Presynaptic congenital myasthenic syndrome

Summary

Presynaptic congenital myasthenic syndrome (MONDO:0700466) is a disease (an umbrella term covering 10 Mondo subtypes) with 4 cohort genes.

At a glance

• Umbrella term: 10 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 6
• Phenotypes (HPO): 68

Clinical features

Signs & symptoms

Clinical features (HPO)

68 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000467	Neck muscle weakness	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0002015	Dysphagia	Very frequent (80-99%)
HP:0002033	Poor suck	Very frequent (80-99%)
HP:0002882	Sudden episodic apnea	Very frequent (80-99%)
HP:0003473	Fatigable weakness	Very frequent (80-99%)
HP:0003701	Proximal muscle weakness	Very frequent (80-99%)
HP:0004661	Frontalis muscle weakness	Very frequent (80-99%)
HP:0004889	Intermittent episodes of respiratory insufficiency due to muscle weakness	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000602	Ophthalmoplegia	Frequent (30-79%)
HP:0000961	Cyanosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001283	Bulbar palsy	Frequent (30-79%)
HP:0001558	Decreased fetal movement	Frequent (30-79%)
HP:0001611	Hypernasal speech	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002804	Arthrogryposis multiplex congenita	Frequent (30-79%)
HP:0002872	Apneic episodes precipitated by illness, fatigue, stress	Frequent (30-79%)
HP:0003324	Generalized muscle weakness	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0004885	Episodic respiratory distress	Frequent (30-79%)
HP:0008443	Spinal deformities	Frequent (30-79%)
HP:0010536	Central sleep apnea	Frequent (30-79%)
HP:0011469	Nasal regurgitation	Frequent (30-79%)
HP:0030842	Choking episodes	Frequent (30-79%)
HP:0100285	EMG: impaired neuromuscular transmission	Frequent (30-79%)
HP:0100295	Muscle fiber atrophy	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000276	Long face	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001612	Weak cry	Occasional (5-29%)
HP:0001618	Dysphonia	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0003306	Spinal rigidity	Occasional (5-29%)
HP:0003325	Limb-girdle muscle weakness	Occasional (5-29%)
HP:0003458	EMG: myopathic abnormalities	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0009053	Distal lower limb muscle weakness	Occasional (5-29%)
HP:0010307	Stridor	Occasional (5-29%)
HP:0012801	Narrow jaw	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	presynaptic congenital myasthenic syndrome
Mondo ID	MONDO:0700466
Orphanet	98914
UMLS	C0751884
MedGen	155651
GARD	0028048
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants · 1 cell line.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › congenital myasthenic syndrome › presynaptic congenital myasthenic syndrome

Related subtypes (7): congenital myasthenic syndrome with tubular aggregates, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 5, congenital myasthenic syndrome 15, postsynaptic congenital myasthenic syndrome, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, myasthenic syndrome, congenital, 22

Subtypes (10): congenital myasthenic syndrome 6, congenital myasthenic syndrome 8, congenital myasthenic syndrome 7, congenital myasthenic syndrome 18, congenital myasthenic syndrome 19, congenital myasthenic syndrome 20, congenital myasthenic syndrome 21, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic

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

6 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
930633	NM_198576.4(AGRN):c.1177+4_1177+50del	AGRN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708244	NM_130811.4(SNAP25):c.164-252del	SNAP25	Likely pathogenic	criteria provided, single submitter
1339240	NM_005560.6(LAMA5):c.2323+1G>A	LAMA5	Uncertain significance	criteria provided, single submitter
1339241	NM_005560.6(LAMA5):c.152A>G (p.Asn51Ser)	LAMA5	Uncertain significance	criteria provided, single submitter
619598	NM_005560.6(LAMA5):c.7975C>T (p.Arg2659Trp)	LAMA5	Uncertain significance	criteria provided, single submitter
585279	NM_006901.4(MYO9A):c.1016A>G (p.Tyr339Cys)	MYO9A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SNAP25	Orphanet:98914	Presynaptic congenital myasthenic syndromes
AGRN	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
AGRN	Orphanet:98914	Presynaptic congenital myasthenic syndromes
LAMA5	Orphanet:521450	LAMA5-related multisystemic syndrome
LAMA5	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
MYO9A	Orphanet:98914	Presynaptic congenital myasthenic syndromes

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SNAP25	HGNC:11132	ENSG00000132639	P60880	Synaptosomal-associated protein 25	clinvar
AGRN	HGNC:329	ENSG00000188157	O00468	Agrin	clinvar
LAMA5	HGNC:6485	ENSG00000130702	O15230	Laminin subunit alpha-5	clinvar
MYO9A	HGNC:7608	ENSG00000066933	B2RTY4	Unconventional myosin-IXa	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SNAP25	Synaptosomal-associated protein 25	t-SNARE involved in the molecular regulation of neurotransmitter release.
AGRN	Agrin	Depending on alternative splicing and post-translational modifications, it has a role in different processes, including neuromuscular junction formation and maintenance, and regulation of neurite outgrowth.
LAMA5	Laminin subunit alpha-5	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
MYO9A	Unconventional myosin-IXa	Myosins are actin-based motor molecules with ATPase activity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SNAP25	Other/Unknown	no		T_SNARE_dom, SNAP-25_dom, SNAP-25_N_SNARE_chord
AGRN	Other/Unknown	no		SEA_dom, EGF, Laminin_G
LAMA5	Other/Unknown	no		Laminin_IV, EGF, TNFR/NGFR_Cys_rich_reg
MYO9A	Other/Unknown	no		IQ_motif_EF-hand-BS, RA_dom, RhoGAP_dom

Expression context

Cohort genes with no expression data: 0.

4 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
metanephros cortex	2
right uterine tube	2
cerebellar cortex	1
cerebellum	1
pons	1
renal medulla	1
right hemisphere of cerebellum	1
calcaneal tendon	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SNAP25	220	broad	marker	pons, cerebellar cortex, cerebellum
AGRN	271	ubiquitous	marker	right uterine tube, metanephros cortex, renal medulla
LAMA5	264	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, metanephros cortex
MYO9A	280	ubiquitous	marker	calcaneal tendon, male germ cell, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGRN	3,117
LAMA5	2,519
MYO9A	2,434
SNAP25	163

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SNAP25	P60880	14
LAMA5	O15230	2
AGRN	O00468	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYO9A	B2RTY4	58.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 86. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the dystrophin-glycoprotein complex (DGC)	2	154.3×	0.005	AGRN, LAMA5
Non-integrin membrane-ECM interactions	2	77.2×	0.007	AGRN, LAMA5
ECM proteoglycans	2	75.1×	0.007	AGRN, LAMA5
Sensory Perception	2	47.6×	0.014	SNAP25, AGRN
Toxicity of botulinum toxin type C (botC)	1	951.7×	0.014	SNAP25
Toxicity of botulinum toxin type E (botE)	1	951.7×	0.014	SNAP25
Toxicity of botulinum toxin type A (botA)	1	713.8×	0.014	SNAP25
Signaling by Interleukins	2	32.1×	0.014	SNAP25, LAMA5
Extracellular matrix organization	2	31.6×	0.014	AGRN, LAMA5
Neurotoxicity of clostridium toxins	1	356.9×	0.022	SNAP25
Early SARS-CoV-2 Infection Events	1	259.6×	0.022	AGRN
Chondroitin sulfate/dermatan sulfate metabolism	1	237.9×	0.022	AGRN
Defective EXT2 causes exostoses 2	1	203.9×	0.022	AGRN
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	1	203.9×	0.022	AGRN
Uptake and actions of bacterial toxins	1	203.9×	0.022	SNAP25
Diseases associated with glycosaminoglycan metabolism	1	190.3×	0.022	AGRN
Acetylcholine Neurotransmitter Release Cycle	1	167.9×	0.022	SNAP25
Serotonin Neurotransmitter Release Cycle	1	158.6×	0.022	SNAP25
Norepinephrine Neurotransmitter Release Cycle	1	158.6×	0.022	SNAP25
GABA synthesis, release, reuptake and degradation	1	158.6×	0.022	SNAP25
MET promotes cell motility	1	150.3×	0.022	LAMA5
Attachment and Entry	1	150.3×	0.022	AGRN
Defective B4GALT7 causes EDS, progeroid type	1	142.8×	0.022	AGRN
Defective B3GAT3 causes JDSSDHD	1	142.8×	0.022	AGRN
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	142.8×	0.022	AGRN
Heparan sulfate/heparin (HS-GAG) metabolism	1	135.9×	0.022	AGRN
HS-GAG degradation	1	124.1×	0.022	AGRN
Dopamine Neurotransmitter Release Cycle	1	124.1×	0.022	SNAP25
Attachment of bacteria to epithelial cells	1	124.1×	0.022	LAMA5
Respiratory syncytial virus (RSV) attachment and entry	1	124.1×	0.022	AGRN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of synaptic assembly at neuromuscular junction	1	4213.0×	0.012	AGRN
trunk neural crest cell migration	1	2106.5×	0.012	LAMA5
morphogenesis of a polarized epithelium	1	1053.2×	0.012	LAMA5
presynaptic dense core vesicle exocytosis	1	1053.2×	0.012	SNAP25
regulation of neuron projection arborization	1	702.2×	0.012	MYO9A
clustering of voltage-gated sodium channels	1	601.9×	0.012	AGRN
postsynapse organization	1	601.9×	0.012	LAMA5
synaptic vesicle fusion to presynaptic active zone membrane	1	421.3×	0.012	SNAP25
cell junction assembly	1	421.3×	0.012	MYO9A
morphogenesis of embryonic epithelium	1	383.0×	0.012	LAMA5
neurotransmitter uptake	1	351.1×	0.012	SNAP25
branching involved in salivary gland morphogenesis	1	351.1×	0.012	LAMA5
obsolete synaptic vesicle docking	1	324.1×	0.012	SNAP25
G protein-coupled acetylcholine receptor signaling pathway	1	263.3×	0.013	AGRN
establishment of epithelial cell apical/basal polarity	1	263.3×	0.013	MYO9A
regulation of epithelial cell proliferation	1	234.1×	0.014	LAMA5
synaptic vesicle priming	1	200.6×	0.015	SNAP25
synaptic vesicle exocytosis	1	191.5×	0.015	SNAP25
filopodium assembly	1	162.0×	0.016	AGRN
receptor clustering	1	156.0×	0.016	AGRN
neuromuscular junction development	1	131.7×	0.018	AGRN
skeletal system morphogenesis	1	123.9×	0.018	LAMA5
associative learning	1	120.4×	0.018	SNAP25
regulation of neuron projection development	1	108.0×	0.020	SNAP25
regulation of insulin secretion	1	98.0×	0.020	SNAP25
hair follicle development	1	95.8×	0.020	LAMA5
branching involved in ureteric bud morphogenesis	1	91.6×	0.021	LAMA5
substrate adhesion-dependent cell spreading	1	86.0×	0.021	LAMA5
regulation of embryonic development	1	82.6×	0.021	LAMA5
regulation of cell adhesion	1	76.6×	0.021	LAMA5

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SNAP25	0	0
AGRN	0	0
LAMA5	0	0
MYO9A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
AGRN	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	SNAP25, AGRN, LAMA5, MYO9A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SNAP25	0	—
AGRN	3	—
LAMA5	0	—
MYO9A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.