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De Novo Paternal FBN1 Mutation Detected in Embryos Before Implantation
Shuling Wang1,2, Ziru Niu3, Hui Wang1
1Reproductive Center, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China (mainland).
Abstract:
BACKGROUND Marfan syndrome (MFS) is an autosomal dominant disease caused by mutations in the Fibrillin (FBN)1 gene and characterized by disorders in the cardiovascular, skeletal, and visual systems. The diversity of mutations and phenotypic heterogeneity of MFS make prenatal molecular diagnoses difficult. In this study, we used pre-implantation genetic diagnosis (PGD) to identify the pathogenic mutation in a male patient with MFS and to determine whether his offspring would be free of the disease. MATERIAL AND METHODS The history and pedigree of the proband were analyzed. Mutation analysis was performed on the couple and immediate family members. The couple chose IVF treatment and 4 blastocysts were biopsied. PGD was carried out by targeted high-throughput sequencing of the FBN1 gene in the embryos, along with single-nucleotide polymorphism haplotyping. Sanger sequencing was used to confirm the causative mutation. RESULTS c.2647T>C (p.Trp883Arg) was identified as the de novo likely pathogenic mutation in the proband. Whole-genome amplification and sequencing of the 3 embryos revealed that they did not carry the mutation, and 1 blastocyst was transferred back to the uterus. The amniocentesis test result analyzed by Sanger sequencing confirmed the PGD. A premature but healthy infant free of heart malformations was born. CONCLUSIONS The de novo mutation c.2647T>C (p.Trp883Arg) in FBN1 was identified in a Chinese patient with MFS. Embryos without the mutation were identified by PGD and resulted in a successful pregnancy.
Insights
Pre-implantation genetic diagnosis (PGD) identified a de novo Fibrillin (FBN)1 gene mutation in a Marfan syndrome patient. This enabled the selection of unaffected embryos, leading to a healthy, disease-free infant.
Area of Science:
- Genetics
- Reproductive Medicine
- Medical Diagnostics
Background:
- Marfan syndrome (MFS) is an autosomal dominant disorder affecting cardiovascular, skeletal, and visual systems.
- Caused by Fibrillin (FBN)1 gene mutations, MFS presents significant diagnostic challenges due to mutation diversity and phenotypic heterogeneity.
- Prenatal diagnosis for MFS is complicated, necessitating advanced genetic screening methods.
Purpose of the Study:
- To utilize pre-implantation genetic diagnosis (PGD) for identifying a pathogenic FBN1 mutation in a Marfan syndrome case.
- To assess the feasibility of PGD in preventing disease transmission to offspring.
- To confirm the successful application of PGD in a clinical setting for Marfan syndrome.
Main Methods:
- Analysis of patient history, pedigree, and mutation screening in family members.
- In vitro fertilization (IVF) followed by blastocyst biopsy for genetic analysis.
- Targeted high-throughput sequencing of the FBN1 gene and single-nucleotide polymorphism (SNP) haplotyping for PGD.
- Sanger sequencing for confirmation of the identified mutation.
Main Results:
- A de novo likely pathogenic mutation, c.2647T>C (p.Trp883Arg), in the FBN1 gene was identified in the proband.
- PGD successfully identified three unaffected embryos out of four biopsied.
- A single unaffected embryo was transferred, resulting in a healthy infant confirmed disease-free via amniocentesis.
Conclusions:
- The study successfully identified a de novo FBN1 mutation in a Chinese Marfan syndrome patient.
- PGD proved effective in selecting embryos free from the Marfan syndrome mutation.
- This approach facilitated a successful pregnancy, yielding a healthy infant unaffected by the genetic disorder.
