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:
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'.
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
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
You’re pregnant and You must know the sex Deep sequencing Ma, It’s all the rage ! BH 2012 SC
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
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
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.
Findings of Unknown Significance Variable Expressivity
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)
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
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%
Berg: Genetics in Medicine 2011 Berg, Genetics In Medicine, June 2011
? 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
Full Scale IQ difference of 28 or 2 SD Mean 80 SD 15 Mean 108 SD 12
Counseling Issues Long term prospective study of individuals identified with pathogenic CNVs and variants of uncertain clinical significance Incomplete Penetrance/ Variable Expressivity
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
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?
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
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 *
Concerns of Increasingly Complex Non-Invasive Fetal Testing Uncertain Reassurance More Uncertain Findings Scope Creep Counseling Ethics of What to Test For