Non-invasive Prenatal Diagnosis (NIPD) - PowerPoint Presentation

1. Non-invasive Prenatal Diagnosis (NIPD)

2. Cell-free fetal DNA (cffDNA)Maternal blood contains maternal AND fetal DNAThe fetal DNA in maternal plasma is called cell free fetal DNA (cffDNA)Originates from trophoblast (placenta)Detectable from 6 weeks gestationAround 5% - 20% of total circulating cell free DNAProportion increases with gestationCleared from circulation within 30 minutes of deliveryShort DNA fragments, whole fetal genome represented2https://portal.e-lfh.org.uk/LearningContent/Launch/671161

3. Non-invasive Prenatal Diagnosis (NIPD)NIPD is a genetic test that is carried out on the cell-free fetal DNA that is found in the maternal bloodstream  requires a blood sample from the mother in order to test the fetus

4. Non-invasive Prenatal Diagnosis (NIPD)9

5. NIPD (diagnosis) vs. NIPT (testing)Both NIPD and NIPT work by analysing cell-free DNA found in the mother’s blood NIPTNIPDMainly used to detect aneuploidies (an abnormal number of chromosomes)Used to identify certain single gene conditionsScreening only, invasive testing required to confirm resultConsidered diagnostic, invasive testing not requiredRisk of placental mosaicism (false-positive results) and maternal chromosomal anomaliesNo placental mosaicism for monogenic conditions. Maternal germline analysed in parallel

6. NIPD for single gene conditionsCan be carried out for:Fetal sexing, for sex-linked conditions, reduces invasive testing by ~50%De-novo conditions (present in the fetus but not in the parents)Paternal gene variant exclusionChecks for a paternal autosomal dominant or recessive gene variant – if this is not found this means the fetus does not carry the variantReduces invasive testing rate by ~50%Measuring relative gene copy amount (haplotype dosage)Compares the amounts of the maternal and paternal gene copy to predict whether the fetus will be affected by a condition (eg Cystic Fibrosis, Spinal Muscular Atrophy) 6

7. https://www.england.nhs.uk/wp-content/uploads/2018/08/Rare-and-Inherited-Disease-Eligibility-Criteria-November-2020-21.pdfNational Genomic testing directory

8. Bespoke NIPDBespoke NIPD can be offered to couples at risk of a pregnancy with a rare single-gene condition with a known genetic variantAssay development ideally pre-pregnancy (takes approximately 8 weeks)Need DNA from an affected parent or previously affected child/ pregnancy to create the assay8

9. Low fetal fraction (too early in pregnancy)Failed/inconclusive results (can repeat)Maternal mosaicismAffected mothersRelative haplotype dosage analysis challenging (costs, time, sufficient samples for validation), only worked up for common conditionsHaplotype dosage not (yet) for consanguineous familiesHaplotype dosage requires samples from father and previous child/ pregnancy – not always available Limitations of NIPD

10. Key PointsNIPD is carried out by analysing cell-free DNA in the mother’s bloodIt is used to identify certain single-gene conditions (listed in the National Genomic Test Directory)Bespoke NIPD can be offered to couples at risk of a pregnancy with a single-gene condition with a known genetic variantIt is a diagnostic test, meaning that invasive testing is not required to confirm the result  this will reduce the number of invasive tests carried out with the small associated risk of miscarriageWhen meeting a family with a history of a monogenic condition who want prenatal diagnosis it is important to contact your local genetics team as the range of tests offered is increasing. This is best done before pregnancy.

11. Resourceshttps://www.genomicseducation.hee.nhs.uk/blog/prenatal-genomics-an-overview/https://www.genomicseducation.hee.nhs.uk/blog/what-is-nipd/https://www.rcog.org.uk/en/guidelines-research-services/guidelines/consensus-statement-prenatal-screening/https://www.england.nhs.uk/publication/national-genomic-test-directories/ https://www.futurelearn.com/courses/non-invasive-prenatal-testing