Hudecova, I;
Jiang, P;
Davies, J;
Lo, YMD;
Kadir, RA;
Chiu, RWK;
(2017)
Noninvasive detection of F8 int22h-related inversions and sequence variants in maternal plasma of hemophilia carriers.
Blood
, 130
(3)
pp. 340-347.
10.1182/blood-2016-12-755017.
Preview |
Text
Abdul-Kadir_Noninvasive detection of F8 int22h-related inversions and sequence variants in maternal plasma of hemophilia carriers_AAM.pdf - Accepted Version Download (7MB) | Preview |
Abstract
Direct detection of F8 and F9 sequence variants in maternal plasma of hemophilia carriers has been demonstrated by microfluidics digital PCR. Noninvasive prenatal assessment of the most clinically relevant group of sequence variants among patients with hemophilia, namely, those involving int22h-related inversions disrupting the F8 gene, poses additional challenges because of its molecular complexity. We investigated the use of droplet digital PCR (ddPCR) and targeted massively parallel sequencing (MPS) for maternal plasma DNA analysis to noninvasively determine fetal mutational status in pregnancies at risk for hemophilia. We designed family-specific ddPCR assays to detect causative sequence variants scattered across the F8 and F9 genes. A haplotype-based approach coupled with targeted MPS was applied to deduce fetal genotype by capturing a 7.6-Mb region spanning the F8 gene in carriers with int22h-related inversions. The ddPCR analysis correctly determined fetal hemophilia status in 15 at-risk pregnancies in samples obtained from 8 to 42 weeks of gestation. There were 3 unclassified samples, but no misclassification. Detailed fetal haplotype maps of the F8 gene region involving int22h-related inversions obtained through targeted MPS enabled correct diagnoses of fetal mutational status in 3 hemophilia families. Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR represents an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma. These advancements may bring benefits for the pregnancy management for carriers of hemophilia sequence variants; in particular, the common F8 int22h-related inversions, associated with the most severe clinical phenotype.
| Type: | Article |
|---|---|
| Title: | Noninvasive detection of F8 int22h-related inversions and sequence variants in maternal plasma of hemophilia carriers |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1182/blood-2016-12-755017 |
| Publisher version: | https://doi.org/10.1182/blood-2016-12-755017 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10067666 |
Archive Staff Only
 |
View Item |
