Answers To Case 12: Thalassemia/Oligonucleotide Probe

Thalassemia/Oligonucleotide Probe Case File
https://medical-phd.blogspot.com/2021/03/thalassemiaoligonucleotide-probe-case.html
Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD
❖ CASE 12
A 25-year-old Mediterranean female presents to her obstetrician at 12-weeks gestation for her first
prenatal visit. This is her first pregnancy, and she is concerned about her baby and the risk of
inheriting a “blood” disease like others in her family. The patient reports a personal history of mild
anemia but nothing as severe as her brother who required frequent transfusions and died at age 10.
The patient was told by her physician that she did not need to take iron supplementation for her
anemia. Patient denies having any anemic symptoms. Her physical exam is consistent with a 12-
week pregnancy and ultrasound confirmed an intrauterine pregnancy at 12-weeks gestation. The
patient’s hemoglobin level shows a hypochromic, microcytic (small sized red cell) anemia
(hemoglobin, 9g/dL) and hemoglobin electrophoresis demonstrated increased hemoglobin A2 level
(4.0 percent) and increased fetal hemoglobin level, a pattern consistent with β-thalassemia minor.
The patient underwent chorionic villus sampling to assess whether the fetus was affected, and the
diagnosis returned in several hours.
◆ What is the molecular genetics behind this disorder?
◆ What was the likely test and what is the biochemical basis?
ANSWERS TO CASE 12: THALASSEMIA/OLIGONUCLEOTIDE PROBE
Summary: A 25-year-old Mediterranean pregnant female has a history of asymptomatic mild

hypochromic, microcytic anemia, elevated hemoglobin A2 and F on electrophoresis. Her brother
had severe hemolytic disease that required transfusions and ultimately caused his premature death
at age 10. She is diagnosed with β-thalassemia minor.
◆ Molecular genetics: Impaired production of β-globin peptide chain. Numerous mutations have

been identified in the production of ribonucleic acid (RNA) including in the promoter region and
splice junctions.
◆ Likely test: Oligonucleotide probe. After chorionic villus sampling is performed, a radioactive

probe can be used and hybridized with specific genetic mutations in the fetus’ deoxyribonucleic
acid (DNA), allowing for prompt detection and prenatal diagnosis.
CLINICAL CORRELATION
Anemia is the abnormally low level of hemoglobin or red blood cell mass, which has the potential
of limiting the delivery of oxygen to tissue. By far, the most common cause of anemia is iron
deficiency, leading to small volume of red blood cells (microcytic). Another common cause of
microcytic anemia is thalassemia. Certain ethnicities have higher incidences of thalassemia, for
example, Mediterranean or East Asian descent.
This patient is of Mediterranean descent, making thalassemia more likely. Furthermore, the
microcytic (small red blood cell size) anemia in the face of elevated hemoglobin A2 and F is
consistent with β-thalassemia minor. Patients with β-thalassemia major (Cooley anemia) typically
have severe anemia requiring frequent transfusions and shortened life expectancy. Infants will
appear healthy after birth, but as the hemoglobin F levels fall, the infant becomes severely anemic.
Females with β-thalassemia major who survive beyond childhood are usually sterile.
APPROACH TO OLIGONUCLEOTIDE PROBES

Objectives
1. Know about the use of oligonucleotide probes for detection of mutations.
2. Know how oligonucleotide segments are synthesized.
3. Be familiar with common mutations that cause thalassemias (substitutions in TATA box,
mutations in splice junction, and changes in stop codon).
Definitions
Erythropoiesis: Erythropoiesis is the development of mature red blood cells containing

hemoglobin (erythrocytes) from pluripotential stem cells via a linear cascade.
Frameshift mutation: Insertion or deletion of a number of nucleotides that are not divisible by
three into a coding sequence, thereby causing an alteration in the reading frame of the entire
sequence downstream of the mutation.
Locus control region: Regulatory region which is believed to regulate transcription by opening
and remodeling chromatin structure. It may also have enhancer activity.
Promoter sequence: A regulatory region present at a short distance upstream from the 5′ end of a
transcription start site that acts as the binding site for RNA polymerase to initiate transcription.
Thalassemia: A group of genetic disorders that is characterized by the absence of or reduced
synthesis of one or more of the four globin chains in hemoglobin. The sequelae can range from
benign to fatal, depending on the severity of the decrease in the globin chain.
Transposons: These are segments of DNA that can move around to different positions in the
genome of a single cell. In the process, they may cause mutations and increase (or decrease) the
amount of DNA in the genome. These mobile segments of DNA are sometimes called “jumping
genes.”

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Thalassemia/Oligonucleotide Probe Case File

◆ What is the molecular genetics behind this disorder?

ANSWERS TO CASE 12: THALASSEMIA/OLIGONUCLEOTIDE PROBE

Summary: A 25-year-old Mediterranean pregnant female has a history of asymptomatic mild

◆ Molecular genetics: Impaired production of β-globin peptide chain. Numerous mutations have

◆ Likely test: Oligonucleotide probe. After chorionic villus sampling is performed, a radioactive

APPROACH TO OLIGONUCLEOTIDE PROBES

Erythropoiesis: Erythropoiesis is the development of mature red blood cells containing

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