11/3/2016
Multiple pregnancies
Ana Bircher, MD American Board Certified Medical Geneticist
Types of twins
Two eggs – two sperm One egg – one sperm
Di-zygotic Mono-zygotic FRATERNAL IDENTICAL
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
1 11/3/2016
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
2 11/3/2016
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 Down syndrome baby
Down syndrome baby 47,XX+21 46,XX
Normal baby
Down syndrome baby
3 11/3/2016
“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 Point mutation
Normal baby Baby with genetic disorder
4 11/3/2016
Discordant for point mutations
Normal baby Achondroplasia baby
Discordant for malformations
“IDENTICAL” twins discordant for mitochondrial disease
Severely affected baby
Normal baby
5 11/3/2016
Skewed X-inactivation
Normal baby
Baby with X-linked condition
Epigenetics - Imprinting
CH3
METHY cap
11 15 11 15
Discordant for imprinting defect
CKNQ1OT1 CKNQ1OT1
CKNQ1OT1
Chromosome 11 Beckwidt-Wiedeman syndrome
6 11/3/2016
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
7 11/3/2016
The Cheng twins: the original The Hilton sisters siamese twins
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 ??
8 11/3/2016
Bad timing – unequal cell amount
Ectoparasitic twin
9 11/3/2016
Arterio-arterial transfusion Placental anastomosis by 18-21 days
Twin Pump twin Reverse Arterial Perfusion
Recipient twin
Recipient twin Pump twin
Umbilical vein Umbilical vein
Artery with Artery reversed flow
“Used”, deoxygenated blood Increased cardiac load caudo-cranial perfusion gradient High output failure upper body disruption Polyhydramnios Hydrops Premature delivery
The acephalus-acardiac twin
Lebel The Fetus.net
10 11/3/2016
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
11 11/3/2016
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
12 11/3/2016
• 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
13 11/3/2016
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
14 11/3/2016
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?
15 11/3/2016
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
16 11/3/2016
17 11/3/2016
“Nope. DNA is 100% foolproof and it doesn’t lie”
TRUE, but we still can’t understand what it is saying
THANK YOU!!!
18