CHRNA1-Associated Fetal Hypo-akinesia Disorder of Prenatal Onset

Mendelian MONDO:0009668 Pathograph 3 Neuromuscular Disease Multiple Pterygium Syndrome

CHRNA1-associated fetal hypo-akinesia disorder of prenatal onset is the prenatal-lethal end of the CHRNA1 congenital myasthenic syndrome spectrum. It is typically caused by biallelic null or other severe loss-of-function variants in the nicotinic acetylcholine receptor alpha-1 subunit, leading to absent or profoundly impaired fetal acetylcholine receptor function at the neuromuscular junction. The resulting marked reduction in fetal movement produces a lethal multiple pterygium syndrome / fetal akinesia deformation sequence presentation with joint contractures, pterygia, cystic hygroma or hydrops, micrognathia, and pulmonary hypoplasia.

Ask OpenScientist

Ask a research question about CHRNA1-Associated Fetal Hypo-akinesia Disorder of Prenatal Onset. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
2
Pathophys.
8
Phenotypes
3
Pathograph
1
Genes
2
Treatments
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
The prenatal-lethal CHRNA1 presentation is reported in families with homozygous or compound heterozygous pathogenic variants, consistent with autosomal recessive inheritance and a 25% recurrence risk for carrier parents.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:36092864 SUPPORT Human Clinical
"subsequent familial segregation showed that both parents transmitted their respective mutation."
Compound heterozygosity with parental segregation supports autosomal recessive inheritance for the prenatal-lethal CHRNA1 phenotype.
⚙

Pathophysiology

2
Fetal acetylcholine receptor alpha-1 deficiency
Biallelic null or functionally severe CHRNA1 variants disrupt the alpha-1 subunit of the fetal muscle nicotinic acetylcholine receptor, preventing normal postsynaptic receptor function at the neuromuscular junction. This produces profound impairment of fetal neuromuscular transmission and places CHRNA1-related disease on a spectrum with later-onset congenital myasthenic syndrome caused by milder alleles.
skeletal muscle fiber link
neuromuscular synaptic transmission link ↓ DECREASED
Downstream
Fetal hypo-akinesia and contracture sequence
Show evidence (1 reference)
PMID:18252226 SUPPORT Human Clinical
"We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype."
This study establishes that homozygous null CHRNA1 variants cause a lethal prenatal phenotype, consistent with severe loss of fetal AChR function.
Fetal hypo-akinesia and contracture sequence
Profound reduction of fetal neuromuscular transmission leads to markedly decreased fetal movement. Secondary consequences include multiple joint contractures, pterygia, edema or hydrops, craniofacial anomalies such as micrognathia, and pulmonary hypoplasia, yielding a prenatal-lethal multiple-pterygium / fetal akinesia deformation sequence presentation.
skeletal muscle fiber link
skeletal muscle contraction link ↓ DECREASED
Show evidence (1 reference)
PMID:18252226 SUPPORT Human Clinical
"We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life."
This directly links severe fetal AChR dysfunction to the prenatal-lethal lethal multiple pterygium / fetal hypokinesia presentation and contrasts it with milder postnatal myasthenic phenotypes.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CHRNA1-Associated Fetal Hypo-akinesia Disorder of Prenatal Onset Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Head and Neck 1
Micrognathia Micrognathia (HP:0000347)
Show evidence (1 reference)
PMID:3344777 SUPPORT Human Clinical
"In eight fetuses who had joint contractures, micrognathia, and pulmonary hypoplasia, the cause of fetal akinesia could be attributed to an abnormal intrauterine environment restricting fetal movement."
Micrognathia is a documented component of the fetal akinesia deformation sequence produced by profound prenatal immobility and is therefore a plausible recurrent feature of prenatal-lethal CHRNA1 disease.
Metabolism 1
Hydrops fetalis Hydrops fetalis (HP:0001789)
Show evidence (1 reference)
PMID:26932181 SUPPORT Human Clinical
"Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS."
Foetal hydrops is explicitly described as part of lethal multiple pterygium syndrome and supports hydrops fetalis in the prenatal-lethal CHRNA1 presentation.
Musculoskeletal 1
Joint contracture Joint contracture (HP:0034392)
Show evidence (1 reference)
PMID:36092864 SUPPORT Human Clinical
"Case presentation: We herein report a Chinese case with a history of three adverse pregnancies demonstrating the same ultrasonic phenotypes, including increased nuchal translucency, edema, fetal neck cystoma, reduced movement, joint contractures, and other congenital features."
Joint contractures were part of the recurrent prenatal ultrasound phenotype in the CHRNA1-affected family.
Respiratory 1
Pulmonary hypoplasia Pulmonary hypoplasia (HP:0002089)
Show evidence (1 reference)
PMID:3344777 SUPPORT Human Clinical
"In eight fetuses who had joint contractures, micrognathia, and pulmonary hypoplasia, the cause of fetal akinesia could be attributed to an abnormal intrauterine environment restricting fetal movement."
Pulmonary hypoplasia is a documented downstream feature of the fetal akinesia deformation sequence and supports its inclusion in the prenatal-lethal CHRNA1 phenotype spectrum.
Other 4
Fetal akinesia sequence Fetal akinesia sequence (HP:0001989)
Show evidence (1 reference)
PMID:36092864 SUPPORT Human Clinical
"Case presentation: We herein report a Chinese case with a history of three adverse pregnancies demonstrating the same ultrasonic phenotypes, including increased nuchal translucency, edema, fetal neck cystoma, reduced movement, joint contractures, and other congenital features."
The affected pregnancy showed reduced fetal movement, supporting fetal akinesia/hypokinesia as a defining prenatal feature.
Arthrogryposis multiplex congenita Arthrogryposis multiplex congenita (HP:0002804)
Show evidence (1 reference)
PMID:26932181 SUPPORT Human Clinical
"It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis."
Severe arthrogryposis is part of the lethal multiple pterygium / fetal akinesia phenotype and supports arthrogryposis multiplex congenita as a recurrent manifestation of this prenatal-lethal presentation.
Pterygium Pterygium (HP:0001059)
Show evidence (1 reference)
PMID:26932181 SUPPORT Human Clinical
"It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis."
This directly supports pterygia as a defining phenotype of the lethal multiple pterygium presentation represented by prenatal-lethal CHRNA1 disease.
Cystic hygroma Cystic hygroma (HP:0000476)
Show evidence (1 reference)
PMID:26932181 SUPPORT Human Clinical
"Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS."
Cystic hygroma is a characteristic severe prenatal feature of lethal multiple pterygium / fetal akinesia presentations.
🧬

Genetic Associations

1
Biallelic CHRNA1 loss-of-function variants (Causative)
Show evidence (2 references)
PMID:18252226 SUPPORT Human Clinical
"We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype."
This paper directly implicates homozygous null CHRNA1 variants in the lethal prenatal phenotype.
PMID:36092864 SUPPORT Human Clinical
"Conclusion: For the first time, we identified an association between the CHRNA1 gene and the recurrent lethal multiple pterygium syndrome (LMPS) in a Chinese family."
This case report independently supports CHRNA1 as a cause of recurrent lethal multiple pterygium syndrome.
💊

Treatments

2
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling is indicated for carrier parents and at-risk relatives, including discussion of autosomal recessive recurrence risk (25% per pregnancy for carrier couples), carrier testing of siblings, and options for prenatal molecular diagnosis and preimplantation genetic testing in future pregnancies.
Perinatal supportive and palliative care
Action: supportive care MAXO:0000950
Given the typically lethal prenatal or perinatal course, management centers on family-directed comfort and supportive care planning. Obstetric counseling regarding delivery options and expectations, neonatology consultation for birth planning, and access to palliative care services should be offered to affected families. Detailed clinical and molecular characterization of affected fetuses supports diagnosis confirmation and future family planning.
{ }

Source YAML

click to show 
name: CHRNA1-Associated Fetal Hypo-akinesia Disorder of Prenatal Onset
creation_date: '2026-04-16T19:26:03Z'
updated_date: '2026-04-21T22:39:00Z'
category: Mendelian
description: >-
  CHRNA1-associated fetal hypo-akinesia disorder of prenatal onset is the
  prenatal-lethal end of the CHRNA1 congenital myasthenic syndrome spectrum.
  It is typically caused by biallelic null or other severe loss-of-function
  variants in the nicotinic acetylcholine receptor alpha-1 subunit, leading to
  absent or profoundly impaired fetal acetylcholine receptor function at the
  neuromuscular junction. The resulting marked reduction in fetal movement
  produces a lethal multiple pterygium syndrome / fetal akinesia deformation
  sequence presentation with joint contractures, pterygia, cystic hygroma or
  hydrops, micrognathia, and pulmonary hypoplasia.
parents:
- Neuromuscular Disease
- Multiple Pterygium Syndrome
disease_term:
  preferred_term: lethal multiple pterygium syndrome
  term:
    id: MONDO:0009668
    label: lethal multiple pterygium syndrome
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The prenatal-lethal CHRNA1 presentation is reported in families with
    homozygous or compound heterozygous pathogenic variants, consistent with
    autosomal recessive inheritance and a 25% recurrence risk for carrier
    parents.
  evidence:
  - reference: PMID:36092864
    reference_title: "Case Report: Novel compound heterozygous variants in CHRNA1 gene leading to lethal multiple pterygium syndrome: A case report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "subsequent familial segregation showed that both parents transmitted their respective mutation."
    explanation: >-
      Compound heterozygosity with parental segregation supports autosomal
      recessive inheritance for the prenatal-lethal CHRNA1 phenotype.
pathophysiology:
- name: Fetal acetylcholine receptor alpha-1 deficiency
  description: >-
    Biallelic null or functionally severe CHRNA1 variants disrupt the alpha-1
    subunit of the fetal muscle nicotinic acetylcholine receptor, preventing
    normal postsynaptic receptor function at the neuromuscular junction. This
    produces profound impairment of fetal neuromuscular transmission and places
    CHRNA1-related disease on a spectrum with later-onset congenital myasthenic
    syndrome caused by milder alleles.
  gene:
    preferred_term: CHRNA1
    description: >-
      Encodes the alpha-1 subunit of the skeletal muscle nicotinic
      acetylcholine receptor required for fetal neuromuscular transmission.
    modifier: DECREASED
    term:
      id: hgnc:1955
      label: CHRNA1
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: neuromuscular synaptic transmission
    modifier: DECREASED
    term:
      id: GO:0007274
      label: neuromuscular synaptic transmission
  evidence:
  - reference: PMID:18252226
    reference_title: "Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype."
    explanation: >-
      This study establishes that homozygous null CHRNA1 variants cause a
      lethal prenatal phenotype, consistent with severe loss of fetal AChR
      function.
  downstream:
  - target: Fetal hypo-akinesia and contracture sequence
- name: Fetal hypo-akinesia and contracture sequence
  description: >-
    Profound reduction of fetal neuromuscular transmission leads to markedly
    decreased fetal movement. Secondary consequences include multiple joint
    contractures, pterygia, edema or hydrops, craniofacial anomalies such as
    micrognathia, and pulmonary hypoplasia, yielding a prenatal-lethal
    multiple-pterygium / fetal akinesia deformation sequence presentation.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: skeletal muscle contraction
    modifier: DECREASED
    term:
      id: GO:0003009
      label: skeletal muscle contraction
  evidence:
  - reference: PMID:18252226
    reference_title: "Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life."
    explanation: >-
      This directly links severe fetal AChR dysfunction to the prenatal-lethal
      lethal multiple pterygium / fetal hypokinesia presentation and contrasts
      it with milder postnatal myasthenic phenotypes.
phenotypes:
- name: Fetal akinesia sequence
  category: Prenatal
  description: >-
    Markedly reduced fetal movement is the core prenatal manifestation of the
    disorder and drives the secondary contracture and malformation sequence.
  phenotype_term:
    preferred_term: Fetal akinesia sequence
    term:
      id: HP:0001989
      label: Fetal akinesia sequence
  evidence:
  - reference: PMID:36092864
    reference_title: "Case Report: Novel compound heterozygous variants in CHRNA1 gene leading to lethal multiple pterygium syndrome: A case report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case presentation: We herein report a Chinese case with a history of three adverse pregnancies demonstrating the same ultrasonic phenotypes, including increased nuchal translucency, edema, fetal neck cystoma, reduced movement, joint contractures, and other congenital features."
    explanation: >-
      The affected pregnancy showed reduced fetal movement, supporting fetal
      akinesia/hypokinesia as a defining prenatal feature.
- name: Joint contracture
  category: Musculoskeletal
  description: >-
    Fixed prenatal contractures involving multiple joints reflect prolonged lack
    of fetal movement and contribute to the arthrogryposis phenotype.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:36092864
    reference_title: "Case Report: Novel compound heterozygous variants in CHRNA1 gene leading to lethal multiple pterygium syndrome: A case report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case presentation: We herein report a Chinese case with a history of three adverse pregnancies demonstrating the same ultrasonic phenotypes, including increased nuchal translucency, edema, fetal neck cystoma, reduced movement, joint contractures, and other congenital features."
    explanation: >-
      Joint contractures were part of the recurrent prenatal ultrasound
      phenotype in the CHRNA1-affected family.
- name: Arthrogryposis multiplex congenita
  category: Musculoskeletal
  description: >-
    Multiple congenital contractures across body regions are characteristic of
    the severe fetal akinesia presentation.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:26932181
    reference_title: "Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis."
    explanation: >-
      Severe arthrogryposis is part of the lethal multiple pterygium / fetal
      akinesia phenotype and supports arthrogryposis multiplex congenita as a
      recurrent manifestation of this prenatal-lethal presentation.
- name: Pterygium
  category: Musculoskeletal
  description: >-
    Multiple webbing anomalies across joints are typical of the lethal multiple
    pterygium syndrome presentation.
  phenotype_term:
    preferred_term: Pterygium
    term:
      id: HP:0001059
      label: Pterygium
  evidence:
  - reference: PMID:26932181
    reference_title: "Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis."
    explanation: >-
      This directly supports pterygia as a defining phenotype of the lethal
      multiple pterygium presentation represented by prenatal-lethal CHRNA1
      disease.
- name: Cystic hygroma
  category: Prenatal
  description: >-
    Nuchal cystic hygroma or neck cystoma may be detected on prenatal imaging in
    severely affected fetuses.
  phenotype_term:
    preferred_term: Cystic hygroma
    term:
      id: HP:0000476
      label: Cystic hygroma
  evidence:
  - reference: PMID:26932181
    reference_title: "Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS."
    explanation: >-
      Cystic hygroma is a characteristic severe prenatal feature of lethal
      multiple pterygium / fetal akinesia presentations.
- name: Hydrops fetalis
  category: Prenatal
  description: >-
    Generalized fetal edema or hydrops can occur in the most severe prenatal
    presentations.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:26932181
    reference_title: "Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS."
    explanation: >-
      Foetal hydrops is explicitly described as part of lethal multiple
      pterygium syndrome and supports hydrops fetalis in the prenatal-lethal
      CHRNA1 presentation.
- name: Micrognathia
  category: Craniofacial
  description: >-
    Small mandible is a recurrent craniofacial feature in the prenatal-lethal
    CHRNA1 presentation.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:3344777
    reference_title: Fetal akinesia deformation sequence in previable fetuses
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In eight fetuses who had joint contractures, micrognathia, and pulmonary hypoplasia, the cause of fetal akinesia could be attributed to an abnormal intrauterine environment restricting fetal movement."
    explanation: >-
      Micrognathia is a documented component of the fetal akinesia deformation
      sequence produced by profound prenatal immobility and is therefore a
      plausible recurrent feature of prenatal-lethal CHRNA1 disease.
- name: Pulmonary hypoplasia
  category: Respiratory
  description: >-
    Pulmonary underdevelopment is part of the fetal akinesia deformation
    sequence and contributes to lethality.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:3344777
    reference_title: Fetal akinesia deformation sequence in previable fetuses
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In eight fetuses who had joint contractures, micrognathia, and pulmonary hypoplasia, the cause of fetal akinesia could be attributed to an abnormal intrauterine environment restricting fetal movement."
    explanation: >-
      Pulmonary hypoplasia is a documented downstream feature of the fetal
      akinesia deformation sequence and supports its inclusion in the
      prenatal-lethal CHRNA1 phenotype spectrum.
genetic:
- name: Biallelic CHRNA1 loss-of-function variants
  association: Causative
  gene_term:
    preferred_term: CHRNA1
    term:
      id: hgnc:1955
      label: CHRNA1
  notes: >-
    The prenatal-lethal presentation is associated with homozygous nonsense or
    compound heterozygous severe variants predicted to abolish or profoundly
    impair fetal acetylcholine receptor alpha-1 function.
  evidence:
  - reference: PMID:18252226
    reference_title: "Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype."
    explanation: >-
      This paper directly implicates homozygous null CHRNA1 variants in the
      lethal prenatal phenotype.
  - reference: PMID:36092864
    reference_title: "Case Report: Novel compound heterozygous variants in CHRNA1 gene leading to lethal multiple pterygium syndrome: A case report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conclusion: For the first time, we identified an association between the CHRNA1 gene and the recurrent lethal multiple pterygium syndrome (LMPS) in a Chinese family."
    explanation: >-
      This case report independently supports CHRNA1 as a cause of recurrent
      lethal multiple pterygium syndrome.
diagnosis:
- name: Prenatal Ultrasound Evaluation
  description: >-
    Prenatal ultrasound is the initial diagnostic modality for detecting
    CHRNA1-associated fetal hypo-akinesia disorder. Characteristic findings
    include increased nuchal translucency, fetal edema, cystic hygroma, reduced
    fetal movement, and joint contractures. The same constellation of ultrasound
    anomalies may recur across successive pregnancies in carrier families.
  evidence:
  - reference: PMID:36092864
    reference_title: "Case Report: Novel compound heterozygous variants in CHRNA1 gene leading to lethal multiple pterygium syndrome: A case report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We herein report a Chinese case with a history of three adverse pregnancies demonstrating the same ultrasonic phenotypes, including increased nuchal translucency, edema, fetal neck cystoma, reduced movement, joint contractures, and other congenital features."
    explanation: >-
      Documents recurrent prenatal ultrasound findings in a CHRNA1-affected
      family, establishing ultrasound as the first-line diagnostic modality.
- name: Molecular Genetic Testing
  description: >-
    Confirmation of the diagnosis requires identification of biallelic pathogenic
    CHRNA1 variants by whole-exome sequencing (WES) or targeted gene panel.
    Parental carrier testing with segregation analysis is essential for
    establishing inheritance and counseling recurrence risk. Once familial
    variants are known, prenatal molecular diagnosis can be offered via chorionic
    villus sampling or amniocentesis in future at-risk pregnancies.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:36092864
    reference_title: "Case Report: Novel compound heterozygous variants in CHRNA1 gene leading to lethal multiple pterygium syndrome: A case report"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This finding may also enrich the mutation spectrum of the CHRNA1 gene and promote the applications of WES technology in etiologic diagnosis of ultrasound anomalies in prenatal examination."
    explanation: >-
      Supports WES as the molecular diagnostic approach for identifying biallelic
      CHRNA1 variants in the context of prenatal ultrasound anomalies.
  - reference: PMID:18252226
    reference_title: "Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype."
    explanation: >-
      Identifies homozygous null CHRNA1 variants as causative of the lethal
      prenatal phenotype, informing interpretation of molecular test results.
treatments:
- name: Genetic counseling
  description: >-
    Genetic counseling is indicated for carrier parents and at-risk relatives,
    including discussion of autosomal recessive recurrence risk (25% per
    pregnancy for carrier couples), carrier testing of siblings, and options for
    prenatal molecular diagnosis and preimplantation genetic testing in future
    pregnancies.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
- name: Perinatal supportive and palliative care
  description: >-
    Given the typically lethal prenatal or perinatal course, management centers
    on family-directed comfort and supportive care planning. Obstetric
    counseling regarding delivery options and expectations, neonatology
    consultation for birth planning, and access to palliative care services
    should be offered to affected families. Detailed clinical and molecular
    characterization of affected fetuses supports diagnosis confirmation and
    future family planning.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
notes: >-
  MONDO new term request  # 8449 proposes the more specific gene-related label
  "CHRNA1 associated fetal hypo-akinesia disorder of prenatal onset". Until
  that class exists in the local MONDO release, this entry is provisionally
  grounded to MONDO:0009668 lethal multiple pterygium syndrome. This entry is
  intended to model the prenatal-lethal CHRNA1 loss-of-function presentation
  rather than the later-onset slow-channel and fast-channel congenital
  myasthenic syndrome phenotypes caused by non-null CHRNA1 variants.
📚

References & Deep Research

Deep Research

1
Codex ▸
Question
gpt-5

Question

Review the evidence base for a new disorder entry modeling CHRNA1-associated fetal hypo-akinesia disorder of prenatal onset, with attention to whether the prenatal-lethal CHRNA1 presentation is best treated as a lethal multiple pterygium / fetal akinesia disease anchor and whether the phenotype section is supported by exact PMID-backed evidence.

Selected PMID-backed evidence

  • PMID:18252226 Foundational CHRNA1 paper showing that homozygous nonsense mutations in CHRNA1 can be lethal and that severe disruption of fetal AChR function produces a lethal multiple pterygium / fetal hypokinesia phenotype.
  • PMID:36092864 Direct CHRNA1 case report with recurrent affected pregnancies, compound heterozygous variants, reduced fetal movement, edema, fetal neck cystoma, and joint contractures.
  • PMID:26932181 LMPS abstract with exact wording for pterygium, severe arthrogryposis, foetal hydrops, and cystic hygroma, useful for phenotype evidence where the core syndrome morphology is shared across genetic causes.
  • PMID:3344777 FADS abstract with exact wording for micrognathia and pulmonary hypoplasia as downstream consequences of fetal akinesia.

Curation decisions

  • Kept the disease entry provisionally grounded to MONDO:0009668 lethal multiple pterygium syndrome because MONDO NTR #8449 is still pending in the local MONDO release.
  • Treated the disorder as the prenatal-lethal loss-of-function end of the CHRNA1 congenital myasthenic syndrome spectrum rather than conflating it with postnatal fast- or slow-channel CHRNA1 CMS phenotypes.
  • Used exact abstract-backed phenotype evidence for all structured phenotypes.
  • Allowed broader LMPS/FADS literature to support phenotype morphology when the CHRNA1-specific literature was sufficient for disease causality but sparse for every individual prenatal feature.