Extended newborn screening using DNA methylation testing for fragile X syndrome in 17,107 infants

Area of Science:

• Genetics
• Newborn Screening
• Molecular Diagnostics

Background:

• Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability.
• Early diagnosis and intervention can improve outcomes for individuals with FXS.
• Newborn screening for FXS offers potential benefits for early treatment and reproductive planning.

Purpose of the Study:

• To evaluate the feasibility of population-scale newborn screening for fragile X syndrome (FXS).
• To assess the effectiveness of Methylation Specific Quantitative Melt Analysis (MS-QMA) as a first-tier screening test for FXS in newborns.

Main Methods:

• Utilized MS-QMA for first-tier screening of Fragile X gene (FMR1) methylation on 17,107 newborn blood spots (NBS).
• Confirmed infant sex using real-time PCR.
• Employed EpiTYPER methylation analysis and AmplideX CGG sizing PCR for second-tier confirmation of MS-QMA positive results.

Main Results:

• First-tier screening detected methylation suggestive of FXS in 3 males and 36 females.
• Second-tier testing confirmed FXS in two males and one female, with one male showing abnormal methylation and a 22 CGG allele.
• Identified FMR1 premutations in two females, which do not cause FXS.

Conclusions:

• MS-QMA is a feasible and effective first-tier screening method for FXS in both sexes in a newborn population.
• The study successfully identified 3 infants with confirmatory results consistent with FXS out of 17,107 screened.
• Population-scale newborn screening for FXS is achievable with current molecular diagnostic technologies.