Megaconial type congenital muscular dystrophy

Summary

Megaconial type congenital muscular dystrophy (MONDO:0011246) is a disease caused by CHKB (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CHKB (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 386

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	megaconial type congenital muscular dystrophy
Mondo ID	MONDO:0011246
MeSH	C566527
OMIM	602541
Orphanet	280671
DOID	DOID:0110632
UMLS	C1865233
MedGen	355943
GARD	0010317
Is cancer (heuristic)	no

Also known as: congenital megaconial myopathy · congenital muscular dystrophy due to phosphatidylcholine biosynthesis defect · congenital muscular dystrophy with mitochondrial structural abnormalities · MDCMC · megaconial congenital muscular dystrophy · megaconial congénital muscular dystrophy · megaconial type congenital muscular dystrophy · muscular dystrophy, congenital, megaconial type

Data availability: 386 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 › inborn errors of metabolism › inherited lipid metabolism disorder › disorder of phospholipids, sphingolipids and fatty acids biosynthesis › megaconial type congenital muscular dystrophy

Related subtypes (16): Sengers syndrome, Sjogren-Larsson syndrome, Barth syndrome, hereditary spastic paraplegia 39, PHARC syndrome, congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, spinocerebellar ataxia type 38, progressive encephalopathy with leukodystrophy due to DECR deficiency, progressive myoclonic epilepsy type 8, neutral lipid storage disease, fatty acid hydroxylase-associated neurodegeneration, hereditary sensory and autonomic neuropathy type 1, GM3 synthase deficiency, nephrotic syndrome 14, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

386 retrieved; paginated sample, class counts are floors:

153 likely benign, 150 uncertain significance, 32 pathogenic, 25 conflicting classifications of pathogenicity, 9 benign, 8 likely pathogenic, 7 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072448	NM_005198.5(CHKB):c.216C>G (p.Tyr72Ter)	CHKB	Pathogenic	criteria provided, single submitter
1075204	NM_005198.5(CHKB):c.1003G>T (p.Glu335Ter)	CHKB	Pathogenic	criteria provided, single submitter
1333660	NM_005198.5(CHKB):c.463del (p.Thr155fs)	CHKB	Pathogenic	criteria provided, single submitter
1456700	NM_005198.5(CHKB):c.808_809insC (p.Tyr270fs)	CHKB	Pathogenic	criteria provided, single submitter
2425317	NC_000022.10:g.(?51017610)(51021210_?)del	CHKB	Pathogenic	criteria provided, single submitter
2765810	NM_005198.5(CHKB):c.536del (p.Met179fs)	CHKB	Pathogenic	criteria provided, single submitter
2849953	NM_005198.5(CHKB):c.187C>T (p.Arg63Ter)	CHKB	Pathogenic	criteria provided, single submitter
30952	NM_005198.5(CHKB):c.810T>A (p.Tyr270Ter)	CHKB	Pathogenic	criteria provided, single submitter
30955	NM_005198.5(CHKB):c.922C>T (p.Gln308Ter)	CHKB	Pathogenic	no assertion criteria provided
30956	NM_005198.5(CHKB):c.677+1G>A	CHKB	Pathogenic	no assertion criteria provided
342172	NM_005198.5(CHKB):c.722A>G (p.Asn241Ser)	CHKB	Pathogenic	criteria provided, single submitter
4073557	NM_005198.5(CHKB):c.592_593del (p.Gln198fs)	CHKB	Pathogenic	criteria provided, single submitter
451378	NM_005198.5(CHKB):c.151C>T (p.Gln51Ter)	CHKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4799581	NM_005198.5(CHKB):c.689_690del (p.Glu230fs)	CHKB	Pathogenic	criteria provided, single submitter
632393	NM_005198.5(CHKB):c.565_568del (p.Phe189fs)	CHKB	Pathogenic	criteria provided, single submitter
1184623	NM_005198.5(CHKB):c.737-1G>C	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
1403550	NM_005198.5(CHKB):c.964_967del (p.Lys322fs)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
1423507	NM_005198.5(CHKB):c.163G>T (p.Glu55Ter)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
1452176	NM_005198.5(CHKB):c.925C>T (p.Gln309Ter)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
2098656	NM_005198.5(CHKB):c.939del (p.Arg314fs)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
2165925	NM_005198.5(CHKB):c.677+1G>C	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
2766178	NM_005198.5(CHKB):c.556del (p.His186fs)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
2840850	NM_005198.5(CHKB):c.446del (p.Pro149fs)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
2863302	NM_005198.5(CHKB):c.224+1G>A	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
2887323	NM_005198.5(CHKB):c.331C>T (p.Gln111Ter)	CHKB-CPT1B	Pathogenic	criteria provided, multiple submitters, no conflicts
30953	NM_005198.5(CHKB):c.116C>A (p.Ser39Ter)	CHKB-CPT1B	Pathogenic	no assertion criteria provided
30954	NM_005198.5(CHKB):c.458dup (p.Leu153fs)	CHKB-CPT1B	Pathogenic	no assertion criteria provided
468473	NM_005198.5(CHKB):c.400C>T (p.Gln134Ter)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
582773	NM_005198.5(CHKB):c.268del (p.His90fs)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter
634595	NM_005198.5(CHKB):c.382G>T (p.Glu128Ter)	CHKB-CPT1B	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
CHKB	Strong	Autosomal recessive	megaconial type congenital muscular dystrophy	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHKB	Orphanet:280671	Megaconial congenital muscular dystrophy
CHKB	Orphanet:521305	Proximal myopathy with focal depletion of mitochondria
PEPD	Orphanet:742	Prolidase deficiency

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHKB	HGNC:1938	ENSG00000100288	Q9Y259	Choline/ethanolamine kinase	gencc,clinvar
LMF2	HGNC:25096	ENSG00000100258	Q9BU23	Lipase maturation factor 2	clinvar
CHKB-CPT1B	HGNC:41998	ENSG00000254413		CHKB-CPT1B readthrough (NMD candidate)	clinvar
PEPD	HGNC:8840	ENSG00000124299	P12955	Xaa-Pro dipeptidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHKB	Choline/ethanolamine kinase	Has a key role in phospholipid metabolism, and catalyzes the first step of phosphatidylethanolamine and phosphatidylcholine biosynthesis.
LMF2	Lipase maturation factor 2	Involved in the maturation of specific proteins in the endoplasmic reticulum.
PEPD	Xaa-Pro dipeptidase	Dipeptidase that catalyzes the hydrolysis of dipeptides with a prolyl (Xaa-Pro) or hydroxyprolyl residue in the C-terminal position.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Protease	1	9.2×	0.205
Kinase	1	6.9×	0.205
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHKB	Kinase	yes	2.7.1.32	Kinase-like_dom_sf
LMF2	Other/Unknown	no		LMF, LMF1/2_C, LMF1/2_N
CHKB-CPT1B	Other/Unknown	no
PEPD	Protease	yes	3.4.13.9	Pept_M24, Peptidase_M24B_aminopep-P_CS, Aminopep_P_N

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
adenohypophysis	2
pituitary gland	1
body of pancreas	1
apex of heart	1
heart left ventricle	1
adult mammalian kidney	1
ileal mucosa	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHKB	134	ubiquitous	marker	pituitary gland, granulocyte, adenohypophysis
LMF2	258	ubiquitous	marker	body of pancreas, granulocyte, adenohypophysis
CHKB-CPT1B	133	broad	yes	granulocyte, apex of heart, heart left ventricle
PEPD	276	ubiquitous	marker	ileal mucosa, adult mammalian kidney, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PEPD	2,471
CHKB	1,154
LMF2	1,034
CHKB-CPT1B	0

Intra-cohort edges

A	B	Sources
CHKB	LMF2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PEPD	P12955	21
CHKB	Q9Y259	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LMF2	Q9BU23	87.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 4 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
Synthesis of PE	1	439.2×	0.007	CHKB
Assembly of active LPL and LIPC lipase complexes	1	300.5×	0.007	LMF2
Plasma lipoprotein remodeling	1	237.9×	0.007	LMF2
Synthesis of PC	1	203.9×	0.007	CHKB
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.010	LMF2
Transport of small molecules	1	12.6×	0.078	LMF2

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
CDP-choline pathway	1	1123.5×	0.006	CHKB
phosphatidylethanolamine biosynthetic process	1	624.1×	0.006	CHKB
amino acid metabolic process	1	267.5×	0.008	PEPD
negative regulation of programmed cell death	1	244.2×	0.008	PEPD
collagen catabolic process	1	130.6×	0.012	PEPD
muscle organ development	1	55.6×	0.021	CHKB
protein maturation	1	54.5×	0.021	LMF2
proteolysis	1	11.4×	0.085	PEPD

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PEPD	CAPTOPRIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PEPD	4	4
CHKB	0	0
LMF2	0	0
CHKB-CPT1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPTOPRIL	4	PEPD
DAUNORUBICIN	4	PEPD
DOXORUBICIN	4	PEPD
GENTAMICIN	4	PEPD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PEPD	31	Binding:31
CHKB	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHKB	2.7.1.32	choline kinase
PEPD	3.4.13.9	Xaa-Pro dipeptidase

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

4 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)
CAPTOPRIL	4	PEPD
DAUNORUBICIN	4	PEPD
DOXORUBICIN	4	PEPD
GENTAMICIN	4	PEPD

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PEPD
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CHKB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LMF2, CHKB-CPT1B

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)
CHKB	11	—
LMF2	0	—
CHKB-CPT1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.