Fetal akinesia deformation sequence 3

Summary

Fetal akinesia deformation sequence 3 (MONDO:0100103) is a disease caused by DOK7 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: DOK7 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 97

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	fetal akinesia deformation sequence 3
Mondo ID	MONDO:0100103
OMIM	618389
DOID	DOID:0111376
UMLS	C4760599
MedGen	1680087
GARD	0016496
Is cancer (heuristic)	no

Also known as: FADS3

Data availability: 97 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › fetal akinesia deformation sequence › fetal akinesia deformation sequence 3

Related subtypes (4): fetal akinesia syndrome, X-linked, fetal akinesia deformation sequence 1, fetal akinesia deformation sequence 2, fetal akinesia deformation sequence 4

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

97 retrieved; paginated sample, class counts are floors:

38 likely pathogenic, 19 pathogenic/likely pathogenic, 14 pathogenic, 11 uncertain significance, 10 conflicting classifications of pathogenicity, 4 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074328	NM_173660.5(DOK7):c.1267C>T (p.Gln423Ter)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1273	NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
1274	NM_173660.5(DOK7):c.1263dup (p.Ser422fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1276	NM_173660.5(DOK7):c.1339_1342dup (p.Gly448fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
1277	NM_173660.5(DOK7):c.1143dup (p.Glu382fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1279	NM_173660.5(DOK7):c.601C>T (p.Arg201Ter)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
1282	NM_173660.5(DOK7):c.1378dup (p.Gln460fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454703	NM_173660.5(DOK7):c.1323del (p.Cys442fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804863	NM_173660.5(DOK7):c.451C>T (p.Gln151Ter)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2059967	NM_173660.5(DOK7):c.1324_1357del (p.Cys442fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
209149	NM_173660.5(DOK7):c.1138dup (p.Ala380fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
210856	NM_173660.5(DOK7):c.596del (p.Ile199fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203504	NM_173660.5(DOK7):c.1001_1011dup (p.Ser338fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242521	NM_173660.5(DOK7):c.1263del (p.Ser422fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674876	NM_173660.5(DOK7):c.1247_1250dup (p.Asp417fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674883	NM_173660.5(DOK7):c.1339_1342del (p.Leu447fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674884	NM_173660.5(DOK7):c.1378del (p.Gln460fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
2674891	NM_173660.5(DOK7):c.1243_1340del (p.Pro415fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674892	NM_173660.5(DOK7):c.1138del (p.Ala380fs)	DOK7	Pathogenic	criteria provided, single submitter
2925372	NM_173660.5(DOK7):c.1236C>A (p.Cys412Ter)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
2925373	NM_173660.5(DOK7):c.1378C>T (p.Gln460Ter)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
3241354	NM_173660.5(DOK7):c.773-2A>G	DOK7	Pathogenic	criteria provided, single submitter
429791	NM_173660.5(DOK7):c.513C>T (p.Gly171=)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449547	NM_173660.5(DOK7):c.331+1G>T	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
465693	NM_173660.5(DOK7):c.957dup (p.Lys320fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560990	NM_173660.5(DOK7):c.437C>T (p.Pro146Leu)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560992	NM_173660.5(DOK7):c.514G>A (p.Gly172Arg)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
654355	NM_173660.5(DOK7):c.28del (p.Gln10fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802049	NM_173660.5(DOK7):c.1143del (p.Glu382fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
813360	NM_173660.5(DOK7):c.1296_1311del (p.Asp433fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts

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
DOK7	Strong	Autosomal recessive	fetal akinesia deformation sequence 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DOK7	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
DOK7	Orphanet:994	Fetal akinesia deformation sequence
DOCK7	Orphanet:411986	Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism syndrome

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
DOK7	HGNC:26594	ENSG00000175920	Q18PE1	Protein Dok-7	gencc,clinvar
DOCK7	HGNC:19190	ENSG00000116641	Q96N67	Dedicator of cytokinesis protein 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DOK7	Protein Dok-7	Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis.
DOCK7	Dedicator of cytokinesis protein 7	Functions as a guanine nucleotide exchange factor (GEF), which activates Rac1 and Rac3 Rho small GTPases by exchanging bound GDP for free GTP.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DOK7	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf
DOCK7	Other/Unknown	no		DOCK_C/D_N, DOCK, C2_DOCK-type_domain

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
right atrium auricular region	1
tibialis anterior	1
calcaneal tendon	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DOK7	180	broad	yes	apex of heart, tibialis anterior, right atrium auricular region
DOCK7	260	ubiquitous	marker	ventricular zone, calcaneal tendon, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DOCK7	1,934
DOK7	704

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DOCK7	Q96N67	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DOK7	Q18PE1	65.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET activates RAP1 and RAC1	1	1038.2×	0.004	DOCK7
CDC42 GTPase cycle	1	72.3×	0.016	DOCK7
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.016	DOCK7
RAC1 GTPase cycle	1	61.1×	0.016	DOCK7

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
Rac protein signal transduction	2	561.7×	5e-05	DOK7, DOCK7
establishment of neuroblast polarity	1	2106.5×	0.003	DOCK7
interkinetic nuclear migration	1	1685.2×	0.003	DOCK7
positive regulation of protein tyrosine kinase activity	1	1053.2×	0.004	DOK7
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.004	DOK7
enzyme-linked receptor protein signaling pathway	1	648.1×	0.004	DOK7
positive regulation of vascular associated smooth muscle cell migration	1	495.6×	0.005	DOCK7
neurotransmitter receptor localization to postsynaptic specialization membrane	1	401.2×	0.005	DOK7
positive regulation of Rac protein signal transduction	1	324.1×	0.005	DOK7
receptor clustering	1	312.1×	0.005	DOK7
neuromuscular junction development	1	263.3×	0.006	DOK7
regulation of Rho protein signal transduction	1	255.3×	0.006	DOCK7
regulation of neurogenesis	1	200.6×	0.007	DOCK7
negative regulation of cold-induced thermogenesis	1	172.0×	0.007	DOCK7
axonogenesis	1	80.2×	0.014	DOCK7
neuron projection development	1	61.1×	0.016	DOCK7
microtubule cytoskeleton organization	1	60.6×	0.016	DOCK7

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
DOK7	0	0
DOCK7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	2	DOK7, DOCK7

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)
DOK7	0	—
DOCK7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.