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:
1Come 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'.
4Chromosomal Microarray (CMA) KaryotypeChromosomal Microarray(CMA)Resolution:>7-10 Million Base Pairs(7-10 Mb)Resolution:< 0.5 Million Base Pairs(< 500 kb)
5Microdeletion Syndromes Non-SyndromicMicro Del /DupsMicrodeletion SyndromesDiGeorge22q11 Deletion3.5MbMiller Dieker17p13.3 deletionPrader Willi15q11-13 deletion4MBSmith Magenis17p11.2 deletion5MbWolf Hirshhorn4p16.3 deletion1.9MbWilliams-Beuren7q11.23Deletion1.5Mb16p11.2Autism0.55Mb1q21.1ID, microcephaly, cardiac, cataracts0.8Mb16p13.11Autism, ID, and schizophreniaPostnatal Studies15-20% yield by CMA in children with unexplained developmental delay/ID, and congenital anomalies compared to ~3% with karyotypeID: Intellectual DisabilityVelo Cardio Facial Syndrome
6Structural AnomaliesArray Adds Significant Clinically Relevant Information in Cases With Normal KaryotypeStructural AnomalyFiorentino6.1 %Rosenfeld /Shaffer6.6 %Schwartz5.7 %NICHD6.0 %
87q11.23 microduplication syndrome Amniocentesis:Karyotype: 46,XYArray: 1.39 Mb gain in 7q11.237q11.23 microduplication syndromeVan der Aa, et al. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. European Journal of Medical Genetics 2009
12Triphalangeal thumb with Polysyndactyly Sequencing AnalysisMutation in SHH geneMutations 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 malformationsTriphalangeal thumb with Polysyndactyly
16BH 2012 SC You’re pregnant and You must know the sex Deep sequencing Ma,It’s all the rage !
17By Indications for Testing Clinically Relevant Information Seen by CMA andReported to Patients in Cases withNormal KaryotypeBy Indications for TestingIndicationTotal Clinically Relevant95%CIAMAN=196634(1.7%)1.2 – 2.4PositiveScreenN=72912(1.6%)0.9 – 2.9
18Recurrent CNVs That Have The Potential To Cause Neurocognitive Impairment Occurred in approximately 1 in 125 (0.8%) cases sampled for AMA or positive screeningDeletionsNNl US1q21.17q11.23115q11.2215q13.2q13.316p11.2316p12.116p13.11p12.316p13.11517q12622q11.211DuplicationsNNl US1q21.115q11.2q13.115q13.2q13.341216p13.11p12.316p13.11317q1222q11.21
19ConclusionBased 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.
20Findings of Unknown Significance Variable Expressivity
21Clinical Significance Variants of UncertainClinical Significance1. Other Cases- known del/dup or Mendelian disordersOMIM, DECIPHER (Sanger)- known benign CNVDGV (Toronto), dbVar (NCBI)- comparison with other casesPubMed, DECIPHER2. Large DatabasesISCAConsortium3. Genomic/Gene Content- correlates with size/locationUCSC, Ensembl (Sanger)
22Variants Of Uncertain Clinical Significance Counseling IssuesVariants Of Uncertain Clinical SignificanceVOUSPathogenicLikely Benign2007 Study Classification94(2.5%)35(0.9%)-2012 Classification57(1.5%)64(1.7%)8As CMA Transitions Into Practice Counseling By Professionals With Knowledge And Expertise In CMA Will Be Required
26? Incomplete penetrance/ Variable Expressivity CVS: del16p13.12p13.11?CVS: del16p13.12p13.11CVS: 2.0 Mb del16p13.12p13.11Described with Autism Spectrum Disorder (ASD)/Developmental Delay, and seizures
27Full Scale IQ difference of 28 or 2 SD Mean 80SD 15Mean 108SD 12
28Incomplete Penetrance/ Variable Expressivity Counseling IssuesIncomplete Penetrance/ Variable ExpressivityLong term prospective study of individuals identified with pathogenic CNVs and variants of uncertain clinical significance
29Non Invasive Prenatal Diagnosis of Common Trisomies (13,18,21) ( 1:500 Pregnancies)VsInvasive Diagnosis with Array Analysis(>1:100)All Patients Should be Counseled about the Relative Advantages and Disadvantages of Each Approach
30PRETEST COUNSELING Issues To Discuss Additional information about the health/developmentof the childFindings of uncertain significanceUnanticipated information about the health of a parentPre-symptomatic recognition of adult on-set conditionDetermination of non-paternityShould be discussed with the patient prior to testing and an understanding of the patients interest in this information should be explored and documentedWho will/can do this?
31Noninvasive 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
32GENOMICSNoninvasive Whole-Genome Sequencing of a Human FetusJacob 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 *
33Concerns of Increasingly Complex Non-Invasive Fetal Testing Uncertain ReassuranceMore Uncertain FindingsScope CreepCounselingEthics of What to Test For