Linear skin defects with multiple congenital anomalies 1

Summary

Linear skin defects with multiple congenital anomalies 1 (MONDO:0024552) is a disease caused by HCCS (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: HCCS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	linear skin defects with multiple congenital anomalies 1
Mondo ID	MONDO:0024552
OMIM	309801
DOID	DOID:0111808
UMLS	C0796070
MedGen	163210
GARD	0025427
Is cancer (heuristic)	no

Also known as: HCCS microphthalmia with linear skin defects syndrome · linear skin defects with multiple congenital anomalies 1 · linear skin defects with multiple congenital anomalies 1, X-linked dominant · LSDMCA1 · microphthalmia with linear skin defects syndrome caused by mutation in HCCS

Data availability: 22 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic microphthalmia › linear skin defects with multiple congenital anomalies › linear skin defects with multiple congenital anomalies 1

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

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

22 retrieved; paginated sample, class counts are floors:

8 likely pathogenic, 7 uncertain significance, 3 pathogenic, 2 not provided, 1 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11670	NM_005333.5(HCCS):c.589C>T (p.Arg197Ter)	HCCS	Pathogenic	no assertion criteria provided
11669	NC_000023.11:g.11106247_11114917del	LOC130067938	Pathogenic	no assertion criteria provided
190302	NM_001135998.3(NDUFB11):c.262C>T (p.Arg88Ter)	NDUFB11	Pathogenic	criteria provided, multiple submitters, no conflicts
11671	NM_005333.5(HCCS):c.649C>T (p.Arg217Cys)	HCCS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064959	NM_005333.5(HCCS):c.2T>C (p.Met1Thr)	HCCS	Likely pathogenic	criteria provided, single submitter
3390915	NM_005333.5(HCCS):c.404G>A (p.Trp135Ter)	HCCS	Likely pathogenic	criteria provided, single submitter
3390916	NM_005333.5(HCCS):c.603G>A (p.Trp201Ter)	HCCS	Likely pathogenic	criteria provided, single submitter
3390917	NM_005333.5(HCCS):c.650G>A (p.Arg217His)	HCCS	Likely pathogenic	criteria provided, single submitter
3390918	NM_005333.5(HCCS):c.715C>T (p.Gln239Ter)	HCCS	Likely pathogenic	criteria provided, single submitter
4291739	NM_005333.5(HCCS):c.163del (p.Ala55fs)	HCCS	Likely pathogenic	criteria provided, single submitter
987889	NM_005333.5(HCCS):c.308_309insAGT (p.Val103dup)	HCCS	Likely pathogenic	criteria provided, single submitter
1320309	NM_005333.5(HCCS):c.736C>T (p.Arg246Cys)	HCCS	Uncertain significance	criteria provided, single submitter
1710275	NM_005333.5(HCCS):c.253-3T>G	HCCS	Uncertain significance	no assertion criteria provided
2573195	NM_005333.5(HCCS):c.608+5G>C	HCCS	Uncertain significance	criteria provided, single submitter
2689196	NM_005333.5(HCCS):c.520G>T (p.Ala174Ser)	HCCS	Uncertain significance	criteria provided, single submitter
4277695	NM_005333.5(HCCS):c.692G>T (p.Gly231Val)	HCCS	Uncertain significance	criteria provided, single submitter
522980	NM_005333.5(HCCS):c.199C>A (p.Pro67Thr)	HCCS	Uncertain significance	criteria provided, single submitter
638355	NM_001135998.3(NDUFB11):c.359G>A (p.Arg120His)	NDUFB11	Uncertain significance	criteria provided, multiple submitters, no conflicts
4086068	NM_005333.5(HCCS):c.252+8A>G	HCCS	Likely benign	criteria provided, single submitter
767117	NM_005333.5(HCCS):c.697G>A (p.Glu233Lys)	HCCS	Benign	criteria provided, multiple submitters, no conflicts
21444	NM_005333.5(HCCS):c.475G>A (p.Glu159Lys)	HCCS	not provided	no classification provided
2581140	NM_005333.5(HCCS):c.334G>A (p.Ala112Thr)	HCCS	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
HCCS	Strong	X-linked	linear skin defects with multiple congenital anomalies 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HCCS	Orphanet:2556	Microphthalmia with linear skin defects syndrome
NDUFB11	Orphanet:2556	Microphthalmia with linear skin defects syndrome
NDUFB11	Orphanet:2609	Isolated complex I deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HCCS	HGNC:4837	ENSG00000004961	P53701	Holocytochrome c-type synthase	gencc,clinvar
NDUFB11	HGNC:20372	ENSG00000147123	Q9NX14	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HCCS	Enzyme (other)	yes	4.4.1.17	Holocyt_c/c1_synthase
NDUFB11	Other/Unknown	no		NADH_UbQ_OxRdtase_ESSS_su

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
apex of heart	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HCCS	2,239
NDUFB11	1,844

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFB11	Q9NX14	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HCCS	P53701	78.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Respiratory electron transport	2	95.2×	3e-04	HCCS, NDUFB11
Aerobic respiration and respiratory electron transport	2	88.5×	3e-04	HCCS, NDUFB11
Metabolism	2	11.6×	0.010	HCCS, NDUFB11
Complex I biogenesis	1	82.8×	0.012	NDUFB11

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytochrome c-heme linkage	1	8426.0×	6e-04	HCCS
respiratory electron transport chain	1	421.3×	0.006	HCCS
proton motive force-driven mitochondrial ATP synthesis	1	131.7×	0.010	NDUFB11
aerobic respiration	1	123.9×	0.010	NDUFB11
animal organ morphogenesis	1	95.8×	0.010	HCCS

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HCCS	0	0
NDUFB11	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: 2; 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	1	NDUFB11

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)
HCCS	1	—
NDUFB11	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.