494Ter)	TRIM32	Likely pathogenic	criteria provided, single submitter
3897046	NM_012210.4(TRIM32):c.1569dup (p.Glu524Ter)	TRIM32	Likely pathogenic	criteria provided, single submitter
100583	NM_012210.4(TRIM32):c.1222C>T (p.Arg408Cys)	ASTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029181	NM_012210.4(TRIM32):c.1837C>T (p.Arg613Ter)	ASTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1069605	NM_012210.4(TRIM32):c.1771G>A (p.Val591Met)	ASTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1135374	NM_012210.4(TRIM32):c.114C>T (p.His38=)	ASTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195280	NM_012210.4(TRIM32):c.558G>C (p.Gln186His)	ASTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
TRIM32	Definitive	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2H	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRIM32	Orphanet:110	Bardet-Biedl syndrome
TRIM32	Orphanet:1878	TRIM32-related limb-girdle muscular dystrophy R8
SLC35D1	Orphanet:3144	Schneckenbecken dysplasia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRIM32	HGNC:16380	ENSG00000119401	Q13049	E3 ubiquitin-protein ligase TRIM32	gencc,clinvar
ASTN2	HGNC:17021	ENSG00000148219	O75129	Astrotactin-2	clinvar
SLC35D1	HGNC:20800	ENSG00000116704	Q9NTN3	Nucleotide sugar transporter SLC35D1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRIM32	E3 ubiquitin-protein ligase TRIM32	E3 ubiquitin ligase that plays a role in various biological processes including neural stem cell differentiation, innate immunity, inflammatory resonse and autophagy.
ASTN2	Astrotactin-2	Mediates recycling of the neuronal cell adhesion molecule ASTN1 to the anterior pole of the cell membrane in migrating neurons.
SLC35D1	Nucleotide sugar transporter SLC35D1	Antiporter that transports nucleotide sugars across the endoplasmic reticulum (ER) membrane in exchange for either their cognate nucleoside monophosphate or another nucleotide sugar.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Complement	1	89.3×	0.033
Transporter	1	25.9×	0.057
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRIM32	Transcription factor	no		Znf_B-box, NHL_repeat, Znf_RING
ASTN2	Complement	yes		MACPF, Astrotactin, FN3_sf
SLC35D1	Transporter	yes		Sugar_P_trans_dom, TPT_transporter

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
stromal cell of endometrium	1
tibialis anterior	1
buccal mucosa cell	1
dorsal root ganglion	1
trigeminal ganglion	1
colonic mucosa	1
mucosa of sigmoid colon	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRIM32	252	ubiquitous	yes	stromal cell of endometrium, tibialis anterior, gastrocnemius
ASTN2	236	ubiquitous	marker	buccal mucosa cell, trigeminal ganglion, dorsal root ganglion
SLC35D1	282	ubiquitous	marker	secondary oocyte, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRIM32	2,322
ASTN2	1,610
SLC35D1	947

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASTN2	O75129	3
TRIM32	Q13049	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC35D1	Q9NTN3	80.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC35D1 causes SCHBCKD	1	5710.0×	0.003	SLC35D1
Formation of the active cofactor, UDP-glucuronate	1	1142.0×	0.007	SLC35D1
Transport of nucleotide sugars	1	571.0×	0.007	SLC35D1
Metabolic disorders of biological oxidation enzymes	1	439.2×	0.007	SLC35D1
Glucuronidation	1	380.7×	0.007	SLC35D1
Regulation of innate immune responses to cytosolic DNA	1	380.7×	0.007	TRIM32
Phase II - Conjugation of compounds	1	139.3×	0.014	SLC35D1
Transport of vitamins, nucleosides, and related molecules	1	135.9×	0.014	SLC35D1
Biological oxidations	1	64.9×	0.026	SLC35D1
Diseases of metabolism	1	40.2×	0.037	SLC35D1
SLC-mediated transmembrane transport	1	29.6×	0.046	SLC35D1
Antigen processing: Ubiquitination & Proteasome degradation	1	18.6×	0.066	TRIM32
Transport of small molecules	1	12.6×	0.090	SLC35D1
Disease	1	6.5×	0.158	SLC35D1
Metabolism	1	5.8×	0.165	SLC35D1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
actin ubiquitination	1	5617.3×	0.002	TRIM32
pyrimidine nucleotide-sugar transmembrane transport	1	5617.3×	0.002	SLC35D1
positive regulation of interleukin-17-mediated signaling pathway	1	5617.3×	0.002	TRIM32
positive regulation of chemokine (C-C motif) ligand 20 production	1	5617.3×	0.002	TRIM32
nucleotide-sugar transmembrane transport	1	2808.7×	0.003	SLC35D1
establishment of body hair planar orientation	1	1123.5×	0.007	ASTN2
positive regulation of striated muscle cell differentiation	1	936.2×	0.007	TRIM32
free ubiquitin chain polymerization	1	802.5×	0.008	TRIM32
negative regulation of protein localization to cell surface	1	432.1×	0.010	ASTN2
negative regulation of toll-like receptor 4 signaling pathway	1	374.5×	0.010	TRIM32
negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage	1	374.5×	0.010	TRIM32
negative regulation of viral transcription	1	351.1×	0.010	TRIM32
positive regulation of tumor necrosis factor-mediated signaling pathway	1	351.1×	0.010	TRIM32
neuron cell-cell adhesion	1	330.4×	0.010	ASTN2
suppression of viral release by host	1	330.4×	0.010	TRIM32
cellular response to stress	1	280.9×	0.010	TRIM32
positive regulation of proteolysis	1	267.5×	0.010	TRIM32
negative regulation of cilium assembly	1	267.5×	0.010	TRIM32
positive regulation of autophagosome assembly	1	267.5×	0.010	TRIM32
positive regulation of cell motility	1	255.3×	0.010	TRIM32
muscle cell cellular homeostasis	1	216.1×	0.010	TRIM32
response to tumor necrosis factor	1	208.1×	0.010	TRIM32
chondroitin sulfate proteoglycan biosynthetic process	1	208.1×	0.010	SLC35D1
positive regulation of neurogenesis	1	193.7×	0.010	TRIM32
tissue homeostasis	1	187.2×	0.010	TRIM32
protein localization to cell surface	1	165.2×	0.011	ASTN2
negative regulation of fibroblast proliferation	1	165.2×	0.011	TRIM32
response to starvation	1	156.0×	0.011	TRIM32
axon development	1	151.8×	0.011	TRIM32
positive regulation of cell cycle	1	147.8×	0.011	TRIM32

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRIM32	0	0
ASTN2	0	0
SLC35D1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	ASTN2
D	Druggable family + AlphaFold only, no drug	1	SLC35D1
E	Difficult family or no structure, no drug	1	TRIM32

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TRIM32	0	—
ASTN2	0	—
SLC35D1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.