Genomics for the Child Neurologist:

Genetic Risk Assessment

Facilitator(s)

Name• Expertise• Credentials

• Titles

Neurologic conditions are complex diseases

Spectrum of Genetic Contribution

GENEGENE

Frequency

Penetrance

GENEGENE

GENEGENE

Neurological conditions encompass all inheritance patterns

Autosomal Dominant

X-Linked

Workshop One:Genetics & Risk Assessment

Risk Assessment Learning Objectives

1. Take a family history with sufficient detail

2. Recognize genetic “red flags”

3. Analyze a detailed family history

4. Develop an appropriate evaluation plan based on personal and family history assessment

5. Communicate with families about genetic information

GENOMICrisk assessment

expands on the family history

Ask the right questions

Identify red flags

Identify patterns

Ask the right questions

3 yo maleDevelopmental delayFamHx: negative for ID/DD

Clinical Scenario: Joseph

HistoryBirth History: •normal

Developmental History: •hearing normal •gross motor milestones on time •cannot dress himself•speech delay •behavioral problems, such as hyperactivity and temper tantrums

Social History: •Joseph lives with his parents and his older sister•both English and Spanish are spoken in the home

Past Medical History: •unremarkable

What questions would you ask about Joseph’s family history?

Please check next to any condition that affects your child, parent, sibling, aunt/uncle or grandparent. For each checked box, explain below who is affected. Mental retardation Learning disabilities X Developmental delay Joseph has speech delay Early-onset deafness Early-onset blindness Birth defects

Neuromuscular Issues Seizures X Abnormal movements Mom’s uncle has a tremor, ataxia, and maybe

dementia Blood clotting or bleeding

disorder

Infant death Pregnancy losses Unexplained death Migraine

X Cancer Paternal grandmother had breast cancer

Family History Collection Demonstration

• Family structure

• Presence and extent of disease• Ages of onset and death• Chronic illness• Infertility, miscarriage

• Intellectual disability

• Birth defects

Questions for a targeted famhx include:

Medical and development information about your relatives can give us clues about what is going on with Joseph. Even a normal family history can help guide us.

“

”

When collecting family history, it is important to set expectations

Record family history so that it can be accessed, updated, and interpreted

Joseph3 y

ID, behavioral issues

2

D. 34 yBreast ca

High cholesterol

33 yMenopause dx 31

~60’sTremor, ?

dementia, ataxia

El SalvadorianIrish/German

FamHx: negative for ID/DD

Identify red flags

Red flags that alert you to genetic risk

• Multiple individuals with related conditions• Intellectual disability• Early age at onset• Less often affected sex• Absence of known risk factors• Severe manifestations• Ethnic predisposition• Consanguinity

What red flags do you see in Joseph’s family history?

Joseph3 y

ID, behavioral issues

2 Key

Intellectual disability

D. 34 yBreast ca

High cholesterol

33 yMenopause dx 31

~60’sTremor, ?

dementia, ataxia

El Salvadorian Irish/German

Movement disorder

Infertility

Joseph3 y

ID, behavioral issues

2 Key

Intellectual disability

D. 34 yBreast ca

High cholesterol

33 yMenopause dx 31

~60’sTremor, ?

dementia, ataxia

El Salvadorian Irish/German

Movement disorder

Infertility

Joseph’s red flags

Based on clinical guidelines for intellectual disability testing consider the

following diagnoses

a) Idiopathic intellectual disability

b) Chromosome abnormality

c) Micro-duplication/deletion syndrome

d) Fragile X syndrome

How would you focus testing based on family history and clinical guidelines?

• Intellectual disability• Early age at onset• Absence of known

risk factors

Joseph3 y

ID, behavioral issues

2 Key

Intellectual disability

D. 34 yBreast ca

High cholesterol

33 yMenopause dx 31

~60’sTremor, ?

dementia, ataxia

El SalvadorianIrish/German

Movement disorder

Infertility

Identify patterns to guide testing

Joseph3 y

ID, behavioral issues

2 Key

Intellectual disability

D. 34 yBreast ca

High cholesterol

33 yMenopause dx 31

~60’sTremor, ?

dementia, ataxia

El Salvadorian Irish/German

Movement disorder

Infertility

Autosomal Recessive

Complex Disease

X-Linked

Autosomal Dominant

Carrier

Idiopathic Intellectual Disability

Chromosome Abnormality

Intellectual disability

Intellectual disability

ID; Congenital heart defect;

Short

Micro-Duplication/Deletion Syndrome

Intellectual disability

Intellectual disability

Learning disability

Fragile X Syndrome

Intellectual disability

Intellectual disability

Infertility

Tremor, ataxia

Based on the red flags and patterns what is the most likely diagnosis?

Joseph3 y

ID, behavioral issues

2 Key

Intellectual disability

D. 34 yBreast ca

High cholesterol

33 yMenopause dx 31

~60’sTremor, ?

dementia, ataxia

El Salvadorian Irish/German

Movement disorder

Infertility

Fragile X

Joseph3 y

ID, behavioral issues

2 Key

Intellectual disability

D. 34 yBreast ca

High cholesterol

33 yMenopause dx 31

~60’sTremor, ?

dementia, ataxia

El Salvadorian Irish/German

Movement disorder

Infertility

What about other red flags?

Joseph3 y

ID, behavioral issues

2 Key

Intellectual disability

D. 34 yBreast ca

High cholesterol

33 yMenopause dx 31

~60’sTremor, ?

dementia, ataxia

El Salvadorian Irish/German

Movement disorder

Infertility

What does this mean?What does this mean?

What do we do next?

Why is this important?

Communicate your findings

What do we communicate about the risk assessment?

Communication about risk assessment

• Explain your findings

• Tie together the red flags and patterns • What is Fragile X syndrome• Why evaluating for this diagnosis is important

– Joseph– Family members

• Next steps in evaluation

Next steps

• Order Fragile X genetic testing

• Refer or consult with genetics

Small Group Practice

Soledad’s family history

3 3

Argentina Argentina

d. 60 yETOH

Liver Cancer

d. 75 yPneumonia

A/W

A/W Luis33 yA/W

Maria32 yA/W

A/W

Daniela7 y

A/W

Carlos5y

Severe HeadacheRegression

Soledad2y

Possible SZ

Pablo2moA/W

A/WA/W

HeterochromiaWhite forelock

Key

A/W Alive & Well

What red flags do you see in Soledad’s family history?

3 3

Argentina Argentina

d. 60 yETOH

Liver Cancer

d. 75 yPneumonia

A/W

A/W Luis33 yA/W

Maria32 yA/W

A/W

Daniela7 y

A/W

Carlos5y

Severe HeadacheRegression

Soledad2y

Possible SZ

Pablo2moA/W

A/WA/W

HeterochromiaWhite forelock

Key

A/W Alive & Well

Red Flags

3 3

Argentina Argentina

d. 60 yETOH

Liver Cancer

d. 75 yPneumonia

A/W

A/W Luis33 yA/W

Maria32 yA/W

A/W

Daniela7 y

A/W

Carlos5y

Severe HeadacheRegression

Soledad2y

Possible SZ

Pablo2moA/W

A/WA/W

HeterochromiaWhite forelock

Key

A/W Alive & Well

What inheritance pattern do you see in Soledad’s family history?

3 3

Argentina Argentina

d. 60 yETOH

Liver Cancer

d. 75 yPneumonia

A/W

A/W Luis33 yA/W

Maria32 yA/W

A/W

Daniela7 y

A/W

Carlos5y

Severe HeadacheRegression

Soledad2y

Possible SZ

Pablo2moA/W

A/WA/W

HeterochromiaWhite forelock

Key

A/W Alive & Well

Autosomal recessive

Luis33 yA/W

Maria32 yA/W

Daniela7 y

A/W

Carlos5y 1moSevere

HeadacheRegression

Soledad2y 3mo

Possible SZ

Also, autosomal dominant

d. 75 yPneumonia

HeterochromiaWhite forelock

How would you communicate about family history collection and interpretation?

What does this mean?What does this mean?

What do we do next?

Why is this important?

Communicate

• Why you are collecting the information and how it can be used

• That collecting family history information is an ongoing process

• Informative questions

• What your finding mean for the patient

• Risks to family members

Communicate in a patient centered way

• Ask about family’s perceptions of condition and risk

• Be sensitive to family reactions and emotions

• Put risk into perspective

Next steps

• Create differential diagnosis • Communicate interpretation and suspected

diagnosis • Genetic testing• Refer or consult with genetics

Risk assessment for complex diseases

Key Points in Genomic Risk Assessment

1. Collect history that indicates family structure and manifestations of disease

2. Assess patterns and red flags

3. Use risk to adapt plan for genetic testing, management, counseling etc.

4. Communicate with families about risk in a patient centered way

Homework/Practice

• Practice identifying red flags & inheritance patterns (Cardiomyopathy Case)

• High comfort level: Practice recurrence risk counseling (Spinal Muscular Atrophy & Duchenne Muscular Dystrophy)

Find the homework at http://www.nchpeg.org/neuro/

Thank you!

[facilitator contact information]