Noninvasive prenatal diagnosis of Mendelian disorders for consanguineous couples by relative genotype dosage

• Published in: Clinical genetics 2023-11, Vol.104 (5), p.505-515
• Main Authors: Fokstuen, Siv, Quteineh, Lina, Schwitzgebel, Valérie M., Köhler‐Ballan, Bettina, Blouin, Jean‐Louis, Abramowicz, Marc, Nouspikel, Thierry
• Format: Article
• Language: English
• Subjects: Aneuploidy; Apoptosis; cell‐free circulating DNA; consanguinity; Deoxyribonucleic acid; DNA; Dosage; fetal DNA; Fetuses; Genotype & phenotype; Genotypes; Haplotypes; monogenic disease; Mutation; noninvasive prenatal diagnosis; Prenatal diagnosis; Single-nucleotide polymorphism
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.14399

Noninvasive prenatal diagnosis relies on the presence in maternal blood of circulating cell‐free fetal DNA released by apoptotic trophoblast cells. Widely used for aneuploidy screening, it can also be applied to monogenic diseases (NIPD‐M) in case of known parental mutations. Due to the confounding effect of maternal DNA, detection of maternal or biparental mutations requires relative haplotype dosage (RHDO), a method relying on the presence of SNPs that are heterozygous in one parent and homozygous in the other. Unavoidably, there is a risk of test failure by lack of such informative SNPs, an event particularly likely for consanguineous couples who often share common haplotypes in regions of identity‐by‐descent. Here we present a novel approach, relative genotype dosage (RGDO) that bypasses this predicament by directly assessing fetal genotype with SNPs that are heterozygous in both parents (frequent in regions of identity‐by‐descent). We show that RGDO is as sensitive as RHDO and that it performs well over a large range of fetal fractions and DNA amounts, thereby opening NIPD‐M to most consanguineous couples. We also report examples of couples, consanguineous or not, where combining RGDO and RHDO allowed a diagnosis that would not have been possible with only one approach. RHDO analysis determines the transmitted parental haplotypes by quantifying allelic imbalances in SNPs that are heterozygous in one parent and homozygous in the other. In consanguineous couples, RGDO analysis bypasses parental haplotype determination and directly determines fetal genotype by quantifying allelic imbalances in SNPs that are heterozygous in both parents.