RAPSN – Fetal Akinesia Deformation Sequence 1

Fetal akinesia deformation sequence (FADS) is a genetically heterogeneous disorder characterized by reduced fetal movement leading to joint contractures, edema, and malformations. RAPSN encodes rapsyn, a postsynaptic protein essential for clustering acetylcholine receptors (AChRs) at the neuromuscular junction. Loss or impairment of AChR clustering disrupts neuromuscular transmission and early somite development, contributing to the FADS phenotype.

In a cohort study of FADS and lethal multiple pterygium syndrome, two unrelated families were found to harbor homozygous missense mutations in RAPSN (c.416T>C (p.Phe139Ser) and c.566C>T (p.Ala189Val)), which resulted in severe but non‐lethal phenotypes and confirmed a developmental role beyond muscle‐specific defects ([PMID:18252226]). A subsequent diagnostic sequencing study identified a third unrelated fetus with homozygous c.484G>A (p.Glu162Lys) in RAPSN presenting with arthrogryposis and fetal akinesia ([PMID:28495245]).

All reported RAPSN variants in FADS follow an autosomal recessive inheritance pattern, with three unrelated probands described and no extended segregation beyond index cases. No affected first‐degree relatives have been documented to date, consistent with biallelic recessive transmission.

The variant spectrum in FADS comprises missense changes affecting conserved residues in rapsyn. The c.484G>A (p.Glu162Lys) allele, observed in a homozygous state, is the first RAPSN variant specifically attributed to FADS and underscores allelic heterogeneity within this gene.

Functional studies in mouse embryos demonstrated RAPSN expression in early somites and developing skeletal muscle, aligning with human phenotypes of fetal hypokinesia, edema, and joint contractures. These expression patterns support a mechanistic link between rapsyn disruption and impaired fetal movement ([PMID:18252226]).

Integration of genetic and experimental data yields a Moderate clinical validity classification for RAPSN in FADS. While additional segregation and functional rescue studies would strengthen the association, current evidence is sufficient to guide molecular diagnosis and genetic counseling in affected families. Key Take-home: RAPSN should be included in gene panels for autosomal recessive FADS to facilitate early genetic diagnosis and inform clinical management.

References

• American Journal of Human Genetics • 2008 • Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. PMID:18252226
• European Journal of Paediatric Neurology • 2017 • Massive parallel sequencing identifies RAPSN and PDHA1 mutations causing fetal akinesia deformation sequence. PMID:28495245

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