CHRND – Lethal Multiple Pterygium Syndrome

Lethal multiple pterygium syndrome (LMPS) is an autosomal recessive, perinatally lethal disorder characterized by fetal akinesia, cystic hygroma, hydrops fetalis, and pterygia. The CHRND gene (encoding the acetylcholine receptor δ‐subunit) is critical during early somite development and neuromuscular junction formation, and its loss leads to the LMPS phenotype. (PMID:18252226, PMID:36733345)

Genetic evidence for CHRND in LMPS includes two unrelated probands with biallelic truncating or splice‐site variants in CHRND. A prenatal case harbored c.1006C>T (p.Arg336Ter) and c.973_975delGTG (p.Val325del) in trans, identified by first‐trimester ultrasound for micrognathia and pterygia (PMID:36733345). Separately, a fetal akinesia cohort revealed a homozygous splice donor variant c.1371+1G>T in a lethal LMPS case (PMID:18252226). No additional familial segregation has been reported.

The variant spectrum in LMPS comprises nonsense (e.g., c.234G>A (p.Trp78Ter)), frameshift (c.1367del (p.Asn456fs)), in‐frame deletion (c.973_975delGTG (p.Val325del)), and canonical splice‐site (c.1371+1G>T) alleles in CHRND, all predicted to cause loss of function. No recurrent or founder variants have yet been described, and carrier frequencies remain undefined.

Functional studies demonstrate CHRND expression in early mouse somites beyond skeletal muscle, implicating a developmental role in limb and vertebral formation (PMID:18252226). In vitro assays using Xenopus oocytes with the delta‐subunit S268F (analogous to human p.Ser283Phe) show impaired channel kinetics, supporting a loss‐of‐function mechanism relevant to LMPS pathogenesis (PMID:11782989).

No conflicting or refuting clinical reports have emerged to date, and the evidence from genetics and model systems is concordant with a recessive loss‐of‐function mechanism.

Overall, CHRND meets ClinGen Limited criteria for association with LMPS, with biallelic loss‐of‐function variants in two unrelated cases and supporting functional data. Key take‐home: CHRND should be included in diagnostic and prenatal gene panels for lethal pterygium syndromes to inform genetic counseling and management.

References

• Frontiers in genetics • 2023 • Case Report: Early diagnosis of lethal multiple pterygium syndrome with micrognathia: Two novel mutations in the CHRND gene. PMID:36733345
• American journal of human genetics • 2008 • Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. PMID:18252226
• Annals of neurology • 2002 • Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms. PMID:11782989

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