Danielle M Esters MD Carrier Screening OBJECTIVES Define the role of carrier screening in perinatal care Review the genetic basis for and limitations of carrier screening Review the guidelines for carrier screening ID: 911438
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Slide1
Genetic Carrier Screening
Danielle M. Esters, MD
Slide2Carrier Screening
OBJECTIVES
Define
the role of carrier screening in perinatal care
Review the genetic
basis for and limitations of carrier
screening
Review the guidelines for carrier screening
Introduce expanded carrier screening
Review genetic disorders included in these carriers screens
Slide3Traditional Carrier Screening
Type of genetic testing used to identify
A
symptomatic individuals
Negative
family history
H
eterozygous trait for a recessive disorder
Autosomal recessive
X-linked
recessive
At risk for passing on the
disorder to their children
Slide4Normal Human Karyotype
ResearchGate
Slide5S3.amazonaws.com
Slide6AllelesForms of the same gene
Small differences in the sequence of DNA bases
Picture by Biology Stack Exchange
Homologous Chromosomes
Similar but not identical
Same genes at same location
Alleles may be different
Slide7Autosomal Recessive
Disorder
Carrier
One of the two alleles for the gene is a pathogenic variant
Affected
Homozygotes
Gene has two
identical pathogenic alleles
on both homologous chromosomes
Compound heterozygotes
Gene has
different pathogenic alleles
on homologous chromosome
Slide8Slide9X-Linked Recessive Disorder
Carrier females
The pathogenic variant is on
one of two X chromosomes
Affected males
The pathogenic variant is on the only X chromosome
Slide10Single-Gene Disorder
Usually inherited
A certain gene is known to cause a particular disease
Over 10,000 human disorders are caused by pathogenic variants in a single gene
Prevalence varies among racial or ethnic groups
Rationale for traditional carrier screening
Slide11Single Gene Disorders
The Disease Burden
Single-gene
disorders –1% of all
newborns
‘
The global prevalence of all single gene diseases at birth is approximately 10/1000. ‘
www.who.int/genomics/public/genetic
diseases/
en
/index2.html
Slide12Birth Defects
United
States
3% of all newborns
120,000 newborns annually
Slide13Birth Defects
United
States
3% of all newborns
120,000 newborns annually
Worldwide births
6% of all newborns
7.9 million newborns annually
Slide14Thompson and Thompson 2016
Birth Defects
Slide15Carrier Screening
The
goal
is
to provide couples with information to optimize pregnancy outcomes based on
their
personal values and preferences.
Slide16Carrier Screening
Full scope of reproductive decision making
Option of prenatal diagnosis for at risk couples
Early identification of affected pregnancies
Condition specific counseling and care
Slide17Carrier Screening – Pretest CounselingInformed consent
Disease
Describe the disorder and range of severity
Conditions vary in severity
The test
Available
literature
Slide18Carrier Screening – Pretest Counseling
Paternity
– biological father
Understand
the limitations of the test
Voluntary
Option to accept / decline
Document
in medical record
Slide19Carrier Screening – Pretest CounselingACOG Patient education brochures April 2017
Cystic Fibrosis – AP 171
Carrier Screening – AP 179
ACOG FAQ brochures April 2017
Carrier Screening – 179
Customized literature
Slide20Carrier Screening – Pretest CounselingCARRIER TEST RESULTS
Screen positive result
Screen negative result
Residual risk for being a carrier
Residual risk for affected offspring
Slide21Residual risk
Numeric
measure of the change of being a carrier after a
negative
result
Carrier frequency x (1-detection rate
)
Ashk
: 1/29 x
(1 - .97) =
3/2900 = 1/967
Euro: 1/29 x
(1 - .80) =
20/2900 = 1/145
Latino: 1/46 x (1 - .57) = 43/4600 = 1/107
Slide22Carrier Screening – Post-test Counseling
Positive carrier status
– “
You do
not
have the disease; you have the trait
.”
Refer for genetic counseling
Test
the partner
Positive / negative couple
No
prenatal diagnosis
Tay
-Sachs*
Positive / positive
couple
Prepregnancy – PGD, donor egg/sperm, adoption
Current pregnancy - offer
prenatal diagnosis
Affected fetus – discuss all
available reproductive
options
Positive carrier status
Relevant family members
Slide23Carrier Screening – Which Disorders?
Disorder is clinically severe
High frequency of carriers in the screened population
The mutations are relatively frequent (prevalence)
Predictive values of the test results
Availability of a reliable test with a high
sensitivity and specificity
Cost-effective, accurate and comprehensive for the majority of the frequent mutations
Fully transparent
Mutations are well characterized
Access to genetic counseling
Availability of prenatal diagnosis for the disorder
Slide24Traditional Ca
rrier Screening – Who
?
Prepregnancy
consult
Pregnant patients
*Family History
Importance
of family history
Ethnicity / ancestry
3-Generation pedigree
Familial
mutations
Sequential
screening
Test one partner
initially
Concurrent screening
Test couple
(time sensitive)
Assess reproductive risks
Prenatal diagnosis
Early diagnosis
& treatment
Options for reproductive
decision making
Information for current and/or future pregnancies
Slide25Traditional Carrier Screening – Who
?
Prepregnancy consult patients
Current pregnancy
Family History
Ethnic groups
African ancestry
Ashkenazi
Jews
Asian ancestry
Cajuns
French Canadians
Mediterranean ancestry
Native Americans
Northern Europeans
Slide26Carrier Screening - Guidelines
2001
- ACOG, ACMG:
Offer cystic fibrosis screen:
Caucasians, Ashkenazim
Make screen available:
African, Asian and Hispanic origin
2005
–
ACOG:
Offer CF to
all
pregnant women
2007
–
ACOG PB #78:
Hemoglobin electrophoresis
African origin, Asian, Mediterranean
Slide27Carrier Screening – 2017
Updates ACOG, ACMG
CF, SMA, CBC with MCV & MCH
ALL
women - pregnant/considering pregnancy
Hemoglobin electrophoresis
(Hemoglobinopathies)
Abnormal CBC / RBC indices
African
Mediterranean
Middle Eastern
Southeast Asian
West Indian
DNA testing
– silent carrier for alpha thalassemia
Slide28Carrier Screening – 2017
Updates ACOG, ACMG
Fragile X premutation carrier screening
Pregnant or considering pregnancy
Family history
Premature unexplained ovarian insufficiency/failure
Elevated FSH <40 years
T
argets
higher prevalence
group
Slide29Carrier Screening – 2017
Updates ACOG, ACMG
Ashkenazi Jewish ancestry -
Recommend
screening
Canavan disease
Cystic fibrosis
Familial
dysautonomia
Tay
Sachs disease
Slide30Ashkenazi Jewish ancestry-
Consider
Screening
Bloom
syndrome
Fanconi
anemia
Gaucher
disease
Glycogen storage disease type I
Joubert
syndrome
Maple syrup urine disease
Mucolipidosis
type IV
Niemann
-Pick disease
Usher syndrome
Slide31Expanded
Carrier Screening
Slide32Expanded Carrier Screening (ECS)2009 - First made available High-Throughput
Genotyping &
Sequencing
Multitudes of conditions are genotyped and sequenced simultaneously
Affordable cost
Slide33ACOG Guidelines - ECSCarrier frequency 1 in 100Well- defined phenotype
Detrimental effect on quality of life
Require surgical or medical intervention
Have onset in early life
Prenatally diagnosable
Antenatal intervention to improve perinatal outcome
Change delivery management
Parental education re special care needs after birth
Not a disease with conditions primarily of adult onset
Slide34Expanded Carrier Screening Same set of conditions is offered (> 100)
All individuals
No regard for race/ethnicity
Slide35TRADITIONAL CARRIER SCREEN
Significantly affect quality of life
Cognitive, physical disabilities
Need lifelong
medical therapies
1 in 100 carrier frequency
Fetal, neonatal or early childhood onset
Well-defined phenotype
EXPANDED CARRIER SCREEN
Additional conditions vary significantly in presentation
Includes conditions not currently recommended for carrier screening
(FVL, hemochromatosis, Fragile X)
*
Rare conditions
Variable age of onset (A1AT)
Less clearly defined phenotype
(
MTHFR
,
HFE
)
Slide36Expanded Carrier ScreeningIncludes rare conditions
Precise
carrier frequency is unknown
Proportion of disease causing variants that can be detected is unknown
Residual risk calculation
Slide37Expanded Carrier Screening ModelIncludes rare conditionsPretest counseling – Less well defined phenotypes
Less reliable residual risks
Negative results = Reduced risks
Carrier rescreening is typically not advised
Slide38Expanded Carrier Screening ModelMolecular methods are less accurateHemoglobinopathies – MCV, hemoglobin electrophoresisTay-Sachs – HEXA enzyme testing is best method for all ethnic groups
Slide39Expanded Carrier Screening ModelAutosomal-recessive (majority)X-linked single gene (some)Autosomal-dominant single gene (some)
Slide40Limitations of Condition-directed Carrier ScreeningInaccurate knowledge of ancestryMultiethnic society
Inter-ethnic marriages
Adoption / unknown ancestry
Population mobility
Genetic conditions do not occur solely in specific ethnic groups
Screening for individual conditions limits the amount of accessible genetic information for participants
Slide41Expanded Carrier Screening – Who?Preconception - women of reproductive ageSequential or Concurrent screening
Pregnancy
Gamete donors
Family history of a genetic condition
ECS does not replace genetic counseling or assessment of familial risk
Newborn screen
Slide42Expanded Carrier Screening – Who?ACOG Committee Opinion #690, March 2017Low level – display posters and pamphletsPatient inquiries
Routinely offer
Slide43Expanded Carrier Screening – PretestVoluntaryInformed consentOption to decline
Document in medical record
Confidential genetic test results
Slide44Expanded Carrier Screening – PretestPossible carrier test results Carrier for more than one conditionPartner testing
Discordant carrier status
Concordant carrier status
New diagnosis of a tested condition
Slide45ECS – More Points to ConsiderMass mediaGINA
Slide46Mass Media & Health InformationEmphasis on health innovations and breakthroughs and individual effect.
(Coleman, Thorson &Wilkins, 2011)
Health issues are framed in mass media
What to think about
Topics
How to think about it
Sources
(McCombs &
Ghanem
, 2001)
Slide47Expanded Carrier Screening – PretestConfidential genetic test resultsGenetic Information Non-Discrimination Act of 2008 (GINA
)
Slide48GINAHealth insurance decisionEmployment decisions
Slide49GINALife insuranceDisability insurance Long term care insurance
Slide50GINAVAThe Federal Employees Health Benefits PlanIndian Health Service
Slide51Concerns About ECSLack of familiarity Providers & patients
Service logistics
Time requirements (pre / post test counseling)
Availability of genetic professionals
Which diseases to include in panel
Cost
Family members
Future insurance plans
Slide52Summary
The contribution of single gene disorders to disease burden of birth defects is significant
Genetic carrier screening is the standard of care nationally and globally
ACOG and ACMG have updated carrier screening guidelines
An informed patient is key
Slide53CYSTIC FIBROSIS
Slide54Cystic Fibrosis
10 Million Americans are asymptomatic
carriers
Slide55CYSTIC FIBROSIS
DISEASE
FREQUENCIES
White newborns – 1 in 2500 to 3500
Hispanic Americans – 1 in 13,500
15.4% of US population are Hispanic
7% of CF patients in the US are Hispanic
African Americans – 1 in 15,100 to 1 in 17
,000
12% US population are African Americans
4.2% of CF patient in the US are African Americans
Asian Americans / Pacific Islanders – 1 in 31
,000
to 1 in 100,000
Native
American Indians/Alaska Natives
Common among American Indians (Pueblo and Zuni)
Slide56CYSTIC FIBROSIS (CF)
Autosomal
recessive disease
Buildup of thick, sticky mucus that can damage multiple organs
Progressive damage to respiratory system
Chronic digestive system problems
Slide57CF Mutations
1700 mutations
Screen panel – minimum of 23 most common mutations
Common mutations
Delta F508
Variants
Poly T tract: 5T/ 7T/9T
Milder forms
Male fertility - CBAVD
Slide58CF Screening Guidelines
Test all women considering pregnancy
Preconception consult
All pregnant women
Family history of CF
Familial mutation
Slide59CF Detection Rates by Ethnic Group
Ashkenazi Jew – 94%
Non-Hispanic white - 88%
Hispanic – 72%
Black – 64%
Asian – 49%
Slide60Wiki Helicase.pbworks.com
Slide61n
chpeg.org
Slide62Learn.genetics.Utah.edu
Slide63ghr.nlm.nih.gov
Slide64Lungpictures.org
Slide65SPINAL MUSCULAR ATROPHY
Slide66SMA Carrier F
requencies
Overall
1/40 to 1/60
N.A. Caucasians 1:37
Ashkenazi Jews 1:46
Asian 1:56
African American 1:91
Hispanic 1:125
Slide67SPINAL MUSCULAR ATROPHY (SMA1)
Prevalence 1 in 6000 to 1 in 10,000 live births
Leading genetic cause of infant death
AR inheritance pattern
Second most common fatal AR disorder after CF
Severe n
euromuscular disease
Degeneration
of
alpha motor neurons in the spinal cord
Progressive proximal muscle weakness
P
aralysis
Slide68Type I SMA (Werdnig-Hoffmann)
At birth or within first 3 months
severe
progressive generalized muscle weakness
hypotonia
Bulbar dysfunction - poor suck ability, reduced swallowing
Death from respiratory failure usually within first 2 years of life
Median survival 7 months
Slide69Type I SMA (Werdnig-Hoffmann)
Impaired fetal movements observed in 30%
Skeletal and limb deformities may be seen at birth
Fasciculation of tongue at 4-6 months
Slide70Type I SMA (Werdnig-Hoffmann)
Prone to pulmonary infections
S
coliosis
J
oint contractures
P
oor head control
R
etarded leg control and weight bearing
U
nable to sit up
I
ntercostal muscle weakness
S
mall chest
Large abdomen
Breathes
through
stomach
Weak cough
Fluid
buildup in
lungs
Risk
of aspiration while eating
Slide71SMA II
Symptom onset by 2 years of age
Can sit
Cannot
stand or walk unaided
Survival is beyond 4 years, possibly to 3
rd
decade of life
SMA III
Mild
form
Symptom onset in infancy or childhood
Walk
unaided
Kugelberg – Welander
SMA IV
Proximal SMA
A
dult
onset form of proximal SMA
muscle weakness &
hypotonia
Due to degeneration
and loss of the lower motor neurons in the
spinal
cord &
brain stem
nuclei
Slide72Childhood SMA
Type I – 70%
Type II and III – 30%
Slide73Screening Guidelines
All
women considering pregnancy
Preconception consult
All
pregnant women
Family history of SMA1
Familial mutation
Goal – identify couple at risk for having child with SMA
Informed reproductive choices
Slide74Survival motor neuron
SMN
gene
Primary
SMA determining gene
5q13
Wikivisually.com
Slide75SMN
Gene
Two almost identical
SMN
genes
SMN1
gene – 9 exons for full length transcript
SMN2
gene –
840
C to T change
C to T change in exon 7 disrupts splicing
Majority of
SMN2
transcripts lack exon 7
Low functional
SMN
protein levels
Slide76Survival motor neuron
Wikivisually.com
Slide77SciELO
. M.T.C
Baioni
J.Pediatr
.(Rio J.)
2010
Slide78SMA Carrier Testing
Dosage analysis*
Detects the number of
SMN1
genes
Highly accurate detection for
SMN1
gene
90% detection rate
False negatives
Slide79SMA – Dosage Analysis
Carrier Test
Negative test result
2 or more
SMN1
gene dosage result
Positive carrier test result
1
SMN1
gene detected
Slide80SMA Carrier Testing – Limitations
SMN1
copy number
5% of
population - 3 copies of
SMN1
gene
Number of
SMN1
genes can vary on a chromosome
Slide81Quest Diagnostics Education Center
Slide82SMA Carrier Testing - Limitations
Carrier
detected
1
SMN1
gene dosage result
Carrier
undetected
2
SMN1
genes, both copies on the same chromosome (cis)
Z
ero
SMN1
on the other chromosome
Carrier
undetected
2
SMN1
genes detected
Point mutation in
1
SMN1
gene
cannot be detected by dosage analysis
Slide83SMA1 Genetics
95% cases
H
omozygous
deletions of exon 7 in
SMN1
gene
5%
cases
C
ompound heterozygotes
:
Deletion of
exon 7
+
small subtle mutation in other allele
Slide84SMA Carrier test
Counseling – pre- and post-test
Couple
Understand dosage testing
Possibility of false negatives
Limitations
Residual risk
2% of cases are due to de novo mutations in
SMN1
Slide85THE HEMOGLOBINOPATHIES
Slide86NORMAL HEMOGLOBIN
Slide87BETA GLOBIN GENE LOCUS
HBB
gene
11 p15.1
Wikiwand
Slide88BETA GLOBIN GENE CLUSTERWeb-Books.com
Slide89BETA GLOBIN GENEExome Sequencing in the Clinic.
Michael
Buckley, S.E.A.L.S. Genetics Lab.
Slide90SICKLE CELL
CARRIERS
AS
AFFECTED
SS
SC
SICKLE
-
BETA THALASSEMIA
HBS
= GLU6VAL
POINT MUTATION
POLYMERS OF HEMOGLOBIN
DISTORT SHAPE OF RBC
HBC
= GLU6LYS
BETA THALASSEMIA
:
NUCLEOTIDE SUBSTITUTIONS, DELETIONS, INSERTIONS
CAUSE FRAMESHIFT
Slide91SICKLE CELL DISEASE
CLINICAL FEATURES
Sickle cell crisis
Vasoocclusive disease
Autosplenectomy
Kidneys, lung, brain
Acute Chest Syndrome
Slide92BETA THALASSEMIA200 different pathogenic variants for
HBB
gene
Frameshift (splice site)
Substitutions, deletions, insertions
B
+
- thalassemia
B
0
- thalassemia
Slide93ALPHA
THALASSEMIA
Chromosome 16
4 Genes
Screening / diagnostic tests
Neither hb electrophoresis or solubility testing can identify individuals with alpha thal trait
Only molecular genetic testing can identify alpha thalassemia
Prenatal diagnosis
Slide94ALPHA GLOBIN GENE LOCATION
Slide95ALPHA GLOBIN GENE CLUSTER
David H. K. Chui et al. Blood 2003;101:791-800
Slide96Ash Lal, MD. Focus on Alpha Thalassemia
Slide97FRAGILE X SYNDROME
Slide98Fragile X Syndrome
X-linked dominant
Clinical features
Intellectual disability or impairment
Learning disabilities
Cognitive disabilities
Behavioral disabilities – autism with intellectual disability; attention deficit – hyperactivity disorder or both
Prevalence – males, females
Phenotype
Slide99Fragile X Syndrome
Diagnosed in 25% of persons with autism or autism spectrum disorder behaviors with intellectual disability
Carrier frequency prevalence
1 in 257
of
US women with no known risk factors for fragile X syndrome
1 in 157 among 36,000 Israeli women with no family history of intellectual disability or developmental abnormalities
1 in 86 with family history of intellectual disability
Slide100Fragile X Syndrome
THE
GENETICS
X-linked disorder
CGG repeat
Expansion of CGG trinucleotide repeat alters transcription of FMR1 gene
DIAGNOSIS
DNA based molecular diagnosis – Southern blot, PCR
Slide101Slide102Summary
The contribution of single gene disorders to disease burden of birth defects is significant
Genetic carrier screening is the standard of care nationally and globally
ACOG and ACMG have updated carrier screening guidelines
An informed patient is key
Slide103Case #125-year old female G1P0 comes in for her first prenatal visit. Her confirmed gestational age by ultrasound earlier in the day is 7 weeks and 0 days and is consistent with her LMP. She is unclear about ‘genetic testing’ that she recently read about in Fit Pregnancy magazine. She has no family history of genetic disease and does not want to undergo any unnecessary testing; however, she would like more information before making a decision.
What is your discussion with this patient?
Slide104Case #2R.T. and S.T., an Ashkenazi Jewish couple, were referred to the genetics clinic for evaluation of their risk for having a child with
Tay
-Sachs disease. S.T. had a sister who died of
Tay
-Sachs disease as a child. R.T. had a paternal uncle living in a psychiatric home, but he did not know what disease his uncle had. Both R.T. and S.T. had declined screening for
Tay
-Sachs carrier status as teenagers
.
What genetic carrier tests would you advise this couple to have?
Why?