Preimplantation genetic testing as a means of preventing hereditary congenital myasthenic syndrome caused by RAPSN
Zhiping Zhang1, Xueluo Zhang1, Huiqin Xue1
1Center of Reproductive Medicine, Affiliated Children's Hospital of Shanxi & Women Health Center of Shanxi Medicine University, Taiyuan, Shanxi, China.
Background:
Congenital myasthenic syndrome is a heterogeneous group of inherited neuromuscular transmission disorders. Variants in RAPSN are a common cause of CMS, accounting for approximately 14%-27% of all CMS cases. Whether preimplantation genetic testing for monogenic disease (PGT-M) could be used to prevent the potential birth of CMS-affected children is unclear.
Methods:
Application of WES (whole-exome sequencing) for carrier testing and guidance for the PGT-M in the absence of a genetically characterized index patient as well as assisted reproductive technology were employed to prevent the occurrence of birth defects in subsequent pregnancy. The clinical phenotypes of stillborn fetuses were also assessed.
Results:
The family carried two likely pathogenic variants in RAPSN(NM_005055.5): c.133G>A (p.V45M) and c.280G>A (p.E94K). And the potential birth of CMS-affected child was successfully prevented, allowing the family to have offspring devoid of disease-associated variants and exhibiting a normal phenotype.
Conclusion:
This report constitutes the first documented case of achieving a CMS-free offspring through PGT-M in a CMS-affected family. By broadening the known variant spectrum of RAPSN in the Chinese population, our findings underscore the feasibility and effectiveness of PGT-M for preventing CMS, offering valuable insights for similarly affected families.
Insights
Preimplantation genetic testing for monogenic disease (PGT-M) successfully prevented the birth of children with Congenital Myasthenic Syndrome (CMS) in a family with RAPSN variants. This demonstrates PGT-M
Area of Science:
- Genetics
- Neuromuscular Disorders
- Reproductive Medicine
Background:
- Congenital Myasthenic Syndrome (CMS) is a group of inherited disorders affecting neuromuscular transmission.
- RAPSN gene variants are a significant cause of CMS, identified in 14%-27% of cases.
- The utility of PGT-M for preventing CMS births was previously uncertain.
Purpose of the Study:
- To investigate the feasibility of using PGT-M to prevent the birth of infants with CMS in a family carrying RAPSN variants.
- To establish a method for carrier testing and PGT-M guidance without a genetically characterized index patient.
Main Methods:
- Whole-exome sequencing (WES) was used for carrier testing.
- Assisted reproductive technologies guided by PGT-M were employed.
- Clinical phenotypes of stillborn fetuses were assessed.
Main Results:
- Two likely pathogenic RAPSN variants (c.133G>A and c.280G>A) were identified in the family.
- The PGT-M strategy successfully prevented the birth of CMS-affected offspring.
- Offspring were born free of disease-associated variants and exhibited normal phenotypes.
Conclusions:
- This is the first report of a CMS-free offspring achieved through PGT-M in a CMS-affected family.
- PGT-M is a feasible and effective method for preventing CMS births.
- Findings expand the known RAPSN variant spectrum in the Chinese population and offer insights for affected families.
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