Session Two: Evaluation and Testing Decisions
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Transcript of Session Two: Evaluation and Testing Decisions
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Genomics for the Child Neurologist:
Evaluation & Testing Decisions
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Facilitator(s)
Name
• Expertise
• Credentials
• Titles
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Re-Cap: Genomic Risk Assessment
Ask the right questions
Identify red flags
Identify patterns
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Workshop Two:Genetics Evaluation & Testing Decisions
Risk Assessment Genetic Testing
Differential Diagnosis
Evaluation bridges the gap
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Evaluation & Testing DecisionsLearning Objectives
1. Use family and clinical histories to narrow the differential
2. Select the appropriate single-gene test, panel, or step-wise protocol
3. Develop a family testing strategy to maximize cost-effectiveness
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Family
Labs
Exam
Imaging
Elements of Evaluation
History
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Narrow the differential
Select appropriate tests
Develop a family testing strategy
Genomic evaluation and testing decisions build on risk assessment
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Narrow the Differential
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10 yo maleHistory of clumsinessRecent increase Some falls with injury
Clinical Scenario: Tim
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Clinical HistoryBirth History: •Normal
Developmental History:•Normal
Past Medical History: •Minor infections
Review of Systems:•Unremarkable
Social History: •Tim lives with his parents and his younger sister
Family History:•Intake form indicates movement/muscle problems in Tim’s father and paternal grandfather
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ExamPhysical Exam: •No dysmorphic features•Normal arches•General exam is normal
Neurological Exam: •Mental status: alert•Speech is dysarthric and scanning•Cranial nerves: slow horizontal saccades•Normal muscle tone, bulk and strength•Reaches with dysmetria•Deep tendon reflexes absent•Decreased vibration sense•Ataxic gait
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What is your initial differential diagnosis?
• Speech is dysarthric and scanning
• Cranial nerves: slow horizontal saccades
• Normal muscle tone, bulk and strength
• Reaches with dysmetria• Deep tendon reflexes
absent• Decreased vibration sense• Ataxic gait
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Initial Differential Diagnosis
• Vitamin deficiencies (E, B vitamins)• Toxicity (heavy metals, alcohol)• Structural abnormalities • Traumatic tissue damage• Genetic ataxias
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Step 1: Rule out non-genetic causes
Neuroimaging:•MRI normal
Laboratory Tests:•E and B vitamins within normal limits•AFP & immunoglobulin normal•Lactose and gluten challenge normal•Other routine studies within normal limits
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Step 2: Use tools to identify potential genetic diagnoses
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Genetic differentials can be overwhelming
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Step 3: Refine the differential with distinctive patient features
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Which of Tim’s features might help differentiate diagnosis?
• Normal MRI, general exam,
routine labs, cognitive status• Motor: Normal tone, bulk and
strength• Speech is dysarthric and scanning• Slow horizontal saccades• Reaches with dysmetria, ataxic
gait• Absent deep tendon reflexes,
decreased vibration sense
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Signs of cerebellar disease with normal labs and imaging
Distinctive findings PRESENT:•Evidence of cerebellar disease•Evidence of posterior column involvement•Absent deep tendon reflexes
Distinctive findings ABSENT:•Dysmorphology and skin findings•Abnormal AFP and immunoglobulin•Evidence of metabolic or muscle disease
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Prioritize your differential based on your clinical evidence
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Refined differential based on clinical features
Condition Defining Features
Likelihood
Ataxia telangiectasia
Friedreich’s ataxia
Neiman Pick type C
Spinocerebellar ataxia
Skin findings, abnormal AFP and immunoglobulin
Dysarthria, spasticity, loss of position and vibration sense, absent lower limb reflexes
Usually accompanied by hepatosplenomegaly and loss of vertical saccades
Progressive incoordination of gait, hands, speech and eyes
Less Likely
Possible
Less Likely
Possible
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Step 4: Use family history patterns to narrow the differential
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What features of Tim’s family history might narrow the differential?
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Possible autosomal dominant with evidence of anticipation
Movement disorder in multiple generations
Early age of onset
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Refined differential based on inheritance patterns
Condition Inheritance Likelihood
Ataxia telangiectasia
Friedreich’s ataxia
Neiman Pick type C
Spinocerebellar ataxia
Family history assessment can save you time!
Autosomal Recessive
Autosomal Recessive
Autosomal Recessive
Most Autosomal Dominant
Less Likely
Less Likely
Most Likely
Less Likely
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SCA Overview
Features:
•Progressive incoordination of gait
•Poor coordination of hands, speech and eye movements
•Atrophy of the cerebellum
Genetics
•Over 35 subtypes with different genetic causes and overlapping features
•6 genes account for 65% of cases
•SCA3 (ATXN3 gene) is the most common form
•Most variants are trinucleotide repeat expansions and demonstrate anticipation
•Usually autosomal dominant inheritance
Management
•Primarily supportive
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Select appropriate tests
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Step 1: Use tools to determine associated genes and available testing
…
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Test choice is complicated by multiple genetic causes
GENE 1
GENE 1
OR
OR
GENE 2
GENE 2
GENE 1
GENE 1
GENE 3
GENE 3
Huntington Disease SCA
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Step 2: Determine whether there is sufficient evidence to target a single gene
Phenotype Prevalence by Subtype
Gene Frequency
Ge
ne
1
Ge
ne
2
Ge
ne
3
Ge
ne
4
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Would you target testing, or use a panel capturing multiple genes?
Phenotype Prevalence by Subtype
Gene Frequency
From GeneReviews
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When in doubt, ask the lab if panels or step-wise protocols are recommended
AND
AND
GENE 2
GENE 2
GENE 1
GENE 1
GENE 3
GENE 3
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HOWEVER, there are cases where targeted testing is the clear choice
Test Cost Detection
Single gene (FXN) analysis
$840 %
Recessive ataxia panel
$6,345 %%
Comprehensive ataxia panel
$18,760 %%%
Alternate example: Freidreich ataxia
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Consider referral or consult for refining differential and targeting testing
When to consult/refer:•Large and overlapping genetic differential•Complex family history is difficult to interpret•There are many candidate genes/variants and multiple testing options are available
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Develop a Family Testing Strategy
Proband First
Test Parents
Test Sibs
Test Relatives
Identify Gene
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Who else in the family is at risk?
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First degree relatives of individuals with AD conditions are at 50% risk
50%
50%25%
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Start testing in an affected individual, or risk uninformative results
Never Tested:Causative variant unknown
Your Patient
SCA panel:No Mutation Found
Can’t predict disease status
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Once a mutation is found, target testing in relatives at lower cost
Step-wise multi-gene panels:
ATXN2 mutation found$ 13,330
Targeted ATXN2 analysis:
$ 790
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Facilitate the testing plan through family communication
Key points to discuss:•Distinctive clinical features and family patterns•Uncertainty about the diagnostic route•How well a test can confirm or rule-out a diagnosis•Next steps based on positive or negative results•Who else is at risk
Stay tuned for Workshop 3!
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Small Group Practice
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What evidence helped you refine the differential?
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Critical evaluations
• Jerky, tremulous movements
• Hand flapping
• Normal growth makes SLO unlikely
• Normal newborn screen makes PKU unlikely
• Normal MRS makes Creatine transporter deficiency unlikely
Unique features
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Which condition is the most likely in Nico?
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Angelman syndrome is the best fit
• Global delay• Autistic-like features• Generalized epilepsy• Jerky, tremulous
movements• Hand flapping• Disruption of imprinting
of UBE3A gene
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Which test is the appropriate first step?
A. Methylation analysis of a specific chromosome region
B. Sequencing of a specific gene
C. Serum and urine amino acids
D. Other specific metabolic/biochemical testing
E. Chromosomal microarray analysis
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Methylation analysis of the critical chr 15 region detects most cases
= Unmethylated = Methylated
68% 7% 3%
© 2008 Angel Syndrome Foundation, Inc.
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Why not order chromosomal microarray analysis?
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Features were sufficient to justify single gene analysis
ACMG recommends CMA as first-line test for ID/autism in the absence of defining features suggestive of a specific syndrome
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Methylation analysis was negative. What is your next step?
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UBE3A sequencing is the next step
11%
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Summary: Genomic Evaluation and Testing Decisions
• Use tools, unique features and inheritance patterns to narrow your differential.
• Consider genetic heterogeneity when selecting from single-gene, multi-gene panels, or step-wise tests
• Start testing with an affected individual• Target testing for known causative familial variants in at-
risk family members• Consider referral or consultation with complicated
differentials and testing options
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Next steps
• Refer or consult with genetics • Pre-test counseling and informed consent• Order testing• Interpret and apply results
To be discussed in workshop 3
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Homework/Practice
• Watch two 5 minute demonstration videos on SimulConsult
• Practice using clinical information and tools to refine the differential diagnosis and testing strategy (Developmental regression)
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