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

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

Protein and Gene Structure

16p13

11p15

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

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.

Sickle Cell Disease Mutation

The amino acid glutamic acid, at the sixth position of the β-globin chain, is substituted by valine.

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

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

Normal and Deleted α-globin Structural Genes

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.

β Thalassemia Major Bone Changes

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

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

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

In Vitro Fertilization (IVF)

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Preimplantation Genetic Diagnosis

(PGD)

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