Human Genetic Variation Copy Number Variation

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1 The Evolution of Laboratory Prenatal Diagnosis Lawrence D. Platt, MD Professor of Obstetrics and Gynecology David Geffen School of Medicine at UCLA Center for Fetal Medicine & Women s Ultrasound Los Angeles, CA 970 s 990 s Types of Human Genetic Variation Nucleotide substitutions Gene Mutations Splice site mutations Promoter mutations Normal polymorphism Variable repeat lengths both normal and disease causing Inversions Translocations (balanced and unbalanced) Deletions/insertions ( bp to several Mb) Human Genetic Variation Copy Number Variation A CNV is a DNA segment (usually larger than kb) present at an altered copy number in comparison with a reference genome Whole chromosome aneuploidy Segmental aneuploidy Deletions Duplications Copy number polymorphisms Comparative Genomic Hybridization (CGH) Identifies chromosomal gains and losses in a single hybridization procedure Effectively reveals any DNA sequence copy number changes, i.e., gains, amplifications, losses and deletions) in a particular specimen and maps these changes on normal chromosomes Comparative Genomic Hybridization Differential labeling of DNA Reference (Normal Genomic) DNA Test DNA from Patient + Human cot- DNA Denature and preanneal Hybridize to normal chromosomes on slides Ratio profile excess of test DNA deficiency of test DNA

2 /6/205 Typical Patterns for Constitutional Deletion/Duplication copy Signal Copy number Signal Copy number Signal Copy number copies GAIN LOSS Heterochromatic Region normal deletion duplication Chromosome CGH in Clinical Cytogenetics Precise identification of extra or missing material Important for diagnostic and prognostic value Important for identifying those genes causative of the clinical phenotype Single step global genome scan prevents FISHing expedition DNA-based analysis Quality of patient metaphase spreads is not a consideration Non-viable tissues are amenable to analysis CGH in a patient with an Apparently Balanced Translocation and Clinical Abnormalities q2 q22 Initial Karyotypic Designation 46,XY,t(;2)(p22;q4.) 2P Telomere 2q Telomere BAC RPCI- 9A Marker Alpha Sat 6 Wcp 6 2

3 Conventional CGH and Array CGH (ccgh) Label patient DNA Label control DNA with Cy3 with Cy5 Mix Label patient DNA Label control DNA with Cy3 with Cy5 Mix Label patient DNA Label control DNA with Cy5 with Cy3 Mix Chromosomal CGH Hybridize DNA to genomic clone microarray Hybridize DNA to olgonucleotide microarray Oligonucleotide-Based Microarrays Oligos are synthesized directly on slides Analyze Cy3/Cy5 fluorescence ratio of patient to control Microarrayed DNA Cy3/Cy5 ratio > Cy3/Cy5 ratio < Duplication Deletion Cy3/Cy5 ratio > Cy3/Cy5 ratio < Duplication Deletion Matrix CGH Modified from Lichter: Seminars in Hematology 37: , 2000 Cy3/Cy5 ratio < Cy3/Cy5 ratio > Duplication Deletion Short target sequences pre-tested for hybridization efficiency Resolution limited only by number of oligos 22q Deletion Inversion? Normal Dup (X)(q.q2.) 3

4 Advantages of Molecular Karyotyping by acgh Higher resolution independent of the ability of the cells to grow and/or generate good metaphase spreads Standard karyotype 5MB resolution acgh Mb to 00 or less resolution Direct mapping or aberrations to the genome sequence Amenable to automation and quality control procedures Higher throughput and shorter reporting times Better AND Cheaper! Postnatal arrays for children with normal conventional karyotype, dysmorphic features and/or developmental delay Higher Resolution Arrays N % with significant CNV De Vries 2005 Whole genome 00 0 tiling-path Friedman kb 00 Menten Mb Targeted Arrays Poss 2006 Targted Aylor 2006 Targeted Schaeffer Targeted Potential issues of acgh for prenatal diagnosis What should a prenatal diagnostic array contain? Targeted array vs. whole genome screen? Results of unknown clinical significant Copy Number variants Mosacism Appropriate counseling Targeted Array 43 unique pericentric regions Marker chromosomes that contain a centromere 4 unique telomere regions Sub-telomere deletions or duplications Specific disease loci (approximately 70) Backbone of approximately 5 Mb density Clones with minimal variation along each chromosome to determine genomic imbalance outside the targeted regions Criteria for disease loci on prenatal microarray A significant proportion of cases caused by deletions or duplications Disease of significant clinical importance Spectrum of disease understood Associated with ultrasound findings Some Suggested Disease Specific Loci Angelman Kallmann/Steroid Sulfatase Rett syndrome deficiency Aniridia/Wilms Tumor Langer-Giedion Smith-Magenis /Trichorhinophalangeal Cat-eye Miller-Dieker/Isolated Sotos Lissencephaly Cri-du-Chat Prader-Willi SRY Test is determining factor DiGeorge /Velocardiofacial Potocki-Shaffer Williams-Beuren (VCF) Jacobsen/q terminal Retinoblastoma/MR Wolf-Hirschhom deletion disorder 4

5 Normal Copy Number Variation Widespread in the human genome Cover approximately 2% (360 Mb) of the human genome CNV varies from 6% to 9% of any chromosome Average of about 2 CNVs per person with 35k resolution Not associated with obvious pathology May contribute to phenotypic variation Almost always inherited May contain known genes Postnatal arrays for children with normal karyotype dysmorphic features and/or developmental delay Higher Resolution Arrays N % with significant CNV Familial CNV or CNV of unknown significance De Vries 2005 Whole genome % with CNV tiling-path Friedman kb 00 00% with CNV 30 CNV per case Menten Mb Targeted Arrays Poss 2006 Targeted Aylor 2006 Targeted Schaeffer Targeted % with CNV The Next Generation Ch 2 - STRs Maternal allelles Paternal allelles Association of Copy Number Variants With Single and Multiple Structural Anomalies of Specific Fetal Organ Systems Lawrence D. Platt, MD Size Fractionated DNA February, 205 Trisomy-2 demonstrated in the fetal DNA 5

6 Background Background Meta-analysis of abnormal fetal ultrasound and chromosomal microarray Incremental detection rate 7% to 0% When a fetal anomaly is diagnosed on ultrasound, microarray may influence counseling offered Provided clinically relevant additional information in 6.0% of anomalous fetuses with a normal karyotype Hillman SC, et al. Ultrasound Obstet Gynecol 203; 4 (6): Aim To quantify the additional benefit of microarray in the presence of an ultrasound detected fetal abnormality and a normal karyotype In a single system In multiple systems To determine the relative frequencies of CNVs in specific systems Conclusions Chromosomal microarray offers significantly greater clinically relevant information above karyotype especially when anomalies present in more than one system Isolated cardiac and renal systems give highest yield even when excluding common deletions Microarray allows for detection of genetic syndromes that may not always display characteristic findings on ultrasound, e.g. 22q.2 Conclusions Larger, prospective databases required To further define clinical usefulness of chromosomal microarray in specific anomalies To define the long-term phenotype, especially important for infrequently occurring CNVs Acknowledgments Lawrence Platt Andrei Rebarber William Grobman Anthony Johnson Michelle DiVito Ronald Wapner Julia Zachary Vinay Bhandaru Melissa Savage The entire Prenatal Microarray Study Group Funded by 6

7 The Follow-up Study Results: Most common CNVs seen (N=6) CNV Del Dup Total N=6 N % 22q % 7q % % q % 0q % 5q Single occurrence % Anomaly by Gestation Anomaly N=752 CNV array Add l benefit P Value ANY % <0.00 ANY <5 weeks ANY >5 weeks % <0.00 Skeletal Anomalies (N=93) Skeletal Anomaly N=93 CNV array Add l benefits P Value Skeletal ALL % Skeletal dysplasia Long bong or joint (excl. 36.7% <0.00* skeletal dysplasia) Talipes ALL** % 0.053* Talipes SINGLE 2 8.3% 0.36* *=Fisher s exact test **excludes skeletal dysplasia Facial Anomalies (N=08) Facial Anomaly N=08 CNV Array Add l benefit PValue Face ALL % <0.00* Face SINGLE 8 5.9% NS Flat profile + ALL % 0.08* Micrognathia + ALL % 0.06* Cleft lip or palate + ALL % 0.063* Thorax Anomalies (N=50) Thorax Anomaly N=50 CNV Array Add l benefit P Value Thorax ALL % 0.004* SINGLE Thorax % 0.558* Congenital Diaphragmatic Hernia % 0.097* *=Fisher s exact test *=Fisher s exact test 7

8 Study Group Control Group Anomalies and 22q.2 del/dup Cardiac Anomalies CNV n=24 % of Total Cardiac Cardiac with 22q 8/ % Cardiac without 22q 6/ % 22q.2 CNV n= % of Anatomical Findings With cardiac findings 8/ 72.2% Other anatomic defects 3/ 8.8% Anomaly System SINGLE system MULTIPLE system Frequency of CNVs in Single and Multiple Ultrasound Anomalies N=752 CNV array findings (n) Add l benefit (%) P value % % <0.00 =increased NT (dup), cystic lung lesion, fetal growth restriction Structural Anomalies Array adds significant clinically relevant information in cases with normal karyotype Structural Anomaly Fiorentino 6.% Rosenfeld / Shaffer 6.6% Schwartz 5.7% NICHD 6.0% Anomaly System N=752 CNV array findings (n) Add l benefit (%) SINGLE system % MULTIPLE system Frequency of CNVs in Single and Multiple Ultrasound Anomalies % 8

9 Ultrasound Detected Anomalies Normal Karyotype Anomaly system N = 752 CNV array findings () Add l benefit (%) P value Cardiac % <0.00 Face % <0.00* Thorax % 0.004* Renal % 0.004* Fetal Growth Restriction * GI % 0.047* CNS % <0.00 Skeletal/Joints % Genital 2 8.3% -- Abdominal Wall % -- *=Fisher s exact test Frequency of Ultrasound Detected Anomalies Single Anomaly system N = 454 CNV array findings () Add l benefit (%) Renal % Cardiac % Fetal Growth Restriction % Face 7 5.9% Thorax % Skeletal % CNS (including NTD) % *=Fisher s exact test Fetuses with Structural Cardiac Defect (N=297) All cardiac defects Isolated cardiac defect N with Normal CNV and Karyotype Normal Karyotype Not Detected by 22q FISH (4.3%) 67% 59 8 (3.6%) 63% Frequency of CNVs in Karyotype Normal Cases Sampled for AMA, Positive Screen, or Anxiety Primary Study N Pathogenic Frequency CNVs Primary Study 3, % Present Study 2, % Total 5, % Variants of Unknown Significance Change in Classification with Time (N=3822 pts, CNVs=65) VOUS Pathogenic Benign % (N=94) 0.9% (=35) 0.9% (N=36) 202.5% (N=58).7% (N=65).% (N=42) 203.2% (N=47).7% (N=65).4% (N=53) % (N=35).8% (N=70).6% (N=60) Where are we going? Non-invasive sequencing of the fetal genome is likely to be a reality in the not-too-distant future Tremendous counseling and ethical issues Uncertain Reassurance Counseling Scope Creep 9

10 Evaluation of Structural Anomaly Seen on Ultrasound 22q Deletion Spectrum of Clinical Features (N=900) Learning Disabilities --none/mild --moderate/severe % Cardiac Defects 75 Genitourinary Defets 36 Palate Anomalies --cleft palate --velopharngeal insufficiency Abnormal facial features Frequent Growth delay (<3 rd %) 36 Psychosis/Behavior Problems 25 Hypoparathyroid 60 Significant Microdeletions Associated with CHD Del p36 ID Del q2. Mild MI Del p6.3 Wolf-Hirschhorn Syndrome Microcephaly, severe ID, seizure Del 5p5.2 Cri-du-chat Severe ID Del 5q35.2 ASD and conduction defect Del 7q.23 Williams-Bueren Syndrome Cognitive deficits, infantile hypocalcemia Del 8p23. ID Del 9q34 Del q23-qter Jacobsen Syndrome ID Del 6p3.3 Rubenstein Taybi + CHD ID Del 20p2.2 Alagille Syndrome Liver disease Del 22q.2 DiGeorge Syndrome ID, Schizophrenia Amniocentesis Karyotype: 4,XY, Array:.39 Mb gain in 7q.23 7q.23 microduplication syndrome CVS: Normal Karyotype Array: arr 7q2( )x Van der Aa, et al. Fourteen new cases contribute to the characterization of the 7q.23 microduplication syndrome. European Journal of Medical Genetics 2009 TCF2 deletion Renal Cysts and Diabetes 0

11 Clinically Relevant Information Seen by CMA and Reported to Patients in Cases with Normal Karyotype Indication By Indications for Testing Totally Clinically Relevant 95% CI AMA (=966) 34 (.7%) Positive Screen 2 (.6%) (N=729) All Low Risk Pregnancies Comparing CNV Rates in Low Risk Pregnancies Analysis of ~2,000 Recent Prenatal Arrays Indication Low Risk Subgroups Pathogenic Samples CNVs (%) Samples Pathogenic CNVs (%) Samples Lee et al. 202 Armengol et al. Other studies a Fiorentino et al., 202 Wapner et al., 202 Combined (n = 37) (n = 906) (n = 000) (n = 3000) (n = 3822) (n=,899) Pathogenic CNVs (%) (0.5) (.) (.0) Samples Pathogenic CNVs (%) Samples Pathogenic CNVs (%) Samples Pathogenic CNVs (%) (0.6) (.6) (0.9%) AMA 9 0 (0.5) (.) 253 (0.4) 8 6 (0.5) (.7) (.0%) Parental Anxiety (0.5) 60 (.7) (0.7) (.3) (0.7%) Abn Serum Screen (0.4) (9.) (.6) (.4%) a Compiled by Fiorentino et al., 202; includes Coppinger at al. 2009; Shaffer et al., 2008; Maya et al., 200; Van den Veyver et al., 2009; Sahoo et al., (low risk = no ultrasound abnormality) Recurrent CNVs that have the Potential to Cause Neurocognitive Impairment Occurred in approximately in 25 (0.%) cases sampled for AMA or positive screening Deletions N Nl US Duplications N N US q2. q q q.2q3. 5q3.2q3.3 5q3.2q3.3 6p p3.p p2. 0 6p p3.p q2 6 7q q q Why would I want to know this? As genomic technologies provide testing for a large spectrum of phenotypes, pregnancy termination is only one of many uses of the information obtained prenatally Advantages of identifying an etiology Referral to appropriate specialists & social services Targeted treatment Identify special education resources Appropriate surveillance & long-term follow-up More accurate recurrence risk estimate Prenatal diagnosis in subsequent pregnancies Referral to parent support groups and online resources Variants of Uncertain Clinical Significance Other cases Known del/dup or Mendelian disorders [OMIM, DECIPHER (Sanger)] Known benign CNV [DGV (Toronto), dbvar (NCBI) Comparison with other cases [PubMed, DECIPHER] Large Databases ISCA Consortium Genomic/Gene Content Correlates with size/location[uscs, Ensembl (Sanger)] Change in Classification of CNVs N=3822, CNVs=65 VOUS Pathogenic Benign % (N=94) 0.9% (=35) 0.9% (N=36) 202.5% (N=58).7% (N=65).% (N-42) 203.2% (N-47).7% (N=65).4% (N=53) % (N=35).8% (N=70).6% (N=60) 203: 5q.2 inherited deletions upgrades from ucnc to pcnc the same 204: 6p3. duplications upgraded to pcnc

12 Han 2008 Chang 202 Frequency of Findings of Uncertain Significance in Amniocentesis Karyotype Mosaic Inversion Balanced Recip Translocation Marker Other Autosomal Trisomy Total 0.5% 0.5% 0.50% 0.0% 0.02% 0.85% 0.3% 0.20% 0.40% 0.08% --.0% CVS: Confined Placental Mosaicism -2% 2

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