Linear skin defects with multiple congenital anomalies

Summary

Linear skin defects with multiple congenital anomalies (MONDO:0010672) is a disease with 3 cohort genes. The dominant Reactome pathway is Respiratory electron transport (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• Phenotypes (HPO): 77

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		55	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

77 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000528	Anophthalmia	Very frequent (80-99%)
HP:0000568	Microphthalmia	Very frequent (80-99%)
HP:0000647	Sclerocornea	Very frequent (80-99%)
HP:0000776	Congenital diaphragmatic hernia	Very frequent (80-99%)
HP:0000953	Hyperpigmentation of the skin	Very frequent (80-99%)
HP:0001000	Abnormality of skin pigmentation	Very frequent (80-99%)
HP:0004334	Dermal atrophy	Very frequent (80-99%)
HP:0007957	Corneal opacity	Very frequent (80-99%)
HP:0008065	Aplasia/Hypoplasia of the skin	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000445	Wide nose	Frequent (30-79%)
HP:0000492	Abnormal eyelid morphology	Frequent (30-79%)
HP:0000499	Abnormal eyelash morphology	Frequent (30-79%)
HP:0000598	Abnormality of the ear	Frequent (30-79%)
HP:0000614	Abnormal nasolacrimal system morphology	Frequent (30-79%)
HP:0001053	Hypopigmented skin patches	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001644	Dilated cardiomyopathy	Frequent (30-79%)
HP:0001671	Abnormal cardiac septum morphology	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0003510	Severe short stature	Frequent (30-79%)
HP:0004327	Abnormal vitreous humor morphology	Frequent (30-79%)
HP:0007703	Abnormality of retinal pigmentation	Frequent (30-79%)
HP:0009939	Mandibular aplasia	Frequent (30-79%)
HP:0011531	Vitritis	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0000035	Abnormal testis morphology	Occasional (5-29%)
HP:0000036	Abnormality of the penis	Occasional (5-29%)
HP:0000037	Male pseudohermaphroditism	Occasional (5-29%)
HP:0000039	Epispadias	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000062	Ambiguous genitalia	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000363	Abnormality of earlobe	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000556	Retinal dystrophy	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000627	Posterior embryotoxon	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0000682	Abnormality of dental enamel	Occasional (5-29%)
HP:0000960	Sacral dimple	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	linear skin defects with multiple congenital anomalies
Mondo ID	MONDO:0010672
MeSH	C537466
OMIM	309801
Orphanet	2556
DOID	DOID:0111875
SNOMED CT	721879006
GARD	0003659
Is cancer (heuristic)	no

Also known as: linear skin defects with multiple congenital anomalies · linear skin defects with multiple congenital anomalies 1 · linear skin defects with multiple congenital anomalies type 1 · LSDMCA1 · MCOPS7 · microphthalmia dermal aplasia and sclerocornea syndrome · microphthalmia with linear skin defects syndrome · microphthalmia-dermal aplasia-sclerocornea syndrome · Micropthalmia syndromic 7 · MIDAS syndrome · MLS syndrome · syndromic microphthalmia type 7

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic microphthalmia › linear skin defects with multiple congenital anomalies

Related subtypes (18): anophthalmia/microphthalmia-esophageal atresia syndrome, COFS syndrome, microphthalmia, syndromic 2, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, microphthalmia, syndromic 1, Matthew-Wood syndrome, MMEP syndrome, microphthalmia with brain and digit anomalies, syndromic microphthalmia type 5, microphthalmia-brain atrophy syndrome, oculoauricular syndrome, microphthalmia, syndromic 11, microphthalmia, syndromic 12, colobomatous microphthalmia-rhizomelic dysplasia syndrome, microphthalmia, Lenz type, Behrens Baumann dust syndrome, microphthalmia microtia fetal akinesia, RAB18 deficiency

Subtypes (3): linear skin defects with multiple congenital anomalies 2, linear skin defects with multiple congenital anomalies 3, linear skin defects with multiple congenital anomalies 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
COX7B	Definitive	X-linked	linear skin defects with multiple congenital anomalies 2	3
HCCS	Strong	X-linked	linear skin defects with multiple congenital anomalies 1	4
NDUFB11	Strong	X-linked	linear skin defects with multiple congenital anomalies 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDUFB11	Orphanet:2556	Microphthalmia with linear skin defects syndrome
NDUFB11	Orphanet:2609	Isolated complex I deficiency
COX7B	Orphanet:2556	Microphthalmia with linear skin defects syndrome
HCCS	Orphanet:2556	Microphthalmia with linear skin defects 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
NDUFB11	HGNC:20372	ENSG00000147123	Q9NX14	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial	gencc
COX7B	HGNC:2291	ENSG00000131174	P24311	Cytochrome c oxidase subunit 7B, mitochondrial	gencc
HCCS	HGNC:4837	ENSG00000004961	P53701	Holocytochrome c-type synthase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDUFB11	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
COX7B	Cytochrome c oxidase subunit 7B, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
HCCS	Holocytochrome c-type synthase	Lyase that catalyzes the covalent linking of the heme group to the cytochrome C apoprotein to produce the mature functional cytochrome.

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)
NDUFB11	Other/Unknown	no		NADH_UbQ_OxRdtase_ESSS_su
COX7B	Other/Unknown	no		Cyt_c_oxidase_suVIIB, Cyt_c_oxidase_suVIIB_dom_sf
HCCS	Enzyme (other)	yes	4.4.1.17	Holocyt_c/c1_synthase

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
apex of heart	2
gastrocnemius	2
biceps brachii	2
hindlimb stylopod muscle	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDUFB11	287	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius
COX7B	295	ubiquitous	marker	heart right ventricle, apex of heart, biceps brachii
HCCS	285	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HCCS	2,239
NDUFB11	1,844
COX7B	1,135

Intra-cohort edges

A	B	Sources
COX7B	HCCS	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFB11	Q9NX14	7
COX7B	P24311	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HCCS	P53701	78.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Respiratory electron transport	3	95.2×	8e-06	NDUFB11, COX7B, HCCS
Aerobic respiration and respiratory electron transport	2	59.0×	0.001	NDUFB11, HCCS
Complex IV assembly	1	76.1×	0.023	COX7B
Cytoprotection by HMOX1	1	61.4×	0.023	COX7B
Complex I biogenesis	1	55.2×	0.023	NDUFB11
TP53 Regulates Metabolic Genes	1	43.3×	0.023	COX7B
Metabolism	2	7.7×	0.023	NDUFB11, HCCS

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
cytochrome c-heme linkage	1	5617.3×	0.001	HCCS
respiratory electron transport chain	1	280.9×	0.010	HCCS
mitochondrial electron transport, cytochrome c to oxygen	1	255.3×	0.010	COX7B
cellular respiration	1	144.0×	0.014	COX7B
proton motive force-driven mitochondrial ATP synthesis	1	87.8×	0.016	NDUFB11
aerobic respiration	1	82.6×	0.016	NDUFB11
animal organ morphogenesis	1	63.8×	0.018	HCCS
central nervous system development	1	38.5×	0.026	COX7B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NDUFB11	0	0
COX7B	0	0
HCCS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NDUFB11	4	Binding:4
HCCS	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HCCS	4.4.1.17	Holocytochrome-c 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	0
D	Druggable family + AlphaFold only, no drug	1	HCCS
E	Difficult family or no structure, no drug	2	NDUFB11, COX7B

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)
NDUFB11	4	—
COX7B	0	—
HCCS	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.