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CHRNG – Lethal Multiple Pterygium Syndrome

Homozygous CHRNG variants cause autosomal recessive lethal multiple pterygium syndrome (LMPS), characterized by pterygia, severe arthrogryposis, fetal hydrops, and cystic hygroma. Whole-exome sequencing in two aborted fetuses from unrelated consanguineous families identified a frameshift variant c.753_754delCT (p.Val253fsTer44) and a missense variant c.715C>T (p.Arg239Cys), both segregating in parents as heterozygous carriers ([PMID:32587836]).

The CHRNG-encoded gamma subunit of the fetal acetylcholine receptor is expressed in early somites and skeletal muscle, and loss-of-function disrupts receptor assembly and somite development, explaining the early lethal phenotype in LMPS ([PMID:18252226]). Clinical testing of CHRNG in high-risk families facilitates prenatal diagnosis and genetic counseling.

References

  • American journal of human genetics • 2008 • Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. PMID:18252226
  • International journal of molecular and cellular medicine • 2019 • Utilization of Whole Exome Sequencing in Lethal Form of Multiple Pterygium Syndrome: Identification of Mutations in Embryonal Subunit of Acetylcholine Receptor. PMID:32587836

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Two unrelated probands with homozygous CHRNG variants and AR segregation; no additional families reported

Genetic Evidence

Limited

Homozygous frameshift and missense variants identified in 2 fetuses from consanguineous families; alleles segregate in parents ([PMID:32587836])

Functional Evidence

Limited

Somite and muscle expression of CHRNG in mouse embryos and in silico structural disruption support loss-of-function mechanism ([PMID:18252226])