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Lethal multiple pterygium syndrome (LMPS) is a fatal, autosomal recessive disorder characterised by prenatal growth failure, multiple pterygia, fetal akinesia and muscle weakness. In a single family, two affected fetuses were identified with novel compound heterozygous RYR1 deletions, including c.4563_4574del (p.Ala1522_Leu1525del), by whole exome sequencing and confirmed by segregation analysis, establishing a causal link to LMPS (PMID:26932181).
Although direct functional assays of these specific LMPS variants are lacking, extensive studies of RYR1 variants demonstrate that loss-of-function in the ryanodine receptor 1 disrupts skeletal muscle excitation–contraction coupling, leading to fetal akinesia and severe arthrogryposis. Cellular Ca2+ photometry, [3H]ryanodine binding, myotube rescue and excitation–contraction uncoupling assays consistently show that RYR1 mutations impair calcium release, supporting a mechanistic basis for the LMPS phenotype.
Key take-home: Biallelic RYR1 variants should be evaluated in fetuses with multiple pterygia, arthrogryposis and akinesia to enable accurate prenatal diagnosis and genetic counselling.
Gene–Disease AssociationLimited2 probands in one family with compound heterozygous RYR1 variants and consistent LMPS phenotype (PMID:26932181) Genetic EvidenceLimitedTwo affected fetuses with confirmed compound heterozygous RYR1 deletions and segregation in parents Functional EvidenceModerateExtensive RYR1 functional studies show disrupted calcium release and excitation–contraction coupling consistent with LMPS mechanism |