Rigid spine syndrome

Summary

Rigid spine syndrome (MONDO:0019951) is a disease caused by HMGCS1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: HMGCS1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 7
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.13	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000467	Neck muscle weakness	Very frequent (80-99%)
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0003306	Spinal rigidity	Very frequent (80-99%)
HP:0011842	Abnormality of skeletal morphology	Very frequent (80-99%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0002090	Pneumonia	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002987	Elbow flexion contracture	Frequent (30-79%)
HP:0003089	Hamstring contractures	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003273	Hip contracture	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0030878	Abnormality on pulmonary function testing	Frequent (30-79%)
HP:0031546	Cardiac conduction abnormality	Frequent (30-79%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0003391	Gowers sign	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	rigid spine syndrome
Mondo ID	MONDO:0019951
MeSH	C535683
Orphanet	97244
ICD-11	801727141
GARD	0004723
Is cancer (heuristic)	no

Also known as: desmin-related myopathies with Mallory bodies · muscular dystrophy, congenital, merosin positive with early spine rigidity · rigid spine congenital muscular dystrophy · rigid spine muscular dystrophy-1

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records · 13 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › qualitative or quantitative protein defects in neuromuscular diseases › neuromuscular disease caused by qualitative or quantitative defects of myofibrillar proteins › qualitative or quantitative defects of desmin › rigid spine syndrome

Related subtypes (4): neurogenic scapuloperoneal syndrome, Kaeser type, myofibrillar myopathy 1, dilated cardiomyopathy 1I, autosomal dominant limb-girdle muscular dystrophy type 1E (DES)

Subtypes (1): rigid spine muscular dystrophy 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

7 retrieved; paginated sample, class counts are floors:

5 pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2580362	NM_001098272.3(HMGCS1):c.1339T>C (p.Ser447Pro)	HMGCS1	Pathogenic	criteria provided, single submitter
2580363	NM_001098272.3(HMGCS1):c.86A>T (p.Gln29Leu)	HMGCS1	Pathogenic	criteria provided, single submitter
2580364	NM_001098272.3(HMGCS1):c.344_345del (p.Ser115fs)	HMGCS1	Pathogenic	criteria provided, single submitter
2580365	NM_001098272.3(HMGCS1):c.1289G>A (p.Arg430Lys)	HMGCS1	Pathogenic	criteria provided, single submitter
2580366	NM_001098272.3(HMGCS1):c.890G>T (p.Gly297Val)	HMGCS1	Pathogenic	criteria provided, single submitter
2580367	NM_001098272.3(HMGCS1):c.803G>C (p.Cys268Ser)	HMGCS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2580368	NM_001098272.3(HMGCS1):c.209T>C (p.Met70Thr)	HMGCS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 13 · 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
SELENON	Definitive	Autosomal recessive	rigid spine muscular dystrophy 1	8
HMGCS1	Strong	Autosomal recessive	rigid spine syndrome	2
ACTA1	Supportive	Autosomal recessive	rigid spine syndrome	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTA1	Orphanet:171430	Severe congenital nemaline myopathy
ACTA1	Orphanet:171433	Intermediate nemaline myopathy
ACTA1	Orphanet:171436	Typical nemaline myopathy
ACTA1	Orphanet:171439	Childhood-onset nemaline myopathy
ACTA1	Orphanet:2020	Congenital fiber-type disproportion myopathy
ACTA1	Orphanet:447977	Progressive scapulohumeroperoneal distal myopathy
ACTA1	Orphanet:97240	Zebra body myopathy
ACTA1	Orphanet:97244	Rigid spine syndrome
ACTA1	Orphanet:98904	Congenital myopathy with excess of thin filaments
SELENON	Orphanet:2020	Congenital fiber-type disproportion myopathy
SELENON	Orphanet:324604	Classic multiminicore myopathy
SELENON	Orphanet:84132	Desmin-related myopathy with Mallory body-like inclusions
SELENON	Orphanet:97244	Rigid spine syndrome

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
HMGCS1	HGNC:5007	ENSG00000112972	Q01581	Hydroxymethylglutaryl-CoA synthase, cytoplasmic	gencc,clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	gencc
SELENON	HGNC:15999	ENSG00000162430	Q9NZV5	Selenoprotein N	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HMGCS1	Hydroxymethylglutaryl-CoA synthase, cytoplasmic	Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate, a precursor for cholesterol synthesis.
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
SELENON	Selenoprotein N	Plays an important role in cell protection against oxidative stress and in the regulation of redox-related calcium homeostasis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HMGCS1	Enzyme (other)	yes	2.3.3.10	HMG_CoA_synt_AS, HMG_CoA_synthase_euk, HMG_CoA_synth_N
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
SELENON	Other/Unknown	no		EF_hand_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
ventricular zone	2
adrenal tissue	1
diaphragm	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HMGCS1	285	ubiquitous	marker	adrenal tissue, ventricular zone, ganglionic eminence
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
SELENON	244	ubiquitous	marker	stromal cell of endometrium, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HMGCS1	2,715
SELENON	800
ACTA1	523

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTA1	P68133	5
HMGCS1	Q01581	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SELENON	Q9NZV5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Regulation of CDH1 Function	1	475.8×	0.013	ACTA1
Lanosterol biosynthesis	1	380.7×	0.013	HMGCS1
Striated Muscle Contraction	1	154.3×	0.015	ACTA1
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.015	ACTA1
Activation of gene expression by SREBF (SREBP)	1	129.8×	0.015	HMGCS1
Activation of STAT3 by cadherin engagement	1	81.6×	0.018	ACTA1
Non-integrin membrane-ECM interactions	1	77.2×	0.018	ACTA1
PPARA activates gene expression	1	47.2×	0.026	HMGCS1
Muscle contraction	1	38.6×	0.029	ACTA1
Extracellular matrix organization	1	31.6×	0.031	ACTA1

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
skeletal muscle fiber development	2	362.4×	4e-04	ACTA1, SELENON
positive regulation of skeletal muscle cell proliferation	1	2808.7×	0.003	SELENON
positive regulation of response to oxidative stress	1	2808.7×	0.003	SELENON
farnesyl diphosphate biosynthetic process, mevalonate pathway	1	1872.4×	0.003	HMGCS1
L-ascorbic acid transmembrane transport	1	1872.4×	0.003	SELENON
regulation of ryanodine-sensitive calcium-release channel activity	1	1872.4×	0.003	SELENON
diaphragm contraction	1	1404.3×	0.003	SELENON
response to muscle activity involved in regulation of muscle adaptation	1	1404.3×	0.003	SELENON
membrane biogenesis	1	1123.5×	0.003	SELENON
mesenchyme migration	1	1123.5×	0.003	ACTA1
skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration	1	936.2×	0.003	SELENON
membrane to membrane docking	1	936.2×	0.003	SELENON
skeletal muscle thin filament assembly	1	936.2×	0.003	ACTA1
acetyl-CoA metabolic process	1	802.5×	0.003	HMGCS1
skeletal muscle satellite cell differentiation	1	702.2×	0.003	SELENON
obsolete mitochondrion-endoplasmic reticulum membrane tethering	1	702.2×	0.003	SELENON
L-ascorbic acid metabolic process	1	510.7×	0.004	SELENON
cellular response to caffeine	1	510.7×	0.004	SELENON
multicellular organismal response to stress	1	432.1×	0.005	SELENON
energy reserve metabolic process	1	351.1×	0.005	SELENON
mitochondrial calcium ion transmembrane transport	1	330.4×	0.005	SELENON
calcium ion import	1	267.5×	0.006	SELENON
membrane organization	1	170.2×	0.009	SELENON
ATP metabolic process	1	156.0×	0.010	SELENON
calcium ion homeostasis	1	147.8×	0.010	SELENON
cholesterol biosynthetic process	1	140.4×	0.010	HMGCS1
lung alveolus development	1	117.0×	0.011	SELENON
cell redox homeostasis	1	114.6×	0.011	SELENON
collagen fibril organization	1	74.9×	0.017	SELENON
muscle contraction	1	69.3×	0.018	ACTA1

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
HMGCS1	0	0
ACTA1	0	0
SELENON	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HMGCS1	2.3.3.10	hydroxymethylglutaryl-CoA synthase

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	HMGCS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ACTA1, SELENON

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)
HMGCS1	0	—
ACTA1	0	—
SELENON	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.