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Come gather 'round people Wherever you roam And admit that the waters Around you have grown And accept it that soon You'll be drenched to the bone. If.

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Presentation on theme: "Come gather 'round people Wherever you roam And admit that the waters Around you have grown And accept it that soon You'll be drenched to the bone. If."— Presentation transcript:

1 Come gather 'round people Wherever you roam And admit that the waters Around you have grown And accept it that soon You'll be drenched to the bone. If your time to you Is worth savin' Then you better start swimmin' Or you'll sink like a stone For the times they are a-changin'.

2 THE NEXT GENERATION: Microarray and Beyond


4 Karyotype Resolution: >7-10 Million Base Pairs (7-10 Mb ) Resolution: < 0.5 Million Base Pairs (< 500 kb) Chromosomal Microarray (CMA)

5 Microdeletion Syndromes DiGeorge22q11 Deletion3.5Mb Miller Dieker17p13.3 deletion Prader Willi15q11-13 deletion4MB Smith Magenis 17p11.2 deletion5Mb Wolf Hirshhorn 4p16.3 deletion1.9Mb Williams- Beuren 7q11.23Deletion1.5Mb Non-Syndromic Micro Del /Dups 15-20% yield by CMA in children with unexplained developmental delay/ID, and congenital anomalies compared to ~3% with karyotype 16p11.2 Autism 0.55Mb 1q21.1 ID, microcephaly, cardiac, cataracts 0.8Mb 16p13.11 Autism, ID, and schizophrenia 0.8Mb ID: Intellectual Disability Velo Cardio Facial Syndrome Postnatal Studies

6 Structural Anomalies Array Adds Significant Clinically Relevant Information in Cases With Normal Karyotype Structural Anomaly Fiorentino 6.1 % Rosenfeld /Shaffer 6.6 % Schwartz 5.7 % NICHD 6.0 %


8 7q11.23 microduplication syndrome Amniocentesis: Karyotype: 46,XY Array: 1.39 Mb gain in 7q11.23 Van der Aa, et al. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. European Journal of Medical Genetics 2009

9 Left Foot Right Foot

10 Differential Diagnosis Aase Syndrome Diamond-blackfan Syndrome DOOR Syndrome Duane-radial Syndrome (DR Syndrome) Fanconi Anemia (Pancytopenia-dysmelia Syndrome) Fetal Hydantoin Syndrome (Dilantin Embryopathy) Goodman Syndrome Holt-Oram Syndrome Hypomelanosis Of Ito IVIC Syndrome Juberg-hayward Syndrome Lacrimo-auriculo-dento-digital Syndrome (LADD Syndrome) (Levy-hollister Syndrome) Mesomelic Dysplasia (Werner Type) Nager Syndrome Normal Variant : Isolated Anomaly Poland Syndrome (Pectoral Muscle Aplasia-syndactyly) Thalidomide Embryopathy Townes-brocks Syndrome Trichorhinophalangeal Dysplasia Type (Langer Gidieon Syndrome) Trisomy 13 Trisomy 22 VATER Association

11 Mutation Sequencing

12 Triphalangeal thumb with Polysyndactyly Mutation in SHH gene Mutations in the Sonic hedgehog limb enhancer, the zone of polarizing activity regulatory sequence (ZRS, located within the gene LMBR1), commonly called the ZRS), cause limb malformations Sequencing Analysis




16 You’re pregnant and You must know the sex Deep sequencing Ma, It’s all the rage ! BH 2012 SC

17 By Indications for Testing IndicationTotal Clinically Relevant 95% CI AMA N=1966 34 (1.7%)1.2 – 2.4 Positive Screen N=729 12 (1.6%)0.9 – 2.9 Clinically Relevant Information Seen by CMA and Reported to Patients in Cases with Normal Karyotype

18 Recurrent CNVs That Have The Potential To Cause Neurocognitive Impairment Occurred in approximately 1 in 125 (0.8%) cases sampled for AMA or positive screening DeletionsNNl US 1q21.1 7q11.23 1111 1010 15q11.222 15q13.2q13.311 16p11.232 16p12.110 16p13.11p12.331 16p13.1153 17q1261 22q11.2113 DuplicationsNNl US 1q21.1 15q11.2q13.1 15q13.2q13.3 411411 211211 16p13.11p12.321 16p13.1143 17q12 22q11.21 3232 2222

19 Conclusion Based on the increased detection of clinically relevant abnormalities in both structurally normal and abnormal pregnancies, chromosomal microarray analysis (CMA) should be transitioned to become the first tier test for invasive prenatal cytogenetic diagnosis.

20 Findings of Unknown Significance Variable Expressivity

21 Variants of Uncertain Clinical Significance 1. Other Cases - known del/dup or Mendelian disorders OMIM, DECIPHER (Sanger) - known benign CNV DGV (Toronto), dbVar (NCBI) - comparison with other cases PubMed, DECIPHER 2. Large Databases ISCAConsortium 3. Genomic/Gene Content - correlates with size/location UCSC, Ensembl (Sanger)

22 Variants Of Uncertain Clinical Significance Counseling Issues VOUSPathogenic Likely Benign 2007 Study Classification 94 (2.5%) 35 (0.9%) - 2012 Classification 57 (1.5%) 64 (1.7%) 8 As CMA Transitions Into Practice Counseling By Professionals With Knowledge And Expertise In CMA Will Be Required


24 MosaicInversionBalanced Recip Translocation MarkerOther Autosmeal Trisomy Total Han 2008.15 %.50 %.10%.02%.85 % Chang 2012.3 %.20 %.40%.08%-1.0 % Frequency of Findings of Uncertain Significance in Amniocentesis Karyotype CVS: Confined Placental Mosaicism 1-2%

25 Berg: Genetics in Medicine 2011 Berg, Genetics In Medicine, June 2011

26 ? CVS: del16p13.12p13.11 CVS: 2.0 Mb del16p13.12p13.11 Described with Autism Spectrum Disorder (ASD)/Developmental Delay, and seizures Incomplete penetrance/ Variable Expressivity

27 Full Scale IQ difference of 28 or 2 SD Mean 80 SD 15 Mean 108 SD 12

28 Counseling Issues Long term prospective study of individuals identified with pathogenic CNVs and variants of uncertain clinical significance Incomplete Penetrance/ Variable Expressivity

29 Non Invasive Prenatal Diagnosis of Common Trisomies (13,18,21) ( 1:500 Pregnancies) Vs Invasive Diagnosis with Array Analysis (>1:100) All Patients Should be Counseled about the Relative Advantages and Disadvantages of Each Approach

30 PRETEST COUNSELING Additional information about the health/development of the child Findings of uncertain significance Unanticipated information about the health of a parent Pre-symptomatic recognition of adult on-set condition Determination of non-paternity Should be discussed with the patient prior to testing and an understanding of the patients interest in this information should be explored and documented Issues To Discuss Who will/can do this?

31 Noninvasive Prenatal Diagnosis of a Fetal Microdeletion Syndrome David Peters, Ph.D.Tianjiao Chu, Ph.D.Svetlana A. Yatsenko, M.D.Nancy Hendrix, M.D.W. Allen Hogge,M.D. UrvashiSurti, Ph.D. Kimberly Bunce, Ph.D.Mary Dunkel, M.S.Patricia ShawB.S.AleksandarRajkovic, M.D. Magee–Womens Research Institute

32 GENOMICS Noninvasive Whole-Genome Sequencing of a Human Fetus Jacob O. Kitzman,1 * Matthew W. Snyder,1 Mario Ventura,1,2 Alexandra P. Lewis,1 Ruolan Qiu,1LaVone E. Simmons,3 Hilary S. Gammill,3,4 Craig E. Rubens,5,6 Donna A. Santillan,7Jeffrey C. Murray,8 Holly K. Tabor,5,9 Michael J. Bamshad,1,5 Evan E. Eichler,1,10 Jay Shendure1 *

33 Concerns of Increasingly Complex Non-Invasive Fetal Testing Uncertain Reassurance More Uncertain Findings Scope Creep Counseling Ethics of What to Test For

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