Add dismech entry/refactor: Curate CHRNA1 fetal hypo-akinesia

[cmungall]

See MONDO_NTR_CANDIDATES.md for full context and lump/split rationale.

[github-actions]

Summary: CHRNA1 Fetal Hypo-Akinesia

Automated summary — see MONDO_NTR_CANDIDATES.md for full lump/split rationale.

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Disease Identity

CHRNA1 fetal hypo-akinesia sits at the severe (lethal) end of the CHRNA1 disease spectrum. It corresponds to Fetal Akinesia Deformation Sequence type 2 (FADS2; OMIM:616054) and largely overlaps with Lethal Multiple Pterygium Syndrome (LMPS) caused specifically by CHRNA1 null/near-null variants.

This is distinct from the milder allelic disease Congenital Myasthenic Syndrome type 1A/1B (CMS1; OMIM:601462), which presents postnatally with manageable weakness from partial AChR loss-of-function.

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Gene & Protein

CHRNA1 (HGNC:1955) encodes the α1 subunit of the muscle-type nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel at the neuromuscular junction. The fetal isoform is (α1)₂β1γδ (the γ subunit is replaced by ε postnatally). The α1 subunit is the primary ACh-binding and channel-gating component.

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Mechanism

Homozygous/compound-het loss-of-function in CHRNA1
    ↓
Complete or severe functional disruption of fetal AChR (Michalk et al. 2008)
    ↓
Absent/severely reduced neuromuscular transmission
    ↓
Fetal hypo-akinesia / akinesia (absent fetal movement)
    ↓
Secondary "deformation sequence":
  • Arthrogryposis multiplex congenita (joint contractures from immobility)
  • Multiple pterygium (skin webbing at joints)
  • Pulmonary hypoplasia (requires fetal breathing movements)
  • Polyhydramnios (reduced fetal swallowing)
  • Cystic hygroma / hydrops fetalis
  • Short umbilical cord, growth restriction
  → Perinatal lethal

CHRNA1 is also expressed in early somite development, suggesting potential developmental roles beyond the NMJ (Michalk et al. 2008, PMID:18252226).

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Clinical Features

Feature	Frequency
Arthrogryposis / joint contractures	Core feature
Pterygium (neck, elbows, knees)	Core feature
Pulmonary hypoplasia	Frequent
Polyhydramnios	Frequent
Cystic hygroma / nuchal edema	Frequent
Fetal hydrops	Variable
Intrauterine / perinatal death	~100% in severe cases
Cleft palate	Occasional
Cardiac defects	Occasional

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Key Literature

PMID	Summary
18252226	Michalk et al. 2008 (Am J Hum Genet) — Landmark paper: first homozygous null mutations in CHRNA1 (nonsense + missense R234L) causing LMPS. Established that "complete or severe functional disruption of fetal AChR causes LMPS." Key mechanistic reference.
36092864	Case Report 2022 (Front Genet) — Novel compound heterozygous CHRNA1 variants c.[1128delG];[505T>C] in a family with recurrent fetal losses; expanded mutation spectrum.
23037934	Exome sequencing 2013 (Genet Med) — Novel CHRNA1 mutation identified by WES in lethal Mendelian fetal phenotype; demonstrates utility of WES for prenatally lethal recessive conditions.
22482962	Review 2012 (Taiwan J Obstet Gynecol) — Comprehensive review of FADS/MPS genetics; places CHRNA1 in context of NMJ gene panel (alongside CHRND, CHRNG, RAPSN, DOK7, MUSK).
18179903	Mutation screening 2008 (Am J Hum Genet) — Systematic screen of CHRNA1, CHRNB1, CHRND, RAPSN in 15 LMPS cases; showed RAPSN frameshift can also cause lethal fetal akinesia via same pathway.

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NMJ Pathway Context (Lump/Split Relevant)

Several NMJ pathway genes cause overlapping LMPS/FADS phenotypes when completely disrupted:

• CHRNA1 → FADS2 (this issue)
• CHRNG → Escobar syndrome (non-lethal MPS) or FADS1 (lethal)
• RAPSN → FADS / LMPS (severe alleles)
• DOK7 → FADS (PMID:19261599)
• MUSK → FADS (PMID:25537362)

The shared mechanism is: complete NMJ signaling blockade → fetal immobility → deformation sequence. The CHRNA1-specific entry is justified by distinct genotype (α1 subunit) and potential for genotype-specific genetic counseling and recurrence risk.

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OMIM / Ontology Alignment

Resource	Term
OMIM	616054 — Fetal akinesia deformation sequence 2 (FADS2)
OMIM gene	100690 — CHRNA1
Orphanet	ORPHA:994 — Fetal akinesia deformation sequence (broad, 10 genes)
ClinVar	26 pathogenic CHRNA1 variants; primary condition = "Lethal multiple pterygium syndrome"
MONDO	Likely needs NTR for CHRNA1-specific FADS (see MONDO_NTR_CANDIDATES.md)

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Suggested dismech Entry Structure

• Pathophysiology nodes: AChR subunit loss → NMJ transmission failure → fetal immobility → deformation sequence
• Cell types: Skeletal muscle fiber (myotube, CL:0000515), Motor neuron (CL:0000100)
• Biological processes: Acetylcholine receptor signaling (GO:0007274), Neuromuscular junction assembly (GO:0051124), Fetal movement (GO:0097247)
• Phenotypes: Arthrogryposis, multiple pterygium, pulmonary hypoplasia, polyhydramnios, cystic hygroma — all with category: Prenatal
• Inheritance: Autosomal recessive
• Key conforms_to candidate: None existing yet; could seed a new fetal_akinesia_deformation_sequence module shared with CHRNG/RAPSN/DOK7 entries

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@dragon-ai-agent please create a new dismech entry for CHRNA1 fetal hypo-akinesia (FADS2, OMIM:616054). Use the mechanism outlined above: CHRNA1 null mutations → complete fetal AChR loss of function → fetal hypo-akinesia → deformation sequence (arthrogryposis, pterygium, pulmonary hypoplasia, polyhydramnios). Key reference: PMID:18252226. Add PMID:36092864 and PMID:22482962 as supporting evidence. Check MONDO for the most appropriate disease term (likely needs NTR per MONDO_NTR_CANDIDATES.md). File should be saved as kb/disorders/CHRNA1_Fetal_Hypo_Akinesia.yaml.

[dragon-ai-agent]

Curation scanner assessment

Status: ✅ Addressed by merged PR #1552 ([codex] curate CHRNA1 prenatal-lethal hypo-akinesia disorder).

Resulting entry: kb/disorders/CHRNA1-associated_Fetal_Hypo-akinesia_Disorder_of_Prenatal_Onset.yaml

What PR #1552 delivered (matches the brief in this issue):

• Prenatal-lethal CHRNA1 LOF → fetal AChR failure → fetal akinesia → deformation sequence (arthrogryposis, pterygium, pulmonary hypoplasia, polyhydramnios)
• Anchored to PMID:18252226 (Michalk et al., landmark paper), plus supporting PMIDs in the fetal-akinesia spectrum
• Provisionally grounded to MONDO:0009668 (lethal multiple pterygium syndrome) pending MONDO NTR #8449, documented in notes

Gap vs. this issue's brief: This issue also floated a potential fetal_akinesia_deformation_sequence module shared across CHRNA1/CHRNG/RAPSN/DOK7/MUSK. That module was not created in PR #1552 — it remains a reasonable follow-up if additional FADS-spectrum disorders get curated, but it is lower priority than the entry itself and does not need to block closing this issue.

Suggested action: Close this issue (entry delivered). Open a small follow-up issue if the fetal_akinesia_deformation_sequence module is still desired.

— automated scan

[github-actions]

Status: Complete ✅

The CHRNA1 fetal hypo-akinesia dismech entry is fully curated, merged, and validated.

Entry file: kb/disorders/CHRNA1-associated_Fetal_Hypo-akinesia_Disorder_of_Prenatal_Onset.yaml
Merged via: PR #1552

Validation results (all passing):

• Schema validation: ✅ No issues found
• Reference validation: ✅ All validations passed (10 checks, 0 errors)
• Research artifact: ✅ research/CHRNA1-associated_Fetal_Hypo-akinesia_Disorder_of_Prenatal_Onset-deep-research-codex.md

Entry covers:

• Mechanism chain: CHRNA1 null LOF → fetal AChR deficiency → fetal hypo-akinesia → deformation sequence (arthrogryposis, pterygia, pulmonary hypoplasia, polyhydramnios)
• 8 phenotypes with evidence (including arthrogryposis, pterygium, cystic hygroma, hydrops, micrognathia, pulmonary hypoplasia, fetal akinesia, joint contracture)
• Genetic section: biallelic CHRNA1 LOF causative, anchored to PMID:18252226 and PMID:36092864
• Inheritance: autosomal recessive
• Treatment: genetic counseling
• Provisional MONDO grounding to MONDO:0009668 (lethal multiple pterygium syndrome), pending MONDO NTR #8449
• 4 PMIDs with cached abstracts and validated snippets

Closing this issue as delivered.