Aortic aneurysm, familial thoracic 4

Summary

Aortic aneurysm, familial thoracic 4 (MONDO:0007568) is a disease caused by MYH11 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: MYH11 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 2,483

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic aneurysm, familial thoracic 4
Mondo ID	MONDO:0007568
MeSH	C537784
OMIM	132900
UMLS	C1851504
MedGen	338704
GARD	0009876
Is cancer (heuristic)	no

Also known as: AAT4 · aortic aneurysm, familial thoracic 4 · aortic aneurysm, familial thoracic type 4 · FAA4 · familial thoracic aortic aneurysm and aortic dissection caused by mutation in MYH11 · MYH11 familial thoracic aortic aneurysm and aortic dissection

Data availability: 2,483 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 › familial thoracic aortic aneurysm and aortic dissection › aortic aneurysm, familial thoracic 4

Related subtypes (8): aortic aneurysm, familial thoracic 2, aortic aneurysm, familial thoracic 6, aortic aneurysm, familial thoracic 7, aortic aneurysm, familial thoracic 8, aortic aneurysm, familial thoracic 9, aortic aneurysm, familial thoracic 10, aortic aneurysm, familial thoracic 1, aortic aneurysm, familial thoracic 12

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

600 retrieved; paginated sample, class counts are floors:

243 likely benign, 202 uncertain significance, 82 conflicting classifications of pathogenicity, 43 benign/likely benign, 13 benign, 9 pathogenic, 8 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14131	NM_022844.2(MYH11):c.[4578+1G>T;5273G>A]		Pathogenic	no assertion criteria provided
1420242	NM_002474.3(MYH11):c.5599C>T (p.Gln1867Ter)	MYH11	Pathogenic	criteria provided, single submitter
1456354	NM_002474.3(MYH11):c.3277C>T (p.Gln1093Ter)	MYH11	Pathogenic	criteria provided, single submitter
1685965	NM_002474.3(MYH11):c.1750-1G>A	MYH11	Pathogenic	criteria provided, single submitter
2008795	NM_002474.3(MYH11):c.2334del (p.Glu779fs)	MYH11	Pathogenic	criteria provided, single submitter
2029392	NM_002474.3(MYH11):c.3297del (p.Asp1100fs)	MYH11	Pathogenic	criteria provided, single submitter
1384395	NM_002474.3(MYH11):c.4116+1del	NDE1	Pathogenic	criteria provided, single submitter
1457720	NC_000016.9:g.(?15802668)(15932109_?)del	NDE1	Pathogenic	criteria provided, single submitter
201075	NM_002474.3(MYH11):c.4401C>G (p.Tyr1467Ter)	NDE1	Pathogenic	criteria provided, single submitter
1334497	NM_002474.3(MYH11):c.2380C>T (p.Gln794Ter)	MYH11	Likely pathogenic	criteria provided, single submitter
1465192	NM_002474.3(MYH11):c.3963+1G>C	MYH11	Likely pathogenic	criteria provided, single submitter
1467492	NM_002474.3(MYH11):c.3858+1G>A	MYH11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1523757	NM_002474.3(MYH11):c.3506+1G>A	MYH11	Likely pathogenic	criteria provided, single submitter
1708058	NM_002474.3(MYH11):c.5295+1G>C	MYH11	Likely pathogenic	criteria provided, single submitter
1923515	NM_002474.3(MYH11):c.2180+1G>A	MYH11	Likely pathogenic	criteria provided, single submitter
1944896	NM_002474.3(MYH11):c.3652-2A>G	MYH11	Likely pathogenic	criteria provided, single submitter
1804129	NM_002474.3(MYH11):c.4578+1del	NDE1	Likely pathogenic	criteria provided, single submitter
1171454	NM_002474.3(MYH11):c.2426G>A (p.Arg809Lys)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172097	NM_002474.3(MYH11):c.2344C>T (p.Arg782Ter)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1175887	NM_002474.3(MYH11):c.3505A>C (p.Arg1169=)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1181922	NM_002474.3(MYH11):c.4072G>T (p.Ala1358Ser)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1318681	NM_002474.3(MYH11):c.2848C>G (p.Gln950Glu)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1329442	NM_002474.3(MYH11):c.2082G>A (p.Leu694=)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1331906	NM_002474.3(MYH11):c.4202T>C (p.Ile1401Thr)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1351585	NM_001040113.2(MYH11):c.644del (p.Ser215fs)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138345	NM_002474.3(MYH11):c.4522A>G (p.Met1508Val)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138346	NM_002474.3(MYH11):c.4578+3A>G	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138349	NM_002474.3(MYH11):c.5160C>T (p.Ser1720=)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138357	NM_002474.3(MYH11):c.5566C>T (p.Leu1856=)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138362	NM_002474.3(MYH11):c.12G>A (p.Lys4=)	MYH11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 7 · 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
MYH11	Definitive	Unknown	familial thoracic aortic aneurysm and aortic dissection	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYH11	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYH11	Orphanet:229	Familial aortic dissection
MYH11	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
MYH11	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
NDE1	Orphanet:2177	Hydranencephaly
NDE1	Orphanet:443162	NDE1-related microhydranencephaly
NDE1	Orphanet:89844	Lissencephaly syndrome, Norman-Roberts type

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
MYH11	HGNC:7569	ENSG00000133392	P35749	Myosin-11	gencc,clinvar
NDE1	HGNC:17619	ENSG00000072864	Q9NXR1	Nuclear distribution protein nudE homolog 1	clinvar
MPV17L	HGNC:26827	ENSG00000156968	Q2QL34	Mpv17-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYH11	Myosin-11	Muscle contraction.
NDE1	Nuclear distribution protein nudE homolog 1	Required for centrosome duplication and formation and function of the mitotic spindle.
MPV17L	Mpv17-like protein	Participates in reactive oxygen species metabolism by up- or down-regulation of the genes of antioxidant enzymes.

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)
MYH11	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
NDE1	Other/Unknown	no		NUDE_dom, NUDE
MPV17L	Other/Unknown	no		Mpv17_PMP22

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
lower esophagus	1
lower esophagus muscularis layer	1
right coronary artery	1
colonic epithelium	1
corpus callosum	1
ventricular zone	1
body of pancreas	1
olfactory segment of nasal mucosa	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYH11	143	broad	marker	right coronary artery, lower esophagus, lower esophagus muscularis layer
NDE1	134	ubiquitous	marker	colonic epithelium, ventricular zone, corpus callosum
MPV17L	137	broad	marker	body of pancreas, olfactory segment of nasal mucosa, skeletal muscle tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH11	3,818
NDE1	1,761
MPV17L	443

Intra-cohort edges

A	B	Sources
MPV17L	NDE1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYH11	P35749	1
NDE1	Q9NXR1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPV17L	Q2QL34	85.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. 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
RHO GTPase Effectors	2	68.0×	0.010	MYH11, NDE1
Signaling by Rho GTPases	2	34.2×	0.013	MYH11, NDE1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	2	33.5×	0.013	MYH11, NDE1
Sema4D in semaphorin signaling	1	335.9×	0.018	MYH11
RHO GTPases activate CIT	1	300.5×	0.018	MYH11
RHO GTPases Activate ROCKs	1	300.5×	0.018	MYH11
Sema4D induced cell migration and growth-cone collapse	1	285.5×	0.018	MYH11
RHO GTPases activate PAKs	1	271.9×	0.018	MYH11
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	271.9×	0.018	MYH11
Semaphorin interactions	1	196.9×	0.021	MYH11
EPHA-mediated growth cone collapse	1	190.3×	0.021	MYH11
RHO GTPases activate PKNs	1	158.6×	0.024	MYH11
Smooth Muscle Contraction	1	132.8×	0.025	MYH11
Centrosome maturation	1	126.9×	0.025	NDE1
Amplification of signal from the kinetochores	1	98.5×	0.028	NDE1
EPH-Ephrin signaling	1	82.8×	0.028	MYH11
Loss of Nlp from mitotic centrosomes	1	79.3×	0.028	NDE1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.028	NDE1
Mitotic Spindle Checkpoint	1	79.3×	0.028	NDE1
AURKA Activation by TPX2	1	76.1×	0.028	NDE1
Signal Transduction	2	10.2×	0.028	MYH11, NDE1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.028	NDE1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.028	NDE1
Mitotic G2-G2/M phases	1	63.4×	0.028	NDE1
G2/M Transition	1	63.4×	0.028	NDE1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.028	NDE1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.028	NDE1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.028	NDE1
Cilium Assembly	1	54.4×	0.028	NDE1
Mitotic Metaphase and Anaphase	1	48.4×	0.030	NDE1

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
chromosome localization	1	2808.7×	0.005	NDE1
skeletal muscle myosin thick filament assembly	1	1872.4×	0.005	MYH11
negative regulation of hydrogen peroxide biosynthetic process	1	1404.3×	0.005	MPV17L
mitotic centrosome separation	1	936.2×	0.006	NDE1
elastic fiber assembly	1	510.7×	0.008	MYH11
negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1	351.1×	0.008	MPV17L
centrosome duplication	1	312.1×	0.008	NDE1
vesicle transport along microtubule	1	295.6×	0.008	NDE1
centrosome localization	1	295.6×	0.008	NDE1
smooth muscle contraction	1	267.5×	0.008	MYH11
microtubule nucleation	1	208.1×	0.008	NDE1
cardiac muscle cell development	1	208.1×	0.008	MYH11
actomyosin structure organization	1	187.2×	0.009	MYH11
establishment of mitotic spindle orientation	1	160.5×	0.009	NDE1
reactive oxygen species metabolic process	1	156.0×	0.009	MPV17L
neuroblast proliferation	1	122.1×	0.011	NDE1
cerebral cortex development	1	68.5×	0.018	NDE1
chromosome segregation	1	57.9×	0.020	NDE1
neuron migration	1	44.6×	0.025	NDE1
cell migration	1	20.5×	0.050	NDE1
cell division	1	15.4×	0.064	NDE1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
MYH11	0	0
NDE1	0	0
MPV17L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	3	MYH11, NDE1, MPV17L

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)
MYH11	0	—
NDE1	0	—
MPV17L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.