Transcript Variants of Uncertain Clinical Significance

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'.
THE NEXT GENERATION:
Microarray and Beyond
Karyotype
Chromosomal Microarray
(CMA)
Resolution:
>7-10 Million Base Pairs
(7-10 Mb)
Resolution:
< 0.5 Million Base Pairs
(< 500 kb)
Microdeletion
Syndromes
DiGeorge
22q11 Deletion
3.5Mb
Miller Dieker
Prader Willi
Smith
Magenis
Wolf
Hirshhorn
WilliamsBeuren
17p13.3 deletion
15q11-13 deletion 4MB
17p11.2 deletion 5Mb
Non-Syndromic
Micro Del /Dups
16p11.2
Autism
0.55Mb
1q21.1
ID, microcephaly,
cardiac, cataracts
0.8Mb
16p13.11 Autism, ID, and
0.8Mb
schizophrenia
4p16.3 deletion
1.9Mb
7q11.23Deletion
1.5Mb
Postnatal Studies
15-20% yield by CMA in children
with unexplained developmental
delay/ID, and congenital anomalies
compared to ~3% with karyotype
ID: Intellectual Disability
Velo Cardio Facial Syndrome
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 %
Amniocentesis:
Karyotype: 46,XY
Array: 1.39 Mb gain in 7q11.23
7q11.23 microduplication syndrome
Van der Aa, et al. Fourteen new cases contribute to the characterization of the
7q11.23 microduplication syndrome. European Journal of Medical Genetics 2009
Left Foot
Right Foot
Differential Diagnosis
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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
Sequencing
Mutation
Sequencing Analysis
• 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
Triphalangeal thumb with
Polysyndactyly
BH
You’re pregnant and
You must know the sex
2012
SC
Deep sequencing Ma,
It’s all the rage !
Clinically Relevant Information Seen by CMA and
Reported to Patients in Cases with
Normal Karyotype
By Indications for Testing
Indication Total 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
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
Deletions
1q21.1
7q11.23
15q11.2
15q13.2q13.3
16p11.2
16p12.1
16p13.11p12.3
16p13.11
17q12
22q11.2
N
1
1
2
1
3
1
3
5
6
11
Nl US
1
0
2
1
2
0
1
3
1
3
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
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)
Counseling Issues
Variants Of Uncertain Clinical Significance
2007 Study
Classification
2012
Classification
VOUS
Pathogenic
94
(2.5%)
57
(1.5%)
35
(0.9%)
64
(1.7%)
Likely
Benign
8
As CMA Transitions Into Practice Counseling By Professionals
With Knowledge And Expertise In CMA Will Be Required
Frequency of Findings of Uncertain
Significance in Amniocentesis Karyotype
Mosaic
Inversion
Balanced Recip
Translocation
Marker
Other Autosmeal
Trisomy
Total
Han
2008
.15 %
.15%
.50 %
.10%
.02%
.85 %
Chang
2012
.3 %
.20 %
.40%
.08%
-
1.0 %
CVS: Confined Placental Mosaicism
1-2%
Berg, Genetics In Medicine, June 2011
Berg: Genetics in Medicine 2011
Incomplete penetrance/ Variable Expressivity
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
Full Scale IQ difference of 28 or 2 SD
20
18
16
Mean 80
SD 15
Mean 108
SD 12
Number of Cases
14
12
10
8
6
4
2
0
Control
Carrier
Counseling Issues
Incomplete Penetrance/ Variable Expressivity
Long term prospective study of individuals
identified with pathogenic CNVs and variants of
uncertain clinical significance
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
Issues To Discuss
• 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
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
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Uncertain Reassurance
More Uncertain Findings
Scope Creep
Counseling
Ethics of What to Test For