Genomics for the Child Neurologist:

Evaluation & Testing Decisions

Facilitator(s)

Name

• Expertise

• Credentials

• Titles

Re-Cap: Genomic Risk Assessment

Ask the right questions

Identify red flags

Identify patterns

Workshop Two:Genetics Evaluation & Testing Decisions

Risk Assessment Genetic Testing

Differential Diagnosis

Evaluation bridges the gap

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

Family

Labs

Exam

Imaging

Elements of Evaluation

History

Narrow the differential

Select appropriate tests

Develop a family testing strategy

Genomic evaluation and testing decisions build on risk assessment

Narrow the Differential

10 yo maleHistory of clumsinessRecent increase Some falls with injury

Clinical Scenario: Tim

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

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

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

Initial Differential Diagnosis

• Vitamin deficiencies (E, B vitamins)• Toxicity (heavy metals, alcohol)• Structural abnormalities • Traumatic tissue damage• Genetic ataxias

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

Step 2: Use tools to identify potential genetic diagnoses

Genetic differentials can be overwhelming

Step 3: Refine the differential with distinctive patient features

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

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

Prioritize your differential based on your clinical evidence

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

Step 4: Use family history patterns to narrow the differential

What features of Tim’s family history might narrow the differential?

Possible autosomal dominant with evidence of anticipation

Movement disorder in multiple generations

Early age of onset

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

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

Select appropriate tests

Step 1: Use tools to determine associated genes and available testing

…

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

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

Would you target testing, or use a panel capturing multiple genes?

Phenotype Prevalence by Subtype

Gene Frequency

From GeneReviews

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

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

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

Develop a Family Testing Strategy

Proband First

Test Parents

Test Sibs

Test Relatives

Identify Gene

Who else in the family is at risk?

First degree relatives of individuals with AD conditions are at 50% risk

50%

50%25%

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

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

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!

Small Group Practice

What evidence helped you refine the differential?

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

Which condition is the most likely in Nico?

Angelman syndrome is the best fit

• Global delay• Autistic-like features• Generalized epilepsy• Jerky, tremulous

movements• Hand flapping• Disruption of imprinting

of UBE3A gene

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

Methylation analysis of the critical chr 15 region detects most cases

= Unmethylated = Methylated

68% 7% 3%

© 2008 Angel Syndrome Foundation, Inc.

Why not order chromosomal microarray analysis?

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

Methylation analysis was negative. What is your next step?

UBE3A sequencing is the next step

11%

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

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

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)

www.nchpeg.org/neuro

Thank you!

eedelman@nchpeg.org