Wherever you roam And admit that the waters Around you have grown And accept it that soon Youll be drenched to the bone If your time to you Is worth savin Then you better start swimmin Or youll sink like a stone ID: 775148
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Slide1
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'.
Slide2THE NEXT GENERATION:Microarray and Beyond
Slide3Slide4Karyotype
Resolution:
>7-10 Million Base Pairs(7-10 Mb)
Resolution:
< 0.5 Million Base Pairs(< 500 kb)
Chromosomal
Microarray
(CMA)
Slide5Microdeletion Syndromes
DiGeorge 22q11 Deletion3.5MbMiller Dieker17p13.3 deletionPrader Willi15q11-13 deletion4MBSmith Magenis 17p11.2 deletion5MbWolf Hirshhorn 4p16.3 deletion1.9MbWilliams-Beuren7q11.23Deletion1.5Mb
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 Autism0.55Mb1q21.1ID, microcephaly, cardiac, cataracts 0.8Mb16p13.11Autism, ID, and schizophrenia 0.8Mb
ID: Intellectual Disability
Velo Cardio Facial Syndrome
Postnatal Studies
Slide6Structural 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 %
Slide7Slide87q11.23 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
Slide9Left Foot
Right Foot
Slide10Differential 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
Slide11Mutation
Sequencing
Slide12Triphalangeal thumb with Polysyndactyly
Mutation 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 malformations
Sequencing Analysis
Slide13Slide14Slide15Slide16You’re pregnant and
You must know the sex
Deep sequencing Ma,
It’s all the rage !
BH
2012 SC
Slide17By Indications for Testing
IndicationTotal Clinically Relevant 95% CIAMAN=196634 (1.7%)1.2 – 2.4Positive ScreenN=72912(1.6%)0.9 – 2.9
Clinically Relevant Information Seen by CMA
and
Reported
to Patients in Cases
with
Normal
Karyotype
Slide18Recurrent 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 US1q21.17q11.23111015q11.22215q13.2q13.31116p11.23216p12.11016p13.11p12.33116p13.115317q126122q11.2113
Duplications
N
Nl
US
1q21.1
15q11.2q13.1
15q13.2q13.3
4
1
1
2
1
1
16p13.11p12.3
2
1
16p13.11
4
3
17q12
22q11.21
3
2
2
2
Slide19Conclusion
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.
Slide20Findings of Unknown Significance
Variable Expressivity
Slide21Variants 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, DECIPHER2. Large Databases ISCAConsortium3. Genomic/Gene Content - correlates with size/location UCSC, Ensembl (Sanger)
Slide22Variants Of Uncertain Clinical Significance
Counseling Issues
VOUSPathogenic Likely Benign2007 Study Classification94(2.5%)35(0.9%)-2012 Classification57(1.5%)64(1.7%)8
As
CMA Transitions
Into Practice Counseling By Professionals With Knowledge And Expertise In
CMA Will
Be Required
Slide23Slide24MosaicInversionBalanced Recip TranslocationMarkerOther Autosmeal TrisomyTotalHan 2008.15 %.15%.50 %.10%.02%.85 %Chang2012.3 %.20 %.40%.08%-1.0 %
Frequency of Findings of Uncertain Significance in Amniocentesis Karyotype
CVS: Confined Placental
Mosaicism
1-2%
Slide25Berg: Genetics in Medicine 2011
Berg,
Genetics In Medicine, June 2011
Slide26?
CVS: del16p13.12p13.11
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
Slide27Full Scale IQ difference of 28 or 2 SD
Mean 80
SD 15
Mean 108
SD 12
Slide28Counseling Issues
Long term prospective study of individuals identified with pathogenic CNVs and variants of uncertain clinical significance
Incomplete Penetrance/ Variable Expressivity
Slide29Non 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
Slide30PRETEST COUNSELING
Additional information about the health/development of the childFindings of uncertain significanceUnanticipated information about the health of a parentPre-symptomatic recognition of adult on-set conditionDetermination 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?
Slide31Noninvasive Prenatal Diagnosis of a Fetal MicrodeletionSyndromeDavid 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
Slide32GENOMICS
Noninvasive 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 *
Slide33Concerns of Increasingly Complex Non-Invasive Fetal Testing
Uncertain Reassurance
More Uncertain Findings
Scope Creep
Counseling
Ethics of What to Test For