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Biallelic loss-of-function variants in NEB, encoding the skeletal muscle thin-filament protein nebulin, have been implicated in a lethal form of multiple pterygium syndrome (LMPS). Exome sequencing of a fetus presenting with hydrops fetalis, large cystic hygromas, bilateral talipes and fetal akinesia revealed compound heterozygosity for c.21198_21199del (p.Tyr7067GlnfsTer4) and c.17457G>A (p.Trp5819Ter), consistent with an autosomal recessive inheritance in a single proband (PMID:38520674). This finding expands the genetic heterogeneity of LMPS beyond canonical neuromuscular genes and underscores the importance of including NEB in prenatal gene panels for pterygium syndromes.
Although the variant spectrum in NEB‐related congenital myopathies is well characterized, only one case has linked NEB to the LMPS phenotype, with no extended family segregation or functional assays performed in the context of pterygia. Additional functional studies in relevant cellular or animal models are needed to elucidate pathogenic mechanisms specific to LMPS. Key Take-home: NEB should be considered in the differential diagnosis of autosomal recessive LMPS to guide genetic counseling and prenatal management.
Gene–Disease AssociationLimitedSingle fetus with compound heterozygous NEB variants consistent with autosomal recessive LMPS ([PMID:38520674]) Genetic EvidenceLimitedOne proband, no segregation or unrelated cases reported ([PMID:38520674]) Functional EvidenceLimitedNo functional studies of NEB in the context of LMPS have been reported |