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Scientific article
Open access
English

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

Published inClinical genetics, vol. 104, no. 5, p. 505-515
Publication date2023-11
First online date2023-07-12
Abstract

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.

eng
Keywords
  • Cell-free circulating DNA
  • Consanguinity
  • Fetal DNA
  • Monogenic disease
  • Noninvasive prenatal diagnosis
  • Pregnancy
  • Female
  • Humans
  • Noninvasive Prenatal Testing
  • Prenatal Diagnosis / methods
  • Genotype
  • DNA / genetics
Citation (ISO format)
FOKSTUEN, Siv et al. Noninvasive prenatal diagnosis of Mendelian disorders for consanguineous couples by relative genotype dosage. In: Clinical genetics, 2023, vol. 104, n° 5, p. 505–515. doi: 10.1111/cge.14399
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Identifiers
ISSN of the journal0009-9163
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Creation27/11/2023 13:28:40
First validation27/11/2023 14:18:55
Update time27/11/2023 14:18:55
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