Come gather 'round people - PowerPoint Presentation

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Uploaded On 2020-04-03

Come gather 'round people - PPT Presentation

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

syndrome uncertain cma cases syndrome uncertain cma cases karyotype diagnosis information significance counseling relevant cvs clinically normal sequencing variable

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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'.

Slide2

THE NEXT GENERATION:Microarray and Beyond

Slide3

Slide4

Karyotype

Resolution:

>7-10 Million Base Pairs(7-10 Mb)

Resolution:

< 0.5 Million Base Pairs(< 500 kb)

Chromosomal

Microarray

(CMA)

Slide5

Microdeletion 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

Slide6

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 %

Slide7

Slide8

7q11.23 microduplication syndrome

Amniocentesis: Karyotype: 46,XY Array: 1.39 Mb gain in 7q11.23

Van der

, et al. Fourteen new cases contribute to the characterization of the 7q11.23

microduplication

syndrome.

European Journal of Medical Genetics

2009

Slide9

Left Foot

Right Foot

Slide10

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

Slide11

Mutation

Sequencing

Slide12

Triphalangeal 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

Slide13

Slide14

Slide15

Slide16

You’re pregnant and

You must know the sex

Deep sequencing Ma,

It’s all the rage !

2012 SC

Slide17

By 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

Slide18

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 US1q21.17q11.23111015q11.22215q13.2q13.31116p11.23216p12.11016p13.11p12.33116p13.115317q126122q11.2113

Duplications

1q21.1

15q11.2q13.1

15q13.2q13.3

16p13.11p12.3

16p13.11

17q12

22q11.21

Slide19

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.

Slide20

Findings of Unknown Significance

Variable Expressivity

Slide21

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, DECIPHER2. Large Databases ISCAConsortium3. Genomic/Gene Content - correlates with size/location UCSC, Ensembl (Sanger)

Slide22

Variants Of Uncertain Clinical Significance

Counseling Issues

VOUSPathogenic Likely Benign2007 Study Classification94(2.5%)35(0.9%)-2012 Classification57(1.5%)64(1.7%)8

CMA Transitions

Into Practice Counseling By Professionals With Knowledge And Expertise In

CMA Will

Be Required

Slide23

Slide24

MosaicInversionBalanced 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%

Slide25

Berg: Genetics in Medicine 2011

Berg,

Genetics In Medicine, June 2011

Slide26

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

Slide27

Full Scale IQ difference of 28 or 2 SD

Mean 80

SD 15

Mean 108

SD 12

Slide28

Counseling Issues

Long term prospective study of individuals identified with pathogenic CNVs and variants of uncertain clinical significance

Incomplete Penetrance/ Variable Expressivity

Slide29

Non 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

Slide30

PRETEST 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?

Slide31

Noninvasive 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

Slide32

GENOMICS

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 *

Slide33

Concerns of Increasingly Complex Non-Invasive Fetal Testing

Uncertain Reassurance

More Uncertain Findings

Scope Creep

Counseling

Ethics of What to Test For