Novel Algorithm for Monogenic Noninvasive Prenatal Testing With Highly Similar Parental Pathogenic Haplotypes: A Representative Case of Congenital Adrenal Hyperplasia Pedigree

Abstract

Noninvasive prenatal testing (NIPT) has been widely used in various monogenic recessive disorders based on relative haplotype dosage (RHDO) analysis. We accepted a congenital adrenal hyperplasia (CAH) pedigree with highly similar parental pathogenic haplotypes. The initial monogenic NIPT attempt was unsuccessful due to a paucity of informative single-nucleotide polymorphisms (SNPs), prompting improvement of the current method. With a refined algorithm that deduces the fetal genotype based on dosage changes at SNPs located on a specific parental haplotype, while also effectively sidestepping allele bias introduced by hybrid capture, monogenic NIPT was successfully carried out in this family, yielding results consistent with invasive prenatal diagnosis. Theoretically, this algorithm can be employed in scenarios involving consanguineous marriages or when parents share a highly homologous haplotype, thereby broadening its applicability. Detailed methodology is described, and the advantages of our algorithm are discussed.