Yan Xu1,2, Xuchao Li3, Hui-Juan Ge3, Bing Xiao1,2, Yan-Yan Zhang3, Xiao-Min Ying1,2, Xiao-Yu Pan3, Lei Wang1,4, Wei-Wei Xie3, Lin Ni1,2, Sheng-Pei Chen3, Wen-Ting Jiang1,2, Ping Liu3, Hui Ye1,2, Ying Cao1,2, Jing-Min Zhang1,2, Yu Liu1,2, Zu-Jing Yang1,4, Ying-Wei Chen1,2, Fang Chen3,5, Hui Jiang3,6, Xing Ji1,2. 1. Department of Prenatal Diagnosis Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China. 2. Department of Genetics, Shanghai Institute of Pediatric Research, Shanghai, China. 3. BGI-Shenzhen, Shenzhen, China. 4. Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China. 5. Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences of Copenhagen, Section of Molecular Disease Biology, Copenhagen, Denmark. 6. Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Abstract
PURPOSE: This study demonstrates noninvasive prenatal testing (NIPT) for Duchenne muscular dystrophy (DMD) using a newly developed haplotype-based approach. METHODS: Eight families at risk for DMD were recruited for this study. Parental haplotypes were constructed using target-region sequencing data from the parents and the probands. Fetal haplotypes were constructed using a hidden Markov model through maternal plasma DNA sequencing. The presence of haplotypes linked to the maternal mutant alleles in males indicated affected fetuses. This method was further validated by comparing the inferred single-nucleotide polymorphism (SNP) genotypes to the direct sequencing results of fetal genomic DNA. Prenatal diagnosis was confirmed with amniocentesis, and those results were interpreted in a blinded fashion. RESULTS: The results showed an average accuracy of 99.98% for the total inferred maternal SNPs. With a mean depth of 30× achieved in the 10-Mb target region of each sample, the noninvasive results were consistent with those of the invasive procedure. CONCLUSION: This is the first report of NIPT for DMD and the first application of a haplotype-based approach in NIPT for X-linked diseases. With further improvements in accuracy, this haplotype-based strategy could be feasible for NIPT for DMD and even other X-linked single-gene disorders.
PURPOSE: This study demonstrates noninvasive prenatal testing (NIPT) for Duchenne muscular dystrophy (DMD) using a newly developed haplotype-based approach. METHODS: Eight families at risk for DMD were recruited for this study. Parental haplotypes were constructed using target-region sequencing data from the parents and the probands. Fetal haplotypes were constructed using a hidden Markov model through maternal plasma DNA sequencing. The presence of haplotypes linked to the maternal mutant alleles in males indicated affected fetuses. This method was further validated by comparing the inferred single-nucleotide polymorphism (SNP) genotypes to the direct sequencing results of fetal genomic DNA. Prenatal diagnosis was confirmed with amniocentesis, and those results were interpreted in a blinded fashion. RESULTS: The results showed an average accuracy of 99.98% for the total inferred maternal SNPs. With a mean depth of 30× achieved in the 10-Mb target region of each sample, the noninvasive results were consistent with those of the invasive procedure. CONCLUSION: This is the first report of NIPT for DMD and the first application of a haplotype-based approach in NIPT for X-linked diseases. With further improvements in accuracy, this haplotype-based strategy could be feasible for NIPT for DMD and even other X-linked single-gene disorders.