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

Direct haplotyping by stLFR long-read sequencing without family members

A novel non-invasive prenatal diagnosis approach via direct haplotyping (DiHNIPD) using single-tube long fragment read (stLFR) sequencing was developed for autosomal recessive single-gene disorders. Parental haplotypes are reconstructed by stLFR WGS and fetal haplotypes inferred via a hidden Markov model with Viterbi algorithm. In 23 at-risk couples, DiHNIPD correctly deduced 23 fetal genotypes with 100% concordance with invasive prenatal diagnosis, requiring no family members, no PCR amplification, and no expensive equipment.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

100% concordance across 23 cases is encouraging but calls for replication in larger cohorts before clinical adoption. The absence of family member sequencing requirements is a major practical advantage for isolated families or those whose key members are deceased. Validation for disorders with high allelic variability or in genomically complex regions remains needed.

Clinical impact: 2/3 · Evidence quality: 2/3 · Novelty: 1/2 · Sample size: 1/1 · Journal quality: 0/1 → Total: 6/10