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«KAI MURU Prenatal screening strategies, long-term outcome of children with marked changes in maternal screening tests and the most common syndromic ...»

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Prenatal screening strategies,

long-term outcome of children

with marked changes in maternal screening tests and the most common syndromic heart anomalies in Estonia






Prenatal screening strategies, long-term outcome of children with marked changes in maternal screening tests and the most common syndromic heart anomalies in Estonia Department of Pediatrics, University of Tartu, Tartu, Estonia Dissertation is accepted for the commencement of the degree of Doctor of Philosophy (in Medicine) on March, 19, 2014 by the Council of the Faculty of Medicine, University of Tartu Estonia Supervisors: Professor Katrin Õunap, MD, PhD Department of Pediatrics, University of Tartu, Tartu, Estonia Associate Professor Tiia Reimand, MD, PhD Department of Human Biology and Genetics at Institute of Biomedicine and Translation Medicine at University of Tartu, Tartu Estonia Department of Paediatrics, University of Tartu, Tartu, Estonia Referees: Professor Avo-Valdur Mikelsaar, MD, PhD Department of Human Biology and Genetics at Institute of Biomedicine and Translation Medicine at University of Tartu, Tartu, Estonia Researcher Kristiina Rull, MD, PhD Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia Department of Obstetrics and Gynecology, University of Tartu Opponent: Associate Professor Vedran Stefanovic, MD, PhD Department of Obstetrics and Gynecology Helsinki University Central Hospital, Helsinki, Finland Commencement: June 12, 2014, Publication of this dissertation is granted by the University of Tartu This research was supported by the European Union through the European Social Fund.

ISSN 1024–395X ISBN 978–9949–32–573–3 (print) ISBN 978–9949–32–574–0 (pdf) Copyright: Kai Muru, 2014 University of Tartu Press www.tyk.ee “Everything you can imagine is real.” Pablo Picasso






2.1. Prenatal screening and diagnosis

2.1.1. Epidemiology of aneuploidy

2.1.2. Principles of prenatal screening

2.1.3. Prenatal screening in the second trimester (Publication III)... 18 2.1.4. Prenatal screening in the first trimester

2.1.5. Different strategies in prenatal screening

2.1.6. Principles of procedures and diagnostic tests for prenatal diagnosis Chorionic villus sampling Amniocentesis Diagnostic tests after invasive procedure

2.2. Associations of marked changes in maternal screening tests and outcome

2.2.1. The significance of increased NT during first trimester ultrasound screening

2.2.2. Significance of marked changes in markers in maternal serum screening

2.3. Genetic causes of congenital heart anomalies (Publication IV)........ 32 2.3.1. Overview

2.3.2. Syndromal congenital heart defect Noonan syndrome LEOPARD syndrome Holt-Oram syndrome

2.3.3. Non-syndromal congenital heart defect GATA4 gene NKX2-5 gene TBX5 gene

2.3.4. Microdeletions and congenital heart defect 22q11.2 deletion syndrome

2.3.5. Prenatal diagnosis of congenital heart defect



4.1. Study subjects

4.1.1. Study group of prenatal screening

4.1.2. Study group of children born to mother after marked changes of markers in prenatal screening tests Prenatal study group Postnatal study group

7 4.1.3. Study group of children with congenital heart defect............. 49

4.2. Methods

4.2.1. Prenatal screening tests Maternal serum screening Ultrasound screening Prenatal cytogenetic investigation

4.2.2. Postnatal clinical examination Chromosomal microarray analysis APEX-array analysis for Noonan syndrome.............. 53 APEX-array and MLPA analyses for congenital adrenal hyperplasia syndrome (17-hydroxylase deficiency)... 53 Metabolic investigations

4.2.3. Sequencing of selected genes (TBX5 and PTPN11)................ 53 4.2.4. Statistical analysis

4.2.5. Ethical considerations


5.1. Contingent screening strategy for Down syndrome in Estonia......... 55 5.1.1. The results of first trimester screening for chromosomal abnormalities (Publication I)

5.1.2. The effectiveness of the used contingent screening protocol (Publication I)

5.2. Risk of chromosomally normal fetuses with marked changes in maternal first or second trimester serum markers and first trimester ultrasound marker NT having a congenital or genetic anomaly or delayed development at 2 years of age (Publication II)

5.2.1. Prenatal study group

5.2.2. Postnatal study group Case report – Congenital adrenal hyperplasia............ 68

5.3. Genetic causes of congenital heart anomalies in Estonian children.. 69 5.3.1. Noonan syndrome Phenotype evaluation of probands with clinical diagnosis of NS Molecular testing for PTPN11 gene Genotype-phenotype correlation of the patients with NS

5.3.2. LEOPARD syndrome (Publication V)

5.3.3. Holt-Oram syndrome (Publication VI)










This thesis is based on the following original publications referred to in the text

by Roman numerals (I–VI), and previous unpublished data:

I. Muru K, Sitska M, Asser K, Ehrenberg A, Karro H, Õunap K, Reimand T.

Prospective experience with contingent screening strategy for Down syndrome in Estonia. J Community Genet 2010; 1(3):133–138.

II. Muru K, Vals M-A, Sitska M, Asser K, Tammur P, Zilina O, Reimand T, Õunap K. Outcome of Children with Marked Changes in Maternal Screening Tests and Normal Karyotype. Hereditary Genetics 2014; 3:123.

III. Sitska M, Reimand T, Muru K. Prenatal diagnosis of fetal chromosomal anomalies: a summary of trimester II serum screening in Estonia (in Estonian). Eesti Arst 2008; 87(1):31−36.

IV. Muru K, Õunap K, Virro S, Kalev I. Genetic basis of congenital heart defects (in Estonian) Eesti Arst 2008; 87(5):357−366.

V. Kalev I, Muru K, Teek R, Zordania R, Reimand T, Köbas K, Õunap K.

LEOPARD syndrome with recurrent PTPN11 mutation Y279C and different cutaneous manifestations: two case reports and a review of the literature. Eur J Pediatr 2010; 169(4):469–473.

VI. Muru K, Kalev I, Teek R, Sõnajalg M, Kuuse K, Reimand T, Õunap K. A Boy with Holt-Oram Syndrome Caused by Novel Mutation c.1304delT in the TBX5 Gene. Mol Syndromol 2011; 1(6):307–310

My contributions to the original articles are:

Publication I: study design, data analysis, writing the paper Publication II: study design, data analysis, clinical evaluation of patients, data and sample collection, writing/co-writing the paper Publication III: data collection, reviewing the manuscript Publication IV: reviewing literature, writing the paper Publication V: clinical investigation of patient 2, data and sample collection, writing/co-writing the paper Publication VI: clinical investigation of patient, data and sample collection, writing the paper 9


AC amniocentesis AD autosomal dominant AFP α-fetoprotein ANF natriuretic peptide precursor A APEX arrayed primer extension AS aortic stenosis ASD atrial septal defect AVSD atrioventricular septal defect BAV bicuspid aortic valve bp base pair CAH congenital adrenal hyperplasia cfDNA cell free deoxyribonucleic acid CHD congenital heart defect CLS café-au-lait spots CMA chromosomal microarray analysis CoA coarctation of aorta CRL crown-rump length CVS chorionic villus sampling DNA deoxyribonucleic acid DORV double-outlet right ventricle DR detection rate DS Down syndrome (trisomy 21) d-TGA transposition of the great arteries DV ductus venosus ECG electrocardiography ECHO echocardiogram ERK extracellular signal-regulated kinases fb-HCG free β-human chorionic gonadotropin FISH fluorescence in situ hybridization FMF Fetal Medicine Foundation FPR false positive rate HCG human chorionic gonadotropin HCM hypertrophic cardiomyopathy HGNC HUGO Gene Nomenclature Committee HLHS hypoplastic left heart syndrome HOS Holt-Oram syndrome HR-CGH high-resolution comparative genomic hybridization HRH hypoplastic right heart ISCN International System for Human Cytogenetic Nomenclature ISPD International Society for Prenatal Diagnosis IUGR intrauterine growth restriction LBW low birth weight 10 LGA large for gestational age LS LEOPARD syndrome MAPK mitogen-activated protein kinases MI mitral insufficiency ML multiple lentigines MLPA multiplex ligation-dependent probe amplification MoM multiples of median NBL nasal bone length NF nuchal skinfold NF1 neurofibromatosis 1 NS Noonan syndrome NT nuchal translucency PA pulmonary atresia PAPP-A pregnancy-associated plasma protein -A PCR polymerase chain reaction PnD prenatal diagnosis PDA persistent truncus arteriosus PIH pregnancy induced hypertension PnS prenatal screening PS pulmonary stenosis SGA small for gestational age SNP single nucleotide polymorphism SRS Silver-Russell syndrome SV single ventricle TAPVC total anomalous pulmonary venous connection TCR tricuspid regurgitation TF transcription factor TOF tetralogy of Fallot uE3 unconjugated oestriol US ultrasound VSD ventricular septal defect

11Nomenclature of genes in text

ABCC9 ATP-binding cassette, sub-family C (CFTR/MRP), member 9 (HGNC_ID: 60) BMPR1A bone morphogenetic protein receptor, type IA (HGNC_ID: 1076)

BRAF v-raf murine sarcoma viral oncogene homolog B (HGNC_ID:

1097) CFC1 cripto, FRL-1, cryptic family 1 (HGNC_ID: 18292)

CHD7 chromodomain helicase DNA binding protein 7 (HGNC_ID:

20626) CRELD1 cysteine-rich with EGF-like domains 1 (HGNC_ID: 14630) CYP21A2 cytochrome P450, family 21, subfamily A, polypeptide 2 (HGNC_ID: 2600) DHCR7 7-dehydrocholesterol reductase (HGNC_ID: 2860) EVC Ellis van Creveld syndrome (HGNC_ID: 3497) FBN1 fibrillin 1 (HGNC_ID: 3603) GATA4 GATA binding protein 4 (HGNC_ID: 4173) HRAS Harvey rat sarcoma viral oncogene homolog (HGNC_ID: 5173) JAG1 jagged 1 (HGNC_ID: 6188) KDM6A lysine (K)-specific demethylase 6A (HGNC_ID: 12637) KMT2D lysine (K)-specific methyltransferase 2D (HGNC_ID: 7133) KRAS Kirsten rat sarcoma viral oncogene homolog (HGNC_ID: 6407) MAP2K1 mitogen-activated protein kinase kinase 1 (HGNC_ID: 6840) MAP2K2 mitogen-activated protein kinase kinase 2 (HGNC_ID: 6842) MYH11 myosin, heavy chain 11, smooth muscle (HGNC_ID: 7569) MYH6 myosin, heavy chain 6, cardiac muscle, alpha (HGNC_ID: 7576) NF1 neurofibromin 1 (HGNC_ID: 7765) NKX2-5 NK2 homeobox 5 (HGNC_ID: 2488) NOTCH1 notch 1 (HGNC_ID: 7881) NOTCH2 notch 2 (HGNC_ID: 7882)

NRAS neuroblastoma RAS viral (v-ras) oncogene homolog (HGNC_ID:

7989) PTEN phosphatase and tensin homolog (HGNC_ID: 9588)

PTPN11 protein tyrosine phosphatase, non-receptor type 11 (HGNC_ID:


RAF1 v-raf-1 murine leukemia viral oncogene homolog 1 (HGNC_ID:


SHOC2 soc-2 suppressor of clear homolog (C. elegans) (HGNC_ID:

15454) SMAD4 SMAD family member 4 (HGNC_ID: 6770) SMN1 survival of motor neuron 1, telomeric (HGNC_ID: 11117) SOS1 son of sevenless homolog 1 (Drosophila) (HGNC_ID: 11187) ZIC3 Zic family member 3 (HGNC_ID: 12874) TBX5 T-box 5 (HGNC_ID: 11604)

12Glossary of used terms

Screening method Description of the method First trimester Ultrasound screening at first trimester usually comprise an ultrasound ultrasound measurement of the width of an area of translucency at screening the back of the fetal neck – nuchal translucency; additionally there may be measurement of nasal bone length, fronto-nasal angel, tricuspid regurgitation etc.

First trimester Risk calculation is usually based on the measurements of PAPP-A serum screening and fb-HCG together with maternal age

–  –  –



The prevalence of chromosomal aneuploidies and structural defects varies at different stages of pregnancy, from approximately 20% of pre-implantation embryos to 0.2–0.93% of fetuses at term. Most of these are incidental mistakes [Baird et al., 1988; ESHRE 2008; Simpson 1990]. Trisomy 21 (Down syndrome, DS) is shown to be the most frequent chromosomal anomaly, with an incidence of 1 in 729 live born [Benn 2010]. Therefore, the development of prenatal screening and diagnostics is very important in clinical practice for detecting chromosomal anomalies as early as possible. The association between maternal age and the risk of having a DS pregnancy was first published in 1933 [Wald et al., 1997]. Prenatal diagnosis (PnD) become feasible for women with a high risk of fetal chromosomal disorders from the early 1970s, after Steele and Breg had succeeded, in 1966, in culturing and karyotyping amniotic fluid cells [Elias 2010; Steele and Breg 1966].

Serum screening in the second trimester was introduced into routine clinical practice in the early 1990s [Haddow et al., 1992]. Within a few years, first trimester markers, both ultrasound (US) and serum screening markers, came into use. First trimester combined screening is now the first choice in the routine care of pregnant women in many places. Nowadays already completely new screening tests are coming into clinical practice (e.g. cell free fetal DNA test) [Benn et al., 2013].

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