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![Page 1: Javad Jamshidi Fasa University of Medical Sciences, December 2015 Prenatal Testing and Hemoglobinopathie s Session 5 Medical Genetics.](https://reader036.fdocuments.us/reader036/viewer/2022062423/5697c0281a28abf838cd6996/html5/thumbnails/1.jpg)
J a v a d J a m s h i d i
F a s a U n i v e r s i t y o f M e d i c a l S c i e n c e s , D e c e m b e r 2 0 1 5
Prenatal Testingand
Hemoglobinopathies
S e s s i o n 5Medical Genetics
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Hemoglobinopathies
At least 250,000 people each year with disorders of hemoglobin (Hb), called Hemoglobinopathies
Hb is the protein present in red blood cells that is responsible for oxygen transport
Hb being made up of a tetramer consisting of two pairs of different polypeptides referred to as the α and β globin chains
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Protein and Gene Structure
16p13
11p15
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Disorders of Hemoglobin
1) Structural globin chain variants such as sickle cell disease
2) Disorders of synthesis of the globin chains such as the thalassemias
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Structural Variants/Disorders
More than 300 Hb electrophoretic variants have been described due to a variety of types of mutation
The majority are rare and not associated with clinical disease
A few are associated with disease and relatively prevalent in certain populations.
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Sickle Cell Disease Mutation
The amino acid glutamic acid, at the sixth position of the β-globin chain, is substituted by valine.
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Disorders of Hemoglobin Synthesis
The thalassemias are the commonest single group of inherited disorders in humans
Persons from the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia
The same pathophysiology, An imbalance of globin-chain production results in the accumulation of free globin chains in the red blood cell
α and β Thalassemia
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α ThalassemiaResults from underproduction of the α-globin chains and occurs most commonly in Southeast Asia
Two main types of α-thalassemia:
The severe formNo α chains are produced, fetal deathHydrops fetalisTetramer of γ chains, called Hb Barts
The milder formSome α chains but still a relative excess of β chainsβ -globin tetramer Hb H-known as Hb H disease
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Normal and Deleted α-globin Structural Genes
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β ThalassemiaCaused by underproduction of the β-globin chain of Hb.
Two main types of β-thalassemia:
The major formHomozygotes for β chains defect, Cooley's anemiaSevere transfusion-dependent anemiaAn unusually shaped face and skullAffected individuals used to die in their teens or early adulthood
The minor formHeterozygotes for β chains defectUsually have no symptoms or signs
Mild hypochromic, microcytic anemia, may be confused with iron deficiency anemia.
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β Thalassemia Major Bone Changes
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Intro
Until recently, couples had to choose between taking the risk or considering other options
Over the past three decades, prenatal diagnosis-the ability to detect abnormalities in an unborn child-has been widely used
The ethical issues surrounding prenatal diagnosis and selective termination of pregnancy are both complex
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Techniques Used in Prenatal Diagnosis
InvasiveAmniocentesisChorionic Villus SamplingFetoscopyCordocentesis
Non-InvasiveMaternal Serum ScreeningUltrasound
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AmniocentesisAspiration of 10 to 20 ml of amniotic fluid , through the abdominal wall under ultrasonographic guidance
Usually performed around the 16th week of gestation.
The sample is spun down to yield a pellet of cells and supernatant fluid
The fluid can be used for assay of α-fetoprotein
Cells for chromosome and DNA analysis
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Amniocentesis
0.5% to 1% risk of miscarriage
Possibility of having to consider a midtrimester termination of pregnancy
Trials of amniocentesis earlier in pregnancy, at 12 to 14 weeks' gestation, yielded comparable rates of success
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Chorionic Villus Sampling
This procedure is usually carried out at 11 to 12 weeks gestation
Either trans cervical or, trans abdominal aspiration of chorionic villus (CV) tissue
Called placental biopsy, when the procedure is carried out at later stages of pregnancy
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Trans abdominal
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Chorionic Villus Sampling
Direct chromosomal analysis of CV tissue usually allows a provisional result to be given within 24 hours
The major advantage of CV sampling is that it offers first-trimester prenatal diagnosis
The procedure conveys a I% to 2% risk of causing miscarriage
Cause limb abnormalities in the embryo if carried out before 9 to 10 weeks‘ gestation
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Fetoscopy
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Ultrasonography
Prenatal diagnosis of structural abnormalities not associated with known chromosomal, biochemical or molecular defects
Require expensive equipment and a skilled, experienced operator.
Offer routinely to all pregnant women at around 18 weeks gestation as screening for structural abnormalities
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Ultrasonographic image of a transverse section ofthe hand of a fetus showing polydactyly2
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Nuchal thickening-an accumulation of fluid atthe back of the neck
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Maternal Serum Screening
Maternal serum screening is offered for NTDs and Down syndrome
A blood sample obtained from the mother at 16 weeks' gestation
In this way up to 75% of all cases of open NTDs and 60% to 70% of all cases of Down syndrome can be detected
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Neural Tube Defects (NTD)
Open NTDs could be detected at 16 weeks' gestation by assay of Alpha-fetoprotein in maternal serum
AFP is the fetal equivalent of albumin and is the major protein in fetal blood
If the fetus has an open NTD, the level of AFP is raised in both the amniotic fluid and maternal serum
Unfortunately maternal serum AFP screening for NTDs is neither 100% sensitive nor 100% specific
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Maternal serum alpha-fetoprotein (AFP) levels at 16 weeks' gestation2
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Screening for Down Syndrome(The Triple Test)
At 16 weeks' gestation maternal serum:
AFP
Unconjugated estriol
human chorionic gonadotropin (hCG)
Inhibin-A
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Ultrasonogram at 18 weeks showing a rocker-bottom foot in a fetus subsequently found to
have trisomy 18.29
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Indications for Prenatal Diagnosis
Advanced Maternal Age
Previous Child with a Chromosome
Abnormality
Family History of a Chromosome Abnormality
Family History of a Single-Gene Disorder
Family History of a Neural Tube Defect
Abnormalities Identified In Pregnancy
Other High-Risk Factors
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Special Problems in Prenatal Diagnosis
Failure to Obtain a Sample or Culture
Failure
An Ambiguous Chromosome Result
An Unexpected Chromosome ResultA Different Numerical Chromosomal AbnormalityA Structural Chromosomal RearrangementThe Presence of a Marker Chromosome
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In Vitro Fertilization (IVF)
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Preimplantation Genetic Diagnosis
(PGD)
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