Abstract
The feasibility of traditional noninvasive prenatal diagnosis (NIPD) relying on proband-based relative haplotype dose analysis has been demonstrated. However, the prognosis of type I spinal muscular atrophy (SMA) is poor, and the proband sample is hard to collect during the second pregnancy. We investigate the feasibility of NIPD for SMA via haplotype construction without the need for a proband. Six samples were collected from both the paternal and maternal families in 36 families at risk of SMA. By enriching the SMN1/2 gene and its upstream and downstream informative SNPs, the family haplotype was constructed, and the Bayes factor was used to infer the fetal genotype by the dose changes of informational SNPs in cell-free DNA. All samples underwent MLPA testing after chorion villus sampling or amniocentesis. The MLPA results showed 100% consistency with NIPD. The earliest gestational week for successful NIPD was 7+ 3 weeks, with a minimum fetal fraction of 1.9%. Haplotype construction based on both paternal and maternal families demonstrated significant reliability and feasibility for families without a proband. Additionally, this approach provides a safer, and earlier prenatal diagnosis option for couples identified as at-risk through SMA carrier screening.