Overview/Approach to Medical Genetics

8/12/2019 Overview/Approach to Medical Genetics

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TheCurrent State

of Neurogeneticsin Pediatrics

Christian Schaaf, MD, PhDTexas Childrens Hospital & Baylor College of Medicine

Houston, TX, USA


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Objectives

Describe genetic diagnostic tests that areconsidered 1stand 2ndtier in the evaluation ofchildren with neurogenetic disease

Know when to consult a medical geneticist in thecare of children with neurogenetic disease

Desired practice change: Choose less invasive,genetic diagnostic tests over more invasivediagnostic tests to optimize the overall diagnosticrate in children with neurogenetic disease.


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I have no financial or commercial

conflict of interest regarding the

content of this presentation.


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What does a medical geneticist do?

Intellectual

disability

anxiety

Intellectual

disability,

seizures

Hemophilia

carrier

Lung cancer


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Medical history

In depth pre- and perinatal

history

In depth developmentalhistory

Social history: schooling,

education, resources

Family history: Pedigree, history

of miscarriages, birth defects,

intellectual disability, psychiatric

disease, etc.


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Evaluation

Physical examination:

measurements, facial features

(dysmorphisms), skin findings,

exam may include examiningfamily members

Chart review

Tests: Chromosome tests,

biochemical studies, DNA

studies.


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Typical questions

for the geneticist

What is the diagnosis?

What is the cause?

What is going to happen in the future?

What is the treatment?

What is the chance of the condition to

happen again in future family members?


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Why is it worth knowing?

Get an answer

Chance of recurrence for future pregnancies

Find support groupsindividuals with same geneticvariant

Anticipatory guidance

Changes in medical follow-up and screening

Specific treatment considerations


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Where are your medical geneticists?

www.abmg.org


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The diagnostic approach to

neurogenetic disordersin 2014


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Diagnostic Approach to

Neurogenetic Disorders

Clinical

Phenotype

Genetic

Etiology

ClinicalPhenotype GeneticEtiology


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Neurogenetic disorders

Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity


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Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity

* *


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Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity

* *Example:Rett

syndrome


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Clinical

Phenotype

Genetic

Etiology

>95% of cases

caused by

mutations inMECP2 gene

Specificity

Heter

ogeneity

* *Example:Rett

syndrome


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Keys to (diagnostic) success:

(1) Good phenotyping

(2) Single gene testing

ClinicalPhenotype

GeneticEtiology

>95% of cases

caused by

mutations in

MECP2 gene

Spe

cificity

Heterogeneity

* *Example:

Rett

syndrome


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How to find labs that offer

specific gene tests

http://www.ncbi.nlm.nih.gov/gtr/ NIH based registry

Filter options (country, state, etc.)


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www.genetests.org

Funded by NCBI until June 2013, now funded byBioreference Laboratories

How to find labs that offerspecific gene tests


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Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity


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Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity

*

*


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Clinical

Phenotype

Genetic

Etiology

Genetic

Etiology

Specificity

Heter

ogeneity

*

*

Example:

Holopros-

encephaly


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Human Genetics: From Molecules to Medicine

(Schaaf,Zschocke, Potocki), 2012


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ClinicalPhenotype

GeneticEtiology

Genetic

Etiology

Sp

ecificity

H

eterogeneity

*

*

Example:

Holopros-

encephaly

Key to (diagnostic) success:Tiered approach, based on phenotype

and a-priori probability


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Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity


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Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity

*

*


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Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity

*

*

Example:

Non-syndromic

hearingloss


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Non-syndromic

hearing loss

Key to (diagnostic)success:

Gene panels(usually next-generation

sequencing technology usedto test ten to severalhundreds of genes

for sequence alterations)

Thomas B. Friedman, NIH


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Clinical

Phenotype

Genetic

Etiology

Clinical

Phenotype

Genetic

Etiology

Specificity

Heter

ogeneity


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Clinical

Phenotype

Genetic

Etiology

ClinicalPhenotype

Genetic

EtiologySpecificity

Heter

ogeneity*

*


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Clinical

Phenotype

Genetic

Etiology

ClinicalPhenotype

Genetic

EtiologySpecificity

Heter

ogeneity*

*

Example:

Autism Spectrum

Disorder


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A neurodevelopmental disorder, characterized by

Persistent deficits in social communicationand social interaction

Restricted, repetitive patterns of behavior,

interests, or activities

Symptoms present in the early developmental period

Symptoms cause clinically significant impairment insocial, occupational, or other important areas

of current functioning.

[DSM V, May 2013]

Autism Spectrum Disorder (ASD)


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ASDdifferent types and manifestations

Syndromic Non-syndromic

Dysmorphic Non-dysmorphic

High-functioning Low-functioning

Simplex Familial

Static Regressive

Essential Complex


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Autism co-morbidities- etiologically independent or key to autism subtypes?

ADHD

Epilepsy

ID

Anxiety

OCD

ODD

Depression

Bipolar

IDintellectual disability; ODDoppositional defiant disorder;

OCDobsessive compulsive disorder


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syndromic

non-syndromic

More than 600 autism genes listed on SFARI Gene (June 2014)

Autism genes


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Autism geneticsthe snowflake hypothesis


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Clinical

Phenotype

Genetic

Etiology

ClinicalPhenotype

Genetic

EtiologySpecifici

ty

Heter

ogeneity*

*

Example:

Autism

Spectrum

Disorder

Key to (diagnostic) success:

Whole genome approaches


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Specificphenotype

,

genetically

distinct

Relatively

specific

phenotype,

genetically

heterogen

eous

Less specific phenotype,

genetically very

heterogeneous

Developmental Delay

Intellectual Disability

Epilepsies

Autism Spectrum Disorder

Mitochondrial Disease

What we see in clinic


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Genomic approaches to

neurologic disease


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1sttier test for every individual with developmental

delay, intellectual disability, autism spectrum

disorder

Whole genome approach to imbalances of

chromosome material (copy number variation)

With a single test, CMA analyzes several hundred

thousand regions of the chromosomes.

CMA has greater sensitivity than older methods of

chromosome analysis.

Chromosomal Microarray Analysis

(CMA)


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Traditional cytogenetic tests

1960s - today

Chromosome analysis

(under the light microscope)

1990s - today

FISH analysis

(Fluorescent in situ hybridization)

Chromosome Microarray Analysis


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Mix

Control

Laser Scanner

Duplication Deletion

[B] Laser Scanner

[C] Actual Array

[D] Array Profile

Patient

Chromosome Microarray Analysis


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A question of resolution

10CMA [average resolution ~5 kb, whole genome]

FISH [40 to 250 kb per probe, single site]Karyotype [4-5 Mb, whole genome]


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A question of resolution

Chromosome analysis

Resolution 5 Mb

World Map

17,500 miles

Chromosome microarray analysis

Resolution 5 kb

Map of Louisville

17.5 miles


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Chromosomal Microarray Analysis

(CMA)

Performed on blood.

Results usually available within 7-14 days.

Will identify clinically relevant causes of DD/ID or ASD in 7-

20% of individuals

The more severe the phenotype, the more syndromic

appearing the child, the higher the yield.


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Whole Exome Sequencing

Offered as a clinical test since fall of 2012 Performed on blood

Results usually available within 3-5 months.


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Chromosome Microarray vs. Exome Sequencing

Library inventory

~ 200,000 regions of

chromosome material

Checking for misspellings

~ 30,000,000 letters of

genetic code


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October 2013

Clinical whole exome sequencing

Clinically mixed cohort, about 80% with neurological

phenotypes

Diagnostic rate 25% [95% CI 20%-31%]


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June 2014

Whole genome sequencing

Only patients with IQ


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Increasing diagnostic yield

by tiered approach

Gilissen et al, 2014


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July 2014

Whole exome sequencing

All with biochemical evidence of multiple respiratory

chain complex defects

Diagnostic yield 53% [95% CI 39%-67%].


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Ethi l id ti f h l


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Ethical considerations of whole

exome/genome sequencing

Proper pre-test counseling and consent

necessary

WES/WGS tests for disorders that were not

the indication for testing

Pre-symptomatic testing of minors

Variants of uncertain clinical significance

Non-paternity, identity by descent, etc.

M t ti l h i ( ll )


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Mutational mechanisms (usually)

neither detected by CMA, nor by WES

Deletions or duplications between

approximately 50 bases and 5000 bases

Mutations in non-coding regions of the

genome (including 5-UTR, 3-UTR, introns,

most miRNAs)

Trinucleotide repeats

Epigenetic mutations


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Neurogenetic testing - overview

Thorough clinical characterization first

Suspicion for a specific disorder1sttier: specific gene testing

2ndtier tests:

- Fragile X testing in females- Metabolic testing

- Whole exome sequencing

DD, ID, ASD1sttier: chromosome microarray analysis

DD, ID, ASD1sttier in males: Fragile X testing

When to cons lt a clinical geneticist


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When to consult a clinical geneticist

in the care of individuals with ASD

In a perfect world:

Refer every individual

diagnosed with DD, ID,ASD, or suspicion for a

specific neurogenetic

disorder

- Evaluation- Counseling

- Testing

- Guidance

When accessibility is

problematic, then order 1sttier

testing yourself.

Consider referral when:

- Genetic diagnosis is made

- Diagnostic findings of

uncertain significance

- Counseling needed that isbeyond the scope of your

own practice

- Ongoing diagnostic dilemma


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Documents

Overview/Approach to Medical Genetics