Noninvasive prenatal diagnosis for X-linked disease by maternal plasma sequencing in a family of Hemophilia B

Abstract

Objective: To apply a Hidden Markov Model to test Hemophilia B in a fetus by maternal plasma sequencing only employing proband and maternal haplotypes. Case Report: A family at risk for Hemophilia B was recruited in this study. We performed genetic diagnosis on the proband using our targeted capture system (containing F9 gene coding region, highly heterozygous SNPs and a 13-kb chromosome Y specific region), and revealed a causative F9 gene mutation (c.190T>C, p.Cys64Arg). Maternal plasma cell-free DNA obtained at 8 weeks of gestation was targeted-captured and sequenced using the customized system. The fetus inherited the F9 (c.190T>C, p.Cys64Arg) mutation according to the Hidden Markov Model. The mother continued the pregnancy. Conclusions: This study is the first report of a haplotype-based approach in NIPD of Hemophilia B. With further evaluation, this method might be useful for NIPD of Hemophilia B and for other X-linked single-gene disorders.

Keywords

• Massively parallel sequencing
• Hemophilia B
• Noninvasive prenatal diagnosis
• Single-gene disorders
• Target-gene capture