Aortic aneurysm, familial thoracic 7

Summary

Aortic aneurysm, familial thoracic 7 (MONDO:0013418) is a disease caused by MYLK (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: MYLK (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 2,122

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic aneurysm, familial thoracic 7
Mondo ID	MONDO:0013418
OMIM	613780
UMLS	C3151077
MedGen	462427
GARD	0015706
Is cancer (heuristic)	no

Also known as: AAT7 · aortic aneurysm, familial thoracic 7 · aortic aneurysm, familial thoracic type 7

Data availability: 2,122 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 7

Related subtypes (8): aortic aneurysm, familial thoracic 4, aortic aneurysm, familial thoracic 2, aortic aneurysm, familial thoracic 6, 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:

309 uncertain significance, 228 likely benign, 31 conflicting classifications of pathogenicity, 11 pathogenic, 9 benign, 9 benign/likely benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069085	NM_053025.4(MYLK):c.4114del (p.Asp1372fs)	MYLK	Pathogenic	criteria provided, single submitter
1356169	NM_053025.4(MYLK):c.4470G>A (p.Trp1490Ter)	MYLK	Pathogenic	criteria provided, single submitter
1391929	NM_053025.4(MYLK):c.4422del (p.Lys1474fs)	MYLK	Pathogenic	criteria provided, single submitter
1415008	NM_053025.4(MYLK):c.3751_3752del (p.Ala1251fs)	MYLK	Pathogenic	criteria provided, single submitter
1451428	NM_053025.4(MYLK):c.3231C>A (p.Cys1077Ter)	MYLK	Pathogenic	criteria provided, single submitter
1454045	NM_053025.4(MYLK):c.4093_4094del (p.Ser1365fs)	MYLK	Pathogenic	criteria provided, single submitter
1457767	NC_000003.11:g.(?123332952)(123386054_?)del	MYLK	Pathogenic	criteria provided, single submitter
2015715	NM_053025.4(MYLK):c.2965A>T (p.Lys989Ter)	MYLK	Pathogenic	criteria provided, single submitter
2024190	NM_053025.4(MYLK):c.3876_3937del (p.Ser1293fs)	MYLK	Pathogenic	criteria provided, single submitter
2199590	NM_053025.4(MYLK):c.2814_2815del (p.Val938_Ser939insTer)	MYLK	Pathogenic	criteria provided, single submitter
1367346	NM_053025.4(MYLK):c.5169del (p.Lys1724fs)	MYLK-AS1	Pathogenic	criteria provided, single submitter
1067883	NM_053025.4(MYLK):c.4962-1G>T	LOC126806791	Likely pathogenic	criteria provided, single submitter
1525501	NM_053025.4(MYLK):c.4962-2A>G	LOC126806791	Likely pathogenic	criteria provided, single submitter
1466109	NM_053025.4(MYLK):c.4620-2A>G	MYLK	Likely pathogenic	criteria provided, single submitter
1013863	NM_053025.4(MYLK):c.992C>A (p.Thr331Lys)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017645	NM_053025.4(MYLK):c.2996G>T (p.Ser999Ile)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1098773	NM_053025.4(MYLK):c.3209A>G (p.Asp1070Gly)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1210975	NM_053025.4(MYLK):c.616C>T (p.Arg206Cys)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315894	NM_053025.4(MYLK):c.26C>T (p.Ser9Leu)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1318562	NM_053025.4(MYLK):c.376A>G (p.Ser126Gly)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1320358	NM_053025.4(MYLK):c.3393dup (p.Thr1132fs)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1329327	NM_053025.4(MYLK):c.1525G>A (p.Val509Met)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1329332	NM_053025.4(MYLK):c.773+10G>A	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1335540	NM_053025.4(MYLK):c.2608C>T (p.Arg870Ter)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1385264	NM_053025.4(MYLK):c.908G>T (p.Gly303Val)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1519381	NM_053025.4(MYLK):c.4455A>C (p.Lys1485Asn)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
155819	NM_053025.4(MYLK):c.2596G>A (p.Gly866Ser)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1601927	NM_053025.4(MYLK):c.2409C>T (p.Cys803=)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1690978	NM_053025.4(MYLK):c.472del (p.Glu158fs)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1741962	NM_053025.4(MYLK):c.4620C>T (p.Ile1540=)	MYLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
MYLK	Strong	Unknown	familial thoracic aortic aneurysm and aortic dissection	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYLK	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYLK	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
ZNF148	Orphanet:708178	Global developmental delay-speech apraxia-facial dysmorphism-limb and palpebral anomalies syndrome

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
MYLK	HGNC:7590	ENSG00000065534	Q15746	Myosin light chain kinase, smooth muscle	gencc,clinvar
ZNF148	HGNC:12933	ENSG00000163848	Q9UQR1	Zinc finger protein 148	clinvar
MYLK-AS1	HGNC:42440	ENSG00000239523		MYLK antisense RNA 1	clinvar
HACD2	HGNC:9640	ENSG00000206527	Q6Y1H2	Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYLK	Myosin light chain kinase, smooth muscle	Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC).
ZNF148	Zinc finger protein 148	Involved in transcriptional regulation.
HACD2	Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 2	Catalyzes the third of the very long-chain fatty acids (VLCFA) elongation four-step cycle (condensation, reduction, dehydration, and reduction).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Kinase	1	6.9×	0.410
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYLK	Kinase	yes	2.7.11.18	Prot_kinase_dom, Ig_sub2, Ig_sub
ZNF148	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, C2H2-ZF_domain
MYLK-AS1	Other/Unknown	no
HACD2	Other/Unknown	no		Tyr_Pase-like_PTPLA

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
saphenous vein	2
cauda epididymis	1
seminal vesicle	1
caput epididymis	1
corpus epididymis	1
esophagogastric junction muscularis propria	1
lower esophagus	1
lower esophagus muscularis layer	1
gingiva	1
gingival epithelium	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYLK	289	ubiquitous	marker	cauda epididymis, saphenous vein, seminal vesicle
ZNF148	294	ubiquitous	marker	caput epididymis, corpus epididymis, saphenous vein
MYLK-AS1	168	ubiquitous	yes	esophagogastric junction muscularis propria, lower esophagus muscularis layer, lower esophagus
HACD2	290	ubiquitous	marker	gingival epithelium, gingiva, lateral globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYLK	2,763
ZNF148	1,819
HACD2	1,734
MYLK-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYLK	Q15746	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HACD2	Q6Y1H2	79.37
ZNF148	Q9UQR1	47.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
RHO GTPases activate PAKs	1	271.9×	0.017	MYLK
Synthesis of very long-chain fatty acyl-CoAs	1	228.4×	0.017	HACD2
Smooth Muscle Contraction	1	132.8×	0.020	MYLK
Muscle contraction	1	38.6×	0.047	MYLK
RHO GTPase Effectors	1	34.0×	0.047	MYLK
Signaling by Rho GTPases	1	17.1×	0.067	MYLK
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.067	MYLK
Signal Transduction	1	5.1×	0.187	MYLK

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
tonic smooth muscle contraction	1	5617.3×	0.004	MYLK
aorta smooth muscle tissue morphogenesis	1	1404.3×	0.008	MYLK
fatty acid elongation	1	802.5×	0.008	HACD2
bleb assembly	1	510.7×	0.008	MYLK
cellular hypotonic response	1	468.1×	0.008	MYLK
very long-chain fatty acid biosynthetic process	1	432.1×	0.008	HACD2
gamete generation	1	295.6×	0.008	ZNF148
regulation of synaptic vesicle endocytosis	1	295.6×	0.008	MYLK
long-chain fatty-acyl-CoA biosynthetic process	1	280.9×	0.008	HACD2
smooth muscle contraction	1	267.5×	0.008	MYLK
positive regulation of calcium ion transport	1	193.7×	0.010	MYLK
positive regulation of wound healing	1	175.5×	0.010	MYLK
substantia nigra development	1	122.1×	0.013	ZNF148
sphingolipid biosynthetic process	1	119.5×	0.013	HACD2
cellular defense response	1	106.0×	0.014	ZNF148
negative regulation of gene expression	1	23.0×	0.056	ZNF148
protein phosphorylation	1	22.6×	0.056	MYLK
positive regulation of cell migration	1	20.6×	0.058	MYLK
negative regulation of DNA-templated transcription	1	10.5×	0.107	ZNF148
negative regulation of transcription by RNA polymerase II	1	5.9×	0.176	ZNF148
positive regulation of transcription by RNA polymerase II	1	5.0×	0.197	ZNF148
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ZNF148

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
MYLK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYLK	28	4
ZNF148	0	0
MYLK-AS1	0	0
HACD2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
NINTEDANIB	4	MYLK
SUNITINIB	4	MYLK
DASATINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
FASUDIL	3	MYLK
DOVITINIB	3	MYLK
LESTAURTINIB	3	MYLK
RUBOXISTAURIN	3	MYLK
VX-702	2	MYLK
SU-014813	2	MYLK
REBASTINIB	2	MYLK
TANZISERTIB	2	MYLK
CEP-32496	2	MYLK
BAFETINIB	2	MYLK
PEXMETINIB	2	MYLK
R-406	2	MYLK
BI-2536	2	MYLK
KW-2449	1	MYLK
IMD-0354	1	MYLK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MYLK	303	Binding:303
HACD2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MYLK	2.7.11.18	myosin-light-chain kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MYLK	303

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

28 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)
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
NINTEDANIB	4	MYLK
SUNITINIB	4	MYLK
DASATINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
FASUDIL	3	MYLK
DOVITINIB	3	MYLK
LESTAURTINIB	3	MYLK
RUBOXISTAURIN	3	MYLK
VX-702	2	MYLK
SU-014813	2	MYLK
REBASTINIB	2	MYLK
TANZISERTIB	2	MYLK
CEP-32496	2	MYLK
BAFETINIB	2	MYLK
PEXMETINIB	2	MYLK
R-406	2	MYLK
BI-2536	2	MYLK
KW-2449	1	MYLK
IMD-0354	1	MYLK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MYLK
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	ZNF148, MYLK-AS1, HACD2

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)
ZNF148	0	—
MYLK-AS1	0	—
HACD2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.