Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome

Summary

Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome (MONDO:0014976) is a disease caused by MIPEP (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MIPEP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 47

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome
Mondo ID	MONDO:0014976
OMIM	617228
Orphanet	478049
DOID	DOID:0111488
UMLS	C4310661
MedGen	934628
GARD	0017865
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 31 · combined oxidative phosphorylation deficiency caused by mutation in MIPEP · combined oxidative phosphorylation deficiency type 31 · COXPD31 · MIPEP combined oxidative phosphorylation deficiency

Data availability: 47 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › combined oxidative phosphorylation deficiency › lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

47 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 11 conflicting classifications of pathogenicity, 9 likely pathogenic, 5 pathogenic, 2 benign, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4076411	Single allele		Pathogenic	criteria provided, single submitter
584431	NM_005932.4(MIPEP):c.787-51_993-181del	LOC130009386	Pathogenic	criteria provided, single submitter
208631	NM_005932.4(MIPEP):c.1804G>T (p.Glu602Ter)	MIPEP	Pathogenic	criteria provided, single submitter
3902481	NM_005932.4(MIPEP):c.1954C>T (p.Gln652Ter)	MIPEP	Pathogenic	criteria provided, single submitter
840481	NM_005932.4(MIPEP):c.1970+2T>A	MIPEP	Pathogenic	criteria provided, single submitter
930107	NM_005932.4(MIPEP):c.541C>T (p.Arg181Ter)	MIPEP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
584455	Single allele	LOC130009384	Likely pathogenic	criteria provided, single submitter
1210219	NM_005932.4(MIPEP):c.1259T>C (p.Leu420Pro)	MIPEP	Likely pathogenic	criteria provided, single submitter
1806091	NM_005932.4(MIPEP):c.890G>C (p.Gly297Ala)	MIPEP	Likely pathogenic	criteria provided, single submitter
2504023	NM_005932.4(MIPEP):c.1848+2T>G	MIPEP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3234957	NM_005932.4(MIPEP):c.1854G>A (p.Trp618Ter)	MIPEP	Likely pathogenic	criteria provided, single submitter
3351825	NM_005932.4(MIPEP):c.1318C>T (p.Arg440Ter)	MIPEP	Likely pathogenic	criteria provided, single submitter
3779851	NM_005932.4(MIPEP):c.790C>T (p.Arg264Ter)	MIPEP	Likely pathogenic	criteria provided, single submitter
584454	NM_005932.4(MIPEP):c.358G>A (p.Asp120Asn)	MIPEP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
986338	NM_005932.4(MIPEP):c.786+1G>C	MIPEP	Likely pathogenic	criteria provided, single submitter
1030040	NM_005932.4(MIPEP):c.40G>A (p.Ala14Thr)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033047	NM_005932.4(MIPEP):c.1354A>C (p.Ile452Leu)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1420118	NM_005932.4(MIPEP):c.2092G>A (p.Val698Ile)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208630	NM_005932.4(MIPEP):c.916C>T (p.Leu306Phe)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208632	NM_005932.4(MIPEP):c.1027A>G (p.Lys343Glu)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208633	NM_005932.4(MIPEP):c.1534C>G (p.His512Asp)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2183775	NM_005932.4(MIPEP):c.1826del (p.Gly609fs)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2223623	NM_005932.4(MIPEP):c.1728+5G>T	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3359977	NM_005932.4(MIPEP):c.1756_1771del (p.Tyr586fs)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
505364	NM_005932.4(MIPEP):c.590T>C (p.Leu197Pro)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
634482	NM_005932.4(MIPEP):c.1670T>C (p.Met557Thr)	MIPEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030037	NM_005932.4(MIPEP):c.1088G>T (p.Gly363Val)	MIPEP	Uncertain significance	criteria provided, single submitter
1030038	NM_005932.4(MIPEP):c.1090G>A (p.Val364Met)	MIPEP	Uncertain significance	criteria provided, single submitter
1030039	NM_005932.4(MIPEP):c.1708G>A (p.Ala570Thr)	MIPEP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033046	NM_005932.4(MIPEP):c.1008T>G (p.Phe336Leu)	MIPEP	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
MIPEP	Strong	Autosomal recessive	lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MIPEP	Orphanet:478049	Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MIPEP	HGNC:7104	ENSG00000027001	Q99797	Mitochondrial intermediate peptidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MIPEP	Mitochondrial intermediate peptidase	Cleaves proteins, imported into the mitochondrion, to their mature size.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MIPEP	Other/Unknown	no		Pept_M3A_M3B_dom, Neurolysin/TOP_dom2, MetalloPept_cat_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MIPEP	248	ubiquitous	marker	right atrium auricular region, apex of heart, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MIPEP	2,016

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MIPEP	Q99797	90.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete protein processing involved in protein targeting to mitochondrion	1	2106.5×	0.001	MIPEP
peptide metabolic process	1	1203.7×	0.001	MIPEP
protein processing	1	170.2×	0.006	MIPEP

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
MIPEP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MIPEP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MIPEP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.