PREVENTION OF HAEMOGLOBINOPATHIES: New methodologies and procedures Non-invasive Prenatal Diagnosis

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1 PREVENTION OF HAEMOGLOBINOPATHIES: New methodologies and procedures Non-invasive Prenatal Diagnosis Marina Kleanthous Cyprus School of Molecular Medicine The Cyprus Institute of Neurology and Genetics 11th Annual Sickle Cell Disease and Thalassaemia Conference (ASCAT) October 2017, London UK

2 Prenatal Diagnosis Prenatal diagnosis by CVS/amniocentesis Preimplantation genetic diagnosis (PGD) Non-invasive prenatal diagnosis (NIPD) 2

3 NIPD Clinical Use 01 Aneuploidies (Chromosomes 21, 18, 13) RHD for haemolytic disease of the newborn Y chromosome detection for X-linked disorders Single gene diseases (Achondroplasia, congenital adrenal hyperplasia, Cystic Fibrosis) 3

4 Cell-Free Fetal DNA Discovery of cell-free fetal DNA in maternal plasma of pregnant women (Lo et al., 1997) Apoptotic placental cells/trophoblasts (Flori et al., 2004) Represents 5-10% of cell-free DNA in maternal plasma (Lo et al., 1998) Fragmented, prominence size at 143bp (Lo et al., 2010) Detectable from 5 th week of gestation (Honda et al., 2002) Increased during pregnancy and disappears rapidly after delivery (Lo et al., 1999) Fetal fraction varies between pregnancies (Galbiati et al., 2005) The entire fetal genome is represented in maternal plasma (Lo et al, 2010)

5 OUR APPROACH Aim N/IVS1-110 N/IVS1-110 Development of a reliable NIPD assay for β-globin gene diseases using SNPs located on the β-globin gene cluster βthal a c g t Normal g t c g a c c g ND a c c g ND Mat. plasma a c c g g t c g ND normal SNPs and haplotype analysis Mutation detection 5

6 METHODS Fast COLD PCR Detection of the paternally-inherited fetal alleles Targeted Next Generation Sequencing Fetal fraction measurement Detection of the paternally-inherited fetal alleles Detection of the maternally-inherited fetal alleles (Relative Variant Dosage) Droplet Digital PCR Fetal fraction measurement Detection of the paternally-inherited fetal alleles Detection of the maternally-inherited fetal alleles (Relative Variant Dosage) Chromosomal Haplotyping (without family study)

7 Fast COLD PCR Preferential amplification of the minor allele over the overwhelming background of the major allele using a critical denaturation temperature, Tc Tc lower than the Tm of the major allele Enrichment of Tm-reducing variations (G:C>A:T or G:C>T:A) Makrigiorgos et al., 2008

8 Selection of SNPs with High Degree of Heterozygosity 130 SNPs located on the β-globin gene cluster (http://www.ncbi.nlm.nih.gov) 75 random samples (Cyprus Population) Sequenom MALDI-TOFF Mass Array 49 SNPs with Tm-reducing higher than variants 6% of for Fast COLD PCR heterozygosity were selected for SNP1 G/A further analysis for NIPD SNP2 G/T 8

9 Fast Temperature- Gradient COLD PCR Fast TG COLD PCR Denature all DNA at 94 C Fetal Maternal Tm-reducing variations Tm Fetal < Tm Maternal Tc < Tm Maternal Primer annealing at 56 C Extend at 72 C 5 cycles SNP 1 SNP 2 Tc1= 77.4 C Tc1= 77.3 C Tc2= 77.6 C Tc2= 77.5 C Tc3= 77.8 C Tc3= 77.8 C Tc4= 78.0 C Denatured fetal (minor) dsdna maternal (major) Primer annealing at 56⁰C 10 cycles for each Tc Extend at 72⁰C

10 Genomic DNA analysis SNP1(G/T) Genomic DNA spikes 95% GG and 5% TT allele Mimic the fetal-maternal relationship in maternal plasma Fulfil the Tm-reducing criterion Sample Run 1 - Replicate 1 Run 1 - Replicate 2 Run 1 - Replicate 3 100% GG 100% TT Assessment of reproducibility 3 replicate reactions/run 3 runs 95% GG & 5% TT ~70% ~60% ~70% 10

11 Genomic DNA analysis SNP2(G/A) Sample Run 1 - Replicate 1 Run 1 - Replicate 2 Run 1 - Replicate 3 100% GG 100% AA 95% GG & 5% AA ~55% ~60% ~55% Specificity, reproducibility and repeatability of the assay were optimized 11

12 Evaluation of Fast TG COLD PCR on maternal plasma samples Blood collection ~8 th wk gestation- 9ml PB cff DNA isolation from maternal plasma 17 maternal plasma samples of pregnancies at risk for β-thalassaemia 8 for SNP 1 (G/T) 9 for SNP 2 (G/A) Assessment of reproducibility 3 replicate reactions/run 3 runs 12

13 8 Maternal plasma analysis-snp1 111 M: GG F: TT CVS: GT MP: GT 167 M: GG F: GT CVS: GT MP: GT 179 M: GG F: GT CVS: GG MP: GG 182 M: GG F: TT CVS: GT MP: GT Fast TG COLD PCR ~95% ~70% 0% ~100% Fast TG COLD Fast TG COLD Regular PCR 0% 0% 0% 0% Fast TG COLD PCR 186 M: GG F: TT CVS: GT MP: GT 194 M: GG F: GT CVS: GT MP: GT ~90% ~95% 199 M: GG F: GT CVS: GT MP: GT ~60% 205 M: GG F: GT CVS: GT MP: GT ~100% Regular PCR 0% Fast TG COLD 0% 0% Fast TG COLD 0% Regular PCR 13

14 9 Maternal plasma analysis-snp2 Fast TT COLD PCR 162 M: GG F: GA CVS: GA MP: GA 165 M: GG F: GA CVS: GA MP: GA 173 M: GG F: GA CVS: GG MP: GG Fam 177 M: GG F: GA CVS: GG MP: GG ~90% ~90% 0% 0% Fast TG COLD Fast TG COLD Regular PCR 0% 0% 0% 0% Fast TT COLD PCR 185 M: GG F: GA CVS: GG MP: GG 190 M: GG F: GA CVS: GA MP: GA 197 M: GG F: GA CVS: GA MP: GA 199 M: GG F: GA CVS: GA MP: GA 203 M: GG F: GA CVS: GA MP: GA 0% ~55% ~70% ~90% ~90% Regular PCR Fast TG COLD Fast TG COLD Regular PCR 0% 0% 0% 0% 0% 14

15 Assessment of accuracy, SNP 1 (minor allele T) NIPD family 205 Mother: GG Father: GT CVS: GT Maternal Plasma: GT Run 1 Replicate 1 Replicate 2 Replicate 3 ~100% ~55% ~90% Run 2 ~55% ~70% ~55% Run 3 ~55% ~0% ~20% 7/9 replicates in agreement (80%) Enrichment of minor allele Fetal genotype: GT 15

16 DETECTION OF FETAL GENOTYPES USING MATERNAL PLASMA Comparison with CVS results SNP 1 1 st run 2 nd run 3 rd run Family number Fetal Genotype (CVS analysis) Fetal Genotype (Maternal plasma analysis) 111 g/t g/t g/t g/t g/t g/t g/t g/t g/t g/t g/t 167 g/t g/t g/t g/t g/t g/t g/t Run out of sample g/t 179 g/g g/g g/g g/g g/g g/g g/g g/g ND ND g/g 182 g/t g/t g/t g/t g/t g/t g/t g/t g/t g/t g/t 186 g/t g/t g/t g/t g/t g/t g/t g/t ND g/t g/t 194 g/t g/t g/t g/t g/t g/t g/t g/t g/t g/t g/t 199 g/t g/t g/t g/t g/t g/t g/t g/t g/t g/t g/t 205 g/t g/t g/t g/t g/t g/t g/t ND g/t g/g g/t 100% concordance with CVS analysis 57 +ve detection of paternal allele 7 -ve detection of paternal allele 4 Not determined 1 False negative 16

17 DETECTION OF FETAL GENOTYPES USING MATERNAL PLASMA Comparison with CVS results SNP 2 1 st run 2 nd run 3 rd run Family number Fetal Genotype (CVS analysis) Fetal Genotype (Maternal plasma analysis) 44 +ve detection of paternal allele 162 g/a g/a g/a g/a g/a g/a g/a Run out of sample g/a 165 g/a g/a g/a g/a g/a g/a g/a Run out of sample g/a 173 g/g g/g g/g g/g g/g g/g g/a g/g g/g g/g g/g 177 g/g g/g g/g g/g g/g g/g g/g g/g g/g g/g g/g 185 g/g g/g g/g g/g g/g g/g g/g g/g g/g g/g g/g 190 g/a g/a g/a g/a g/a g/a g/a g/a g/a g/a g/a 197 g/a g/a g/a g/a g/a g/a g/g g/a g/a g/a g/a 100% concordance with CVS analysis 199 g/a g/a g/a g/a g/a g/a g/a Run out of sample g/a 203 g/a g/a g/a g/a g/a g/a g/a g/a g/a g/a g/a 26 -ve detection of paternal allele 1 False positive 1 False negative 17

18 Haplotype analysis NIPD family 199 NIPD: β-thal trait or normal Invasive prenatal diagnosis is avoided 18

19 NIPD with Fast TG COLD PCR Clinical Use High sensitivity and specificity Paternaly inherited fetal alleles NGS is the method of choice Fast TG COLD PCR can be used as a confirmatory method 19

20 ACKNOWLEDGEMENTS THE CYPRUS INSTITUTE OF NEUROLOGY & GENETICS, NICOSIA, CYPRUS Dr. Thessalia Papasavva Stefania Byrou (PhD student) Dr. Petros Kountouris Prof. Marina Kleanthous DANA FARBER CANCER INSTITUTE, HARVARD MEDICAL SCHOOL Prof. Mike Makrigiorgos ERASMUS CENTER FOR BIOMICS, ERASMUS MEDICAL CENTRE (EMC), ROTTERDAM, THE NETHERLANDS Assistant Prof. Wilfred van Ijcken Dr. Rutger Brouwer THALASSAEMIA CLINIC, MAKARIOS HOSPITAL, CYPRUS FETAL MEDICINE UNIT AND ULTRASOUND AND PRENATAL DIAGNOSIS UNIT, MAKARIOS HOSPITAL, CYPRUS Dr Agathoklis Christofides AAK ULTRASOUND AND FETAL MEDICINE CENTRE, NICOSIA, CYPRUS Dr. Ioannis Kallikas Funded by - TELETHON 2015, CYPRUS

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