Nebulin-related early-onset distal myopathy

Summary

Nebulin-related early-onset distal myopathy (MONDO:0018371) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003722	Neck flexor weakness	Frequent (30-79%)
HP:0003798	Nemaline bodies	Frequent (30-79%)
HP:0006466	Ankle flexion contracture	Frequent (30-79%)
HP:0009005	Weakness of the intrinsic hand muscles	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0009063	Progressive distal muscle weakness	Frequent (30-79%)
HP:0009077	Weakness of long finger extensor muscles	Frequent (30-79%)
HP:0012036	Sternocleidomastoid amyotrophy	Frequent (30-79%)
HP:0001533	Slender build	Occasional (5-29%)
HP:0002875	Exertional dyspnea	Occasional (5-29%)
HP:0009073	Progressive proximal muscle weakness	Occasional (5-29%)
HP:0012548	Fatty replacement of skeletal muscle	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	nebulin-related early-onset distal myopathy
Mondo ID	MONDO:0018371
Orphanet	399103
UMLS	C5190827
MedGen	1677937
GARD	0021656
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › muscular dystrophy › distal myopathy › nebulin-related early-onset distal myopathy

Related subtypes (10): myopathy, distal, infantile-onset, MYH7-related skeletal myopathy, Miyoshi myopathy, distal myopathy with anterior tibial onset, myopathy, distal, 5, myopathy, distal, with rimmed vacuoles, autosomal dominant distal myopathy, myopathy, distal, 7, adult-onset, X-linked, oculopharyngodistal myopathy, asymptomatic hyperckemia-myalgia-rhabdomyolysis syndrome

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

3 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
447758	NM_001164508.2(NEB):c.4469T>C (p.Met1490Thr)	NEB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339896	NM_001164508.2(NEB):c.24040G>A (p.Val8014Ile)	RIF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339897	NM_001164508.2(NEB):c.2971C>G (p.Leu991Val)	NEB	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEB	Orphanet:171430	Severe congenital nemaline myopathy
NEB	Orphanet:171433	Intermediate nemaline myopathy
NEB	Orphanet:171436	Typical nemaline myopathy
NEB	Orphanet:171439	Childhood-onset nemaline myopathy
NEB	Orphanet:33108	Lethal multiple pterygium syndrome
NEB	Orphanet:399103	Autosomal recessive distal nebulin myopathy
NEB	Orphanet:708123	Autosomal dominant distal nebulin myopathy

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
RIF1	HGNC:23207	ENSG00000080345	Q5UIP0	Telomere-associated protein RIF1	clinvar
LRIF1	HGNC:30299	ENSG00000121931	Q5T3J3	Ligand-dependent nuclear receptor-interacting factor 1	clinvar
NEB	HGNC:7720	ENSG00000183091	P20929	Nebulin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RIF1	Telomere-associated protein RIF1	Key regulator of TP53BP1 that plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage: acts by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs.
LRIF1	Ligand-dependent nuclear receptor-interacting factor 1	Together with SMCHD1, involved in chromosome X inactivation in females by promoting the compaction of heterochromatin.
NEB	Nebulin	This giant muscle protein may be involved in maintaining the structural integrity of sarcomeres and the membrane system associated with the myofibrils.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RIF1	Other/Unknown	no		ARM-like, ARM-type_fold, Rif1_N
LRIF1	Other/Unknown	no		LRIF1
NEB	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulin-like

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
buccal mucosa cell	1
gastrocnemius	1
hindlimb stylopod muscle	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
biceps brachii	1
gluteal muscle	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RIF1	279	ubiquitous	marker	buccal mucosa cell, gastrocnemius, hindlimb stylopod muscle
LRIF1	271	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
NEB	204	tissue_specific	marker	gluteal muscle, tibialis anterior, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RIF1	2,384
NEB	1,402
LRIF1	1,295

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NEB	P20929	3
RIF1	Q5UIP0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRIF1	Q5T3J3	48.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Striated Muscle Contraction	1	154.3×	0.018	NEB
Nonhomologous End-Joining (NHEJ)	1	84.0×	0.018	RIF1
Muscle contraction	1	38.6×	0.026	NEB

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
cardiac muscle thin filament assembly	1	1872.4×	0.004	NEB
somatic muscle development	1	1404.3×	0.004	NEB
regulation of actin filament length	1	1404.3×	0.004	NEB
telomere maintenance in response to DNA damage	1	624.1×	0.006	RIF1
dosage compensation by inactivation of X chromosome	1	510.7×	0.006	LRIF1
subtelomeric heterochromatin formation	1	510.7×	0.006	RIF1
positive regulation of isotype switching	1	432.1×	0.006	RIF1
positive regulation of double-strand break repair via nonhomologous end joining	1	330.4×	0.007	RIF1
negative regulation of double-strand break repair via homologous recombination	1	208.1×	0.010	RIF1
negative regulation of gene expression, epigenetic	1	133.8×	0.013	RIF1
telomere maintenance	1	89.2×	0.018	RIF1
somatic stem cell population maintenance	1	82.6×	0.018	RIF1
muscle organ development	1	55.6×	0.024	NEB
cellular response to leukemia inhibitory factor	1	53.0×	0.024	RIF1
DNA repair	1	21.3×	0.056	RIF1
DNA damage response	1	17.8×	0.062	RIF1
regulation of DNA-templated transcription	1	10.5×	0.098	LRIF1
negative regulation of transcription by RNA polymerase II	1	5.9×	0.160	RIF1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RIF1	1	2
LRIF1	0	0
NEB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RIF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RIF1	7	Binding:7

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	RIF1

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	1	RIF1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LRIF1, NEB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LRIF1	0	—
NEB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.