Novel Haplotype-Based Noninvasive Prenatal Diagnosis for Recessive Single-Gene Disorders: A Proof-of-Concept Study

Area of Science:

• Genetics
• Molecular Biology
• Bioinformatics

Background:

• Accurate parental haplotype information is essential for noninvasive prenatal diagnosis of recessive single-gene disorders (NIPD-SGD).
• Conventional methods for NIPD-SGD are limited by complex techniques or the need for family members (trio-based analysis).

Purpose of the Study:

• To develop and validate a novel direct haplotyping-based noninvasive prenatal diagnosis approach (DiHNIPD) for single-gene disorders.
• To assess the accuracy and clinical applicability of DiHNIPD using single-tube long fragment read (stLFR) sequencing.

Main Methods:

• Reconstructed parental genome-wide haplotypes using stLFR-based whole genome sequencing (WGS).
• Identified SNPs in maternal plasma using WGS.
• Determined fetal haplotypes via a parental haplotype-assisted hidden Markov model and Viterbi algorithm.

Main Results:

• DiHNIPD successfully phased parental haplotypes and accurately deduced fetal genotypes in 23 at-risk couples.
• Achieved 100% concordance with diagnostic results from invasive prenatal diagnosis.
• Demonstrated DiHNIPD as a sensitive, user-friendly, and inexpensive strategy.

Conclusions:

• DiHNIPD offers a direct haplotyping approach for NIPD-SGD, eliminating the need for complex equipment or family members.
• This method shows significant promise for clinical application in high-risk pregnancies, even without prior offspring.
• DiHNIPD provides a sensitive, user-friendly, and cost-effective solution for NIPD-SGD.