11/3/2016
Multiple pregnancies
Ana Bircher, MD
American Board Certified Medical Geneticist
Types of twins
Two eggs – two sperm
One egg – one sperm
Mono-zygotic
Di-zygotic
IDENTICAL
FRATERNAL
Zygote: a cell formed by the union of one sperm and one egg
Di-zygotic twins
Two eggs – two sperm
Two placentas
Two amniotic cavities
Two genetically different babies
Same or different sex
They share 50% of the genes
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Mono-zygotic twins
One sperm – One egg
Number of placentas (chorions) and amnions
depend on the time of splitting
Share 100% of the genes
Paradigms
• Monozygotic twins (Identical twins) are
identical
• There are two types of twins: MZ and
DZ
• MZ twins happen by chance alone
Paradigms
• Monozygotic twins (Identical twins) are
identical
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Identical twins are NOT identical
• Last decades discordant MZ twins have been
increasingly reported
• In fact, MZ twins are rarely identical
• Mistakenly confused as dizygotic (“fraternal”)
• Benefits to accurately assess zygosity:
– Solid organ transplantation matching
– Preventive management of disorders
– Better counseling of parents of uniqueness
“Identical twins are not identical
- Chromosomal mosaicism
- Point mutations
- Mitochondrial mutations
- X-inactivation differences
- Epigenetics
- Split egg differences
Discordant twins in chromosome
disease
47,XX+21
47,XX+21
46,XX
Down syndrome baby
Down syndrome baby
Normal baby
Down syndrome baby
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“Identical” twins different sex
Normal boy
Girl with Turner syndrome
NIPT sensitivity
•
•
•
•
•
Positive predictive value
Trisomy 21: 83%
Trisomy 18: 65%
Trisomy 13: 43%
X-Y abnormalities: 50%
Discordant twins in point-mutations
Normal
Normal baby
Normal baby
Normal
Normal baby
Point mutation
Baby with genetic disorder
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Discordant for point mutations
Normal baby
Achondroplasia baby
Discordant for malformations
“IDENTICAL” twins discordant for
mitochondrial disease
Severely affected baby
Normal baby
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Skewed X-inactivation
Normal baby
Baby with X-linked condition
Epigenetics - Imprinting
CH3
METHY cap
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11
15
15
Discordant for imprinting defect
CKNQ1OT1
CKNQ1OT1
CKNQ1OT1
Chromosome 11
Beckwidt-Wiedeman syndrome
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Imprinting defect
CKNQ1OT1
Beckwidt-Wiedeman
Twinning
Monozygotic twins - ART
ART predisposes to
imprinting errors AND to
MZ twinning
MZ more than 2-fold in ART
Twinning gene?
Smith’s Recognizable patterns of Human Malformation
Mirror image monozygotic twins
Reverse laterality
Up to 25% for small findings such as:
– Fingerprint patterns
– Hair patterns
– Face
– Brain laterality
• More common in
conjoined twins
70-95% are girls
40% stillbirth
30% neonatal death
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The Cheng twins: the original
siamese twins
The Hilton sisters
Identical Non-identical
• 17 months MZ
• Severely malnourished
size 8 months old
• Global developmental delay
• Extensive medical issues
• Smaller HBP – Bigger LBP
• Different personalities
Why two children that share SAME genetics, SAME environment
and even SAME head be so different??
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Bad timing – unequal cell amount
Ectoparasitic twin
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Arterio-arterial transfusion
Placental anastomosis by 18-21 days
Twin
Reverse
Arterial
Perfusion
Pump twin
Recipient twin
Recipient twin
Umbilical vein
Artery with
reversed flow
“Used”, deoxygenated blood
caudo-cranial perfusion gradient
upper body disruption
Pump twin
Umbilical vein
Artery
Increased cardiac load
High output failure
Polyhydramnios
Hydrops
Premature delivery
The acephalus-acardiac twin
Lebel The Fetus.net
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Paradigms
• Monozygotic twins (Identical twins) are
identical
• There are two types of twins: MZ and
DZ
• MZ twins happen by chance alone
Two types of twins
2/3 of twins are DIZYGOUS
1/3 of twins are MONOZYGOUS
Intermediate forms of twins
Polar body twinning
Dizygotic twins with fusion of trophoblast
ART is a risk factor
Intermediate twins – polar body
twinning
DZ twins: 50% genes
MZ: 100% genes
75% of genetic material
Semi-monozygotic twins
ART is a risk factor
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Intermediate forms – Chimerism
• Greek mythology: monster with body of a
lioness the head of a goat and the tail of a
snake
• Two or more different populations of cells
• More common than
previously thought
DZ with fusion
Chimerism
• Chimerism exists in
animals and humans
• We just started
understanding causes
• IVF is a risk factor
ABC news – Aug 15, 2006
• Lydia Fairchild = 26 y/o mother unemployed applied for
public assistance at Washington state
• Testing to prove all were related
• Her DNA did NOT match the DNA of her children
• “Nope. DNA is 100% foolproof and it doesn’t lie”
• Three court hearings – Court told her to find a lawyer –
lawyers didn’t want to help
• Family planned to hide children from authorities
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• Karen Keegan Boston
• Needed a kidney transplant
• “We’ve never had this happen before, your
children DNA don’t match your DNA
• Tested plenty of tissues (hair/blood/saliva)
• - psychologically unstable – surrogate mother
• Thyroidectomy -
CHIMERA
Paradigms
• Monozygotic twins (Identical twins) are
identical
• There are two types of twins: MZ and
DZ
• MZ twins happen by chance alone
Familial monozygotic twinning
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
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Medical studies on twins
• MZ twin pairs are living human laboratories
• Twin studies allow researchers to learn about
complex conditions
Why are they born different
When do they start to diverge?
In the past: it is the “environment”
At present: epigenetic events may be
the underlying cause
Complex disorders
Multifactorial = genetic predisposing factors
associated to environmental factors
- Most isolated birth defects
NTD - CL/P - CHD
- Most common diseases
DM – Psychiatric disorders – heart disease
dementia – autoimmune disorders - arthritis
Complex disorders
FAMILY STUDIES
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Family studies
Confirmation that these disorders do in fact run in families
Common complex disorders
• Always run more frequently in families
• Genetics? Environment?
• Family studies don’t help disentangling this
question
• TWIN pair studies
TWIN STUDIES
• MZ (identical) twins share 100% of the genes
• DZ twins share 50%
• No matter DZ or MZ both share same
environment (intrauterine, born at same time,
same family)
• Assumption: any discordance between MZ and
DZ in the disease we are studying is due to
genetic factors
• In one of the twins is affected, what is the chance of
the second twin is affected?
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None of these is purely genetics, concordant for MZ should be
100%
But it is higher so it means that genetics play a role in etiology
EPIGENETICS
Epigenetics in smoking
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“Nope. DNA is 100% foolproof and
it doesn’t lie”
TRUE, but we still can’t understand
what it is saying
THANK YOU!!!
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