RAPSN-Related Fetal Akinesia Deformation Sequence with Low-Lying Conus Medullaris: A Case Report and Literature Review

Technical Summary: RAPSN-Related Fetal Akinesia Deformation Sequence with Low-Lying Conus Medullaris

Problem Statement
Fetal Akinesia Deformation Sequence (FADS) is a severe, often lethal condition characterized by reduced fetal movement leading to multiple joint contractures, pulmonary hypoplasia, and facial anomalies. While pathogenic variants in the RAPSN gene are a known cause of FADS and Congenital Myasthenic Syndromes (CMS), the prenatal phenotypic spectrum remains incompletely defined. Conventional diagnostic tools, such as karyotyping and chromosomal microarray analysis (CMA), frequently yield normal results in these cases, necessitating advanced genetic testing. Furthermore, the specific association between RAPSN mutations and central nervous system (CNS) anomalies, particularly spinal cord development, has not been well-documented in the prenatal literature.

Methodology
The authors present a case report of a 29-year-old primigravida at 23+5 weeks of gestation. The diagnostic workflow included:

• Serial Ultrasound: Detailed anatomical surveys at 23+5 and 26+2 weeks to monitor fetal movement, nuchal skin fold (NF) thickness, pleural effusions, stomach bubble dynamics, and spinal cord positioning.
• Standard Genetic Screening: Amniotic fluid chromosomal microarray analysis (CMA) and TORCH serology were performed to rule out aneuploidy and infectious causes.
• Molecular Diagnosis: Trio whole-exome sequencing (WES) was conducted on the fetus and both parents to identify pathogenic variants.
• Follow-up: A subsequent pregnancy underwent targeted prenatal diagnosis via amniocentesis to screen for the specific parental variants identified in the first case.

Key Results

• Clinical Phenotype: The fetus exhibited significantly reduced movements, increased NF thickness (progressing from 8.2 mm to 11 mm), a small non-dynamic stomach bubble, a right-sided pleural effusion, fixed clenched fists, and an enlarged gallbladder. A notable finding was a low-lying conus medullaris positioned at the L4-L5 level with an irregular filum terminale.
• Genetic Findings: Trio WES identified compound heterozygous variants in the RAPSN gene: a missense variant (c.538G>A) inherited from one parent and an insertion/deletion variant (c.149_153delins) inherited from the other. The missense variant is currently classified as a Variant of Uncertain Significance (VUS) in ClinVar, while the indel is a known pathogenic frameshift/null allele.
• Outcome: Due to the poor prognosis associated with severe FADS, the pregnancy was terminated at 27 weeks. The stillborn infant displayed generalized joint stiffness and fixed postures. In the subsequent pregnancy, targeted testing confirmed the absence of the parental RAPSN variants, resulting in the delivery of a healthy infant.
• Literature Review: A review of existing literature (summarized in Table 1) indicates that while RAPSN mutations cause a spectrum from lethal FADS to treatable CMS, CNS anomalies like a low-lying conus medullaris have not been previously reported in association with RAPSN mutations.

Key Contributions

1. Expansion of Prenatal Imaging Spectrum: This report documents a low-lying conus medullaris in a fetus with RAPSN-related FADS. While the authors suggest this may be an incidental finding or a secondary consequence of chronic akinesia rather than a direct phenotypic expansion, it represents a novel sonographic observation in this context.
2. Diagnostic Utility of WES: The case demonstrates the critical role of WES in diagnosing lethal fetal anomalies when CMA and karyotyping are normal, specifically identifying RAPSN as the causative agent.
3. Clinical Management: The report highlights the efficacy of targeted prenatal testing in subsequent pregnancies for families with identified RAPSN variants, enabling informed reproductive decisions and the birth of unaffected children.

Significance and Claims
The paper claims that accurate prenatal diagnosis via WES is essential for predicting prognosis and guiding genetic counseling in cases of FADS. The authors emphasize that while RAPSN-related disorders exhibit significant clinical heterogeneity (ranging from lethal prenatal akinesia to treatable CMS), the specific combination of alleles influences severity. They note that while the low-lying conus medullaris is a new observation in this context, it should be interpreted cautiously as a potential incidental anomaly until further pathological evidence links fetal akinesia to impaired conus ascension. The study concludes that integrating WES into the diagnostic pipeline for fetal akinesia improves diagnostic precision and facilitates nuanced prognostic discussions, particularly regarding the potential for acetylcholinesterase inhibitor therapy in live-born infants with less severe phenotypes.