Familial restrictive cardiomyopathy

Summary

Familial restrictive cardiomyopathy (MONDO:0016340) is a disease (an umbrella term covering 10 Mondo subtypes) with 7 cohort genes. The dominant Reactome pathway is Striated Muscle Contraction (4 cohort genes).

At a glance

• Umbrella term: 10 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 33

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial restrictive cardiomyopathy
Mondo ID	MONDO:0016340
OMIM	115210
Orphanet	217635
SNOMED CT	233878008
UMLS	C0340429
MedGen	468561
GARD	0020532
Is cancer (heuristic)	no

Also known as: hereditary restrictive cardiomyopathy

Data availability: 33 ClinVar variants.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › restrictive cardiomyopathy › familial restrictive cardiomyopathy

Related subtypes (2): endomyocardial fibrosis, non-familial restrictive cardiomyopathy

Subtypes (10): cardiomyopathy, familial restrictive, 1, Gaucher disease type I, glycogen storage disease II, idiopathic hypereosinophilic syndrome, cardiomyopathy, familial restrictive, 2, cardiomyopathy, familial restrictive, 3, dilated cardiomyopathy 1KK, atrial standstill, ATTRV122I amyloidosis, cardiomyopathy, familial restrictive, 6

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

33 retrieved; paginated sample, class counts are floors:

14 conflicting classifications of pathogenicity, 11 uncertain significance, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
210091	NM_001100.4(ACTA1):c.867C>T (p.Ile289=)	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296059	NM_001100.4(ACTA1):c.108C>T (p.Ile36=)	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464116	NM_001100.4(ACTA1):c.1125A>G (p.Lys375=)	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706552	NM_001100.4(ACTA1):c.786G>C (p.Thr262=)	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
740066	NM_001100.4(ACTA1):c.888T>C (p.Tyr296=)	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873830	NM_001100.4(ACTA1):c.1128C>T (p.Cys376=)	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874835	NM_001100.4(ACTA1):c.435C>T (p.Tyr145=)	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876668	NM_001100.4(ACTA1):c.*248G>A	ACTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201758	NM_004006.3(DMD):c.2273A>C (p.Asp758Ala)	DMD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
664831	NM_004006.3(DMD):c.8996C>T (p.Ala2999Val)	DMD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
199875	NM_004415.4(DSP):c.2774G>A (p.Arg925Gln)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636992	NM_000363.5(TNNI3):c.624dup (p.Glu209Ter)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
691826	NM_001267550.2(TTN):c.25064-4A>G	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
691834	NM_001267550.2(TTN):c.68329+2_68329+3insTT	TTN-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296051	NM_001100.4(ACTA1):c.1113C>G (p.Ile371Met)	ACTA1	Uncertain significance	criteria provided, single submitter
296052	NM_001100.4(ACTA1):c.966G>A (p.Leu322=)	ACTA1	Uncertain significance	criteria provided, single submitter
296057	NM_001100.4(ACTA1):c.454+3G>T	ACTA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
296058	NM_001100.4(ACTA1):c.129+14T>C	ACTA1	Uncertain significance	criteria provided, single submitter
873885	NM_001100.4(ACTA1):c.453C>G (p.Thr151=)	ACTA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
876669	NM_001100.4(ACTA1):c.*66G>A	ACTA1	Uncertain significance	criteria provided, single submitter
876712	NM_001100.4(ACTA1):c.480C>A (p.Gly160=)	ACTA1	Uncertain significance	criteria provided, single submitter
876767	NM_001100.4(ACTA1):c.81C>T (p.Asp27=)	ACTA1	Uncertain significance	criteria provided, single submitter
60726	NM_022114.4(PRDM16):c.2447A>G (p.Asn816Ser)	PRDM16	Uncertain significance	criteria provided, multiple submitters, no conflicts
691814	NM_022114.4(PRDM16):c.2372G>A (p.Gly791Asp)	PRDM16	Uncertain significance	criteria provided, single submitter
691815	NM_001267550.2(TTN):c.39709+1G>T	TTN	Uncertain significance	criteria provided, single submitter
257445	NM_001100.4(ACTA1):c.453C>A (p.Thr151=)	ACTA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
296056	NM_001100.4(ACTA1):c.549G>A (p.Ala183=)	ACTA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
296062	NM_001100.4(ACTA1):c.-66C>T	ACTA1	Benign	reviewed by expert panel
93546	NM_001100.4(ACTA1):c.130-10G>C	ACTA1	Benign	criteria provided, multiple submitters, no conflicts
93547	NM_001100.4(ACTA1):c.130-5T>C	ACTA1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 43 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNI3	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
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
PRDM16	Orphanet:154	Familial isolated dilated cardiomyopathy
PRDM16	Orphanet:1606	1p36 deletion syndrome
PRDM16	Orphanet:54260	Left ventricular noncompaction
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome
DSP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSP	Orphanet:476096	Erythrokeratodermia-cardiomyopathy syndrome
DSP	Orphanet:50942	Striate palmoplantar keratoderma
DSP	Orphanet:65282	Carvajal syndrome

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNI3	HGNC:11947	ENSG00000129991	P19429	Troponin I, cardiac muscle	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	clinvar
PRDM16	HGNC:14000	ENSG00000142611	Q9HAZ2	Histone-lysine N-methyltransferase PRDM16	clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNI3	Troponin I, cardiac muscle	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
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.
PRDM16	Histone-lysine N-methyltransferase PRDM16	Transcription regulator that acts both as a histone methyltransferase or chromatin adapter, depending on the context.
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 3 · Druggable fraction: 0.14

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
Kinase	1	4.0×	0.454
Transcription factor	2	2.4×	0.454
Scaffold/PPI	1	2.5×	0.455
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNI3	Other/Unknown	no		Troponin, Troponin-I_N, Troponin_sf
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
PRDM16	Transcription factor	no	2.1.1.367	SET_dom, Znf_C2H2_type, Znf_C2H2_sf
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
TTN-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right atrium auricular region	2
gluteal muscle	2
skeletal muscle tissue of biceps brachii	2
apex of heart	1
left ventricle myocardium	1
biceps brachii	1
diaphragm	1
ascending aorta	1
pigmented layer of retina	1
sural nerve	1
dorsal root ganglion	1
skeletal muscle tissue of rectus abdominis	1
trigeminal ganglion	1
hair follicle	1
skin of hip	1
upper leg skin	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNI3	169	broad	marker	apex of heart, left ventricle myocardium, right atrium auricular region
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
PRDM16	202	broad	marker	sural nerve, pigmented layer of retina, ascending aorta
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
TTN-AS1	174	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
DSP	2,897
PRDM16	2,633
DMD	2,479
TNNI3	1,836
ACTA1	523
TTN-AS1	0

Intra-cohort edges

A	B	Sources
TNNI3	TTN	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
TNNI3	P19429	39
DMD	P11532	6
ACTA1	P68133	5
DSP	P15924	4
PRDM16	Q9HAZ2	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 7 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	4	205.8×	2e-08	TNNI3, TTN, ACTA1, DMD
Formation of the dystrophin-glycoprotein complex (DGC)	2	102.9×	0.001	ACTA1, DMD
Non-integrin membrane-ECM interactions	2	51.4×	0.003	ACTA1, DMD
Apoptotic cleavage of cell adhesion proteins	1	173.0×	0.021	DSP
Regulation of CDH1 Function	1	158.6×	0.021	ACTA1
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	63.4×	0.044	PRDM16
RND1 GTPase cycle	1	44.3×	0.049	DSP
RND3 GTPase cycle	1	43.3×	0.049	DSP
Ion homeostasis	1	34.0×	0.055	TNNI3
Activation of STAT3 by cadherin engagement	1	27.2×	0.057	ACTA1
PKMTs methylate histone lysines	1	26.8×	0.057	PRDM16
Platelet degranulation	1	14.6×	0.087	TTN
Formation of the cornified envelope	1	14.6×	0.087	DSP
Muscle contraction	1	12.9×	0.091	ACTA1
Extracellular matrix organization	1	10.5×	0.104	ACTA1
Keratinization	1	9.3×	0.109	DSP
Neutrophil degranulation	1	3.9×	0.234	DSP

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
cardiac muscle contraction	3	200.6×	3e-05	TNNI3, TTN, DMD
skeletal muscle thin filament assembly	2	936.2×	7e-05	TTN, ACTA1
muscle filament sliding	2	351.1×	4e-04	TNNI3, TTN
skeletal muscle contraction	2	170.2×	0.001	TNNI3, TTN
regulation of muscle system process	1	2808.7×	0.004	DMD
regulation of cellular response to growth factor stimulus	1	2808.7×	0.004	DMD
muscle contraction	2	69.3×	0.004	TTN, ACTA1
regulation of systemic arterial blood pressure by ischemic conditions	1	1404.3×	0.006	TNNI3
cardiac muscle cell action potential	1	1404.3×	0.006	DMD
negative regulation of white fat cell differentiation	1	1404.3×	0.006	PRDM16
skeletal muscle myosin thick filament assembly	1	936.2×	0.007	TTN
sarcomerogenesis	1	936.2×	0.007	TTN
beige fat cell differentiation	1	936.2×	0.007	PRDM16
tolerance induction in gut-associated lymphoid tissue	1	702.2×	0.008	PRDM16
regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion	1	702.2×	0.008	DMD
peptide biosynthetic process	1	702.2×	0.008	DMD
mesenchyme migration	1	561.7×	0.009	ACTA1
regulation of skeletal muscle contraction	1	468.1×	0.010	DMD
regulation of cellular respiration	1	468.1×	0.010	PRDM16
ventricular compact myocardium morphogenesis	1	401.2×	0.010	DSP
detection of muscle stretch	1	401.2×	0.010	TTN
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1	401.2×	0.010	DSP
desmosome organization	1	351.1×	0.010	DSP
negative regulation of granulocyte differentiation	1	351.1×	0.010	PRDM16
regulatory T cell differentiation	1	351.1×	0.010	PRDM16
regulation of calcium ion transmembrane transport	1	351.1×	0.010	DMD
protein localization to cell-cell junction	1	312.1×	0.010	DSP
cardiac muscle hypertrophy	1	280.9×	0.010	TTN
negative regulation of ATP-dependent activity	1	280.9×	0.010	TNNI3
negative regulation of muscle cell differentiation	1	280.9×	0.010	PRDM16

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 5 of 7 evidence-associated genes (71%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNNI3	0	0
TTN	0	0
ACTA1	0	0
PRDM16	0	0
DMD	0	0
DSP	0	0
TTN-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TNNI3	2	Binding:2
PRDM16	2	Binding:2
DSP	2	Binding:2
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
PRDM16	2.1.1.367, 2.1.1.370	[histone H3]-lysine9 N-methyltransferase, [histone H3]-lysine4 N-dimethyltransferase

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	1	TTN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	TNNI3, ACTA1, PRDM16, DMD, DSP, TTN-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNNI3	2	—
TTN	1	—
ACTA1	0	—
PRDM16	2	—
DMD	0	—
DSP	2	—
TTN-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.