Fetal akinesia-cerebral and retinal hemorrhage syndrome

Summary

Fetal akinesia-cerebral and retinal hemorrhage syndrome (MONDO:0014149) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	fetal akinesia-cerebral and retinal hemorrhage syndrome
Mondo ID	MONDO:0014149
OMIM	615368
Orphanet	363409
DOID	DOID:0061261
SNOMED CT	763346009
UMLS	C4706410
MedGen	1631944
GARD	0017553
Is cancer (heuristic)	no

Also known as: LCCS5 · lethal congenital contracture syndrome 5 · lethal congenital contracture syndrome type 5

Data availability: 11 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › lethal congenital contracture syndrome › fetal akinesia-cerebral and retinal hemorrhage syndrome

Related subtypes (11): lethal congenital contracture syndrome 1, lethal congenital contracture syndrome 2, lethal congenital contracture syndrome 3, lethal congenital contracture syndrome 4, lethal congenital contracture syndrome 6, lethal congenital contracture syndrome 7, lethal congenital contracture syndrome 8, lethal congenital contracture syndrome 9, NEK9-related lethal skeletal dysplasia, lethal congenital contracture syndrome 11, lethal congenital contracture syndrome 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

11 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 2 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
7285	NM_001005361.3(DNM2):c.1856C>T (p.Ser619Leu)	DNM2	Pathogenic	reviewed by expert panel
327987	NM_001005361.3(DNM2):c.2179C>T (p.His727Tyr)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60688	NM_001005361.3(DNM2):c.1135T>G (p.Phe379Val)	DNM2	Conflicting classifications of pathogenicity	no assertion criteria provided
3583400	NM_001005361.3(DNM2):c.1799T>C (p.Leu600Pro)	DNM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
465285	NM_001005361.3(DNM2):c.2356G>T (p.Gly786Cys)	DNM2	Uncertain significance	criteria provided, single submitter
562194	NM_001005361.3(DNM2):c.197G>A (p.Arg66Gln)	DNM2	Uncertain significance	criteria provided, single submitter
656321	NM_001005361.3(DNM2):c.695T>C (p.Ile232Thr)	DNM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
812030	NM_001005361.3(DNM2):c.471G>T (p.Lys157Asn)	DNM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
158527	NM_001005361.3(DNM2):c.2543+7C>G	DNM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
238207	NM_001005361.3(DNM2):c.2160C>T (p.Asp720=)	DNM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
256866	NM_001005361.3(DNM2):c.236-29C>G	DNM2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
DNM2	Supportive	Autosomal recessive	fetal akinesia-cerebral and retinal hemorrhage syndrome	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNM2	Orphanet:100044	Autosomal dominant intermediate Charcot-Marie-Tooth disease type B
DNM2	Orphanet:169189	Autosomal dominant centronuclear myopathy
DNM2	Orphanet:228179	Autosomal dominant Charcot-Marie-Tooth disease type 2M
DNM2	Orphanet:363409	Fetal akinesia-cerebral and retinal hemorrhage syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNM2	HGNC:2974	ENSG00000079805	P50570	Dynamin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNM2	Dynamin-2	Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission at plasma membrane during endocytosis and filament remodeling at many actin structures during organization of the actin cytoskeleton.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNM2	Scaffold/PPI	no	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, PH_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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
metanephros cortex	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNM2	234	ubiquitous	marker	metanephros cortex, granulocyte, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNM2	4,715

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNM2	P50570	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 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
NOSTRIN mediated eNOS trafficking	1	2284.0×	0.004	DNM2
Formation of annular gap junctions	1	1038.2×	0.004	DNM2
Gap junction degradation	1	951.7×	0.004	DNM2
Retrograde neurotrophin signalling	1	815.7×	0.004	DNM2
Lysosome Vesicle Biogenesis	1	326.3×	0.007	DNM2
NGF-stimulated transcription	1	285.5×	0.007	DNM2
Recycling pathway of L1	1	223.9×	0.007	DNM2
Golgi Associated Vesicle Biogenesis	1	200.3×	0.007	DNM2
Degradation of CDH1	1	196.9×	0.007	DNM2
Toll Like Receptor 4 (TLR4) Cascade	1	131.3×	0.009	DNM2
MHC class II antigen presentation	1	89.2×	0.012	DNM2
Clathrin-mediated endocytosis	1	85.2×	0.012	DNM2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vesicle scission	1	8426.0×	0.001	DNM2
negative regulation of membrane tubulation	1	8426.0×	0.001	DNM2
actin filament bundle organization	1	5617.3×	0.001	DNM2
membrane tubulation	1	5617.3×	0.001	DNM2
synaptic vesicle budding from presynaptic endocytic zone membrane	1	3370.4×	0.001	DNM2
transferrin transport	1	1532.0×	0.003	DNM2
regulation of axon extension	1	1296.3×	0.003	DNM2
post-Golgi vesicle-mediated transport	1	1053.2×	0.003	DNM2
protein polymerization	1	991.3×	0.003	DNM2
synaptic vesicle transport	1	842.6×	0.003	DNM2
stress fiber assembly	1	766.0×	0.003	DNM2
antigen processing and presentation of exogenous peptide antigen via MHC class II	1	543.6×	0.004	DNM2
membrane organization	1	510.7×	0.004	DNM2
centrosome cycle	1	337.0×	0.005	DNM2
receptor internalization	1	324.1×	0.005	DNM2
G2/M transition of mitotic cell cycle	1	312.1×	0.005	DNM2
neuron projection morphogenesis	1	276.3×	0.005	DNM2
phagocytosis	1	240.7×	0.006	DNM2
receptor-mediated endocytosis	1	221.7×	0.006	DNM2
autophagy	1	110.1×	0.011	DNM2
endocytosis	1	95.2×	0.013	DNM2
positive regulation of apoptotic process	1	56.7×	0.020	DNM2
regulation of DNA-templated transcription	1	31.6×	0.034	DNM2
positive regulation of DNA-templated transcription	1	27.9×	0.037	DNM2
signal transduction	1	16.1×	0.062	DNM2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
DNM2	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
DNM2	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNM2	3.6.5.5	dynamin GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	DNM2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DNM2	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.