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Biallelic variants in MUSK were identified in a fetus with absent movements and multiple ultrasonographic features of Fetal Akinesia Deformation Sequence 1. A compound heterozygous genotype, c.220C>T (p.Arg74Trp) and c.422del (p.Pro141HisfsTer15), was detected by NGS in one proband, consistent with autosomal recessive inheritance and parental carrier status (PMID:31750350).
Loss-of-function of MuSK has been shown to abolish receptor expression and disrupt neuromuscular junction formation in cellular and murine models; frameshift and null alleles lead to absent MuSK protein and impaired agrin-dependent AChR clustering, recapitulating severe synaptic defects in vivo (PMID:15496425).
Although functional data support a mechanism of MuSK deficiency, clinical validity remains limited by a single molecularly characterised family without extended segregation or replication. Further cases and segregation analyses are required to establish a definitive gene–disease relationship.
Key take-home: Biallelic loss-of-function variants in MUSK cause autosomal recessive FADS, informing molecular diagnosis and prenatal genetic counseling.
Gene–Disease AssociationLimitedSingle compound heterozygous family (1 proband) with AR segregation; preliminary functional support Genetic EvidenceLimitedGenetic data from one affected fetus with biallelic variants; no additional segregation or cases Functional EvidenceModerateIn vitro and in vivo assays demonstrate MuSK loss-of-function disrupts neuromuscular junction formation |