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Genetic testing of banked umbilical cord blood
Cytotherapy (1999) Vol. 1, No. 4, 275–278
Letter to the Editor
Genetic testing of banked umbilical cord blood M Wick, ME Clay, T Eastlund, DE Vawter, R McGlennen and J McCullough Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, USA
With the establishment of UC banks and the use of cord
transplant is for treatment of these disorders, it is re-
blood for transplantation, it is necessary to consider testing
commended that the UC blood unit intended for transplant
of banked cord blood for inherited diseases [1–3]. Genetic
be tested for the specific disease. This is currently being
testing of UC blood involves many issues, including:
done in those few centers that transplant these patients.
n The diseases for which testing should be done. n Test methods and the potential impact of methods
presently under development. n The cost. n The nature of consent that must be obtained. n Which individuals should give consent? n The management of test results [2,3].
A secondary benefit of genetic screening of the UC blood unit for a specific metabolic disease is the possibility, although remote, that the blood from an unrelated donor could be shown to have the same genetic disease as the recipient. In this situation, early detection of the disease could possibly lead to early treatment for the donor and avoidance of nervous system damage. General screening of all UC blood samples for metabolic diseases would not be
In this letter we focus on the first of these issues and propose
indicated because these disorders are relatively uncommon
an approach to considering testing of cord blood for
and testing is costly.
inherited diseases.
The third category comprises those diseases for which
Genetic testing should be considered only for diseases
transplantation of stem cells containing the defective (or
involving hematopoietic tissue since other genetic diseases,
absent) gene could lead to disease manifestation in the
even if present in the UC blood donor (infant), would not
transplant recipient. Examples are hemoglobin C, hemoglo-
become manifest in the hematopoietic stem-cell recipient.
bin E, sickle cell disease (HbS), glucose-6-phosphate
Based on the potential consequences in the hematopoietic
dehydrogenase (GGPD) deficiency and pyruvate kinase
stem-cell transplantation setting, we have classified genetic
(PK) deficiency. Molecular and/or other laboratory testing
diseases into four categories and present a proposed test (or
for each of these diseases is available and economically
non-test) strategy for each. This information is summarized
feasible. All US States have newborn-screening programs for
in Table 1, along with examples of ‘common’ genetic
HbS, the results of which are usually sent to the infant’s
disorders within each category.
physician and medical record. Hemoglobin electrophoresis,
The first category includes those diseases which would
which is routinely used for the laboratory diagnosis of HbS,
not be expected to have a clinical effect on the recipient of
also detects other common hemoglobinopathies, b-thalasse-
a hematopoietic cell transplant (e.g. Factor V Leiden,
mia and combinations of the two. Thus, additional testing
Duchenne muscular dystrophy). Testing for these diseases
for the most common diseases in this group can be avoided
is not indicated.
by reviewing the potential donor’s medical records.
The second category includes those genetic diseases that
In contrast to previously mentioned hemoglobino-
are treated by BM transplantation. This involves primarily
pathies, definitive testing for a-thalassemia, which is
inherited metabolic diseases. Obviously, if the UC blood
molecular-based, is time- and labor-intensive. Thus, rather
donor and recipient are affected with the same metabolic
than screening for this disorder, testing would be indicated
disease, transplantation would be of no benefit. Thus, when
only in specific situations, such as where the ethnic back
Correspondence to: Myra Wick, Assistant Professor, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA ß 1999 ISHAGE
275
276
M Wick et al.
Table 1. Genetic screening of banked cord blood Disease
Disease frequency
Affected tissue/ organ
Category 1 Diseases unlikely to affect recipient Cystic fibrosis 1/2500 Lung/pancreas Fragile X 1/2000 males Brain Hemochromatosis 1/2000–1/5000 Many organs (European)
Duchenne muscular dystrophy Factor V Leiden
Gaucher disease
1/10 000 males
Muscle fibres
2/100–13/100
Predeposition to thrombophilia
1/600 Ashkenazi Jewish, CNS, spleen, bone rare in others
Category 2 Diseases treated by transplantation MPS I–VII Ranges from rare to All cells 1/25 000 B cells XLA (Bruton) 1 in 105
X-linked SCID
Rare
ADA deficiency
Fairly rare, > 200 familiesLymphocytes documented 1/500000 T and B cell dysfunction
Wiskott Aldrich
T and B cell deficiency
Category 3 Diseases for which testing is recommended Sickle cell Prevalent in Africa, India, RBC Mediterranean and Middle East a-thalassemia High frequency in Asian, RBC Mediterranean and African population Hemoglobin E Common in Eastern RBC India to SE Asia, portions of China, Thailand and the Malay peninsula
Potential effect on BMT recepient
Pathology involves abnormal intestinal iron absorption Effect on BMT recipient should be minimal
Availability of genetic testing þ þ þ
þ Protein synthesized by þ hepatocytes and endothelial cells. Effect on BMT recipient should be minimal ? (Recipient enzyme may be þ adequate)
Presence of recipient enzyme For most types is adequate ? Deficient enzyme is ecto-5- þ prime-nucleotidase; recipient enzyme may be adequate þ ? Abnormal expression of HLA molecules due to defective synthesis of an abnormal transacting regulatory gene located outside the major histocompatibility complex; presence of recipient gene may be adequate ? Recipient enzyme may be Research adequate ? WAS protein believed to þ play a role in lymphocyte and platelet regulation; presence of recipient protein may be adequate þ
þ
þ
þ
Heterozygous state is not þ associated with clinical disability, but does have effects in compound heterozygotes for HbE and b-thal
Genetic testing of banked umbilical cord blood
277
Table 1. Continued Disease
Disease frequency
Affected tissue/ organ
Potential effect on BMT recepient
Hemoglobin C
Gene frequency in African Americans is 0.01–0.02
RBC
G6PD deficiency
Varies; most common in Erythrocyte: Africa, Middle East, hemolytic anemia subtropical Asia PK deficiency is 1/ Erythrocyte: 20 000; all others are rarehemolytic anemia
HbC heterozygotes have no clinical disability; HbC/HbS and HbC/b-thal compound heterozygotes have clinical symptoms ? (Recipient enzyme may be adequate)
Erythrocyte enzymopathies
Category 4 Diseases for which effect on receipient is unknown Huntington’s disease 1/10 000 Neuronal cells Spinocerebellar 1/50 000 Neuronal cells ataxias (SCA 1, 2, 3, 6, 7)
Availability of genetic testing þ
þ
? (Recipient enzyme may be adequate)
þ
?? ??
þ þ
ground of donor and recipient suggested a high frequency of
a framework within which testing of UC blood for inherited
the disease (Asian, Mediterranean, or African). Both
diseases could be approached, if other ethical, practical,
biochemical and direct DNA analysis are available for the
technologic and economic factors were resolved.
detection of PK and G6PD deficiencies. It is recommended
In the framework described here, genetic screening of
that biochemical analysis be used to screen for these two
UC blood units selected for transplantation would include
disorders and molecular studies used for confirmation of
the following disorders: hemoglobin E, HbS (based on
positive biochemical results.
results of newborn-screening by public health agencies),
The fourth category of inherited disorders comprises
G6PD or PK deficiency. Testing for a specific metabolic
those diseases for which the effects on the recipient are as yet
disorder is indicated when the patient is receiving the
unknown. Of greatest concern are autosomal dominant
transplant for treatment of that disorder. The list of genetic
diseases which are caused by a mutant ‘gain of function’
disorders for which screening of UC blood is indicated will
protein. The most familiar of these are the neurodegenera-
change as we gain experience with UC blood transplantation
tive ‘CAG repeat disorders’, such as Huntington’s disease
and as we acquire a greater understanding of the molecular
and the Spinocerebellar ataxias (SCA1, 2, 3, 6 and 7). The
pathogenesis of genetic diseases. Finally, if genetic testing is
pathology of each of these diseases is attributed to novel
to be done, there are many complex issues that remain to be
mutant proteins, which interfere with the normal function of
resolved.
other neuronal proteins. It is not known whether transplantation of hematopoietic stem cells carrying these abnormal
References
genes would affect the recipient. Although transgenic mice
1
expressing the abnormal gene demonstrate the disease phenotype [4], it seems unlikely that postnatal transplantation would adversely affect an individual with a normal
2
neurologic system. Thus, screening for these diseases is not recommended. Genetic testing of UC blood donated to an allogeneic bank is a sensitive and complex issue. This letter does not address many important considerations. We have proposed
3 4
McCullough J, Clay ME, Fautsch S, et al. Proposed policies and procedures for the establishment of a cord blood bank. Blood Cells 1994;20:609–26. Sugarman J, Reisner EG, Durtzberg J. Ethical aspects of banking placental blood for transplantation. J Am Med Assoc 1995;274:1783–5. Haley R, Harvath L, Sugarman J. Ethical issues in cord blood banking workshop. Transfusion. In press. Mangiarini L, Sathasivam K, Mahal A, et al. Instability of highly expanded CAG repeats in mice transgeneic for the Huntington’s disease mutation. Nature Genet 1997;15:193–200.
Letter to the Editor
Genetic testing of banked umbilical cord blood M Wick, ME Clay, T Eastlund, DE Vawter, R McGlennen and J McCullough Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, USA
With the establishment of UC banks and the use of cord
transplant is for treatment of these disorders, it is re-
blood for transplantation, it is necessary to consider testing
commended that the UC blood unit intended for transplant
of banked cord blood for inherited diseases [1–3]. Genetic
be tested for the specific disease. This is currently being
testing of UC blood involves many issues, including:
done in those few centers that transplant these patients.
n The diseases for which testing should be done. n Test methods and the potential impact of methods
presently under development. n The cost. n The nature of consent that must be obtained. n Which individuals should give consent? n The management of test results [2,3].
A secondary benefit of genetic screening of the UC blood unit for a specific metabolic disease is the possibility, although remote, that the blood from an unrelated donor could be shown to have the same genetic disease as the recipient. In this situation, early detection of the disease could possibly lead to early treatment for the donor and avoidance of nervous system damage. General screening of all UC blood samples for metabolic diseases would not be
In this letter we focus on the first of these issues and propose
indicated because these disorders are relatively uncommon
an approach to considering testing of cord blood for
and testing is costly.
inherited diseases.
The third category comprises those diseases for which
Genetic testing should be considered only for diseases
transplantation of stem cells containing the defective (or
involving hematopoietic tissue since other genetic diseases,
absent) gene could lead to disease manifestation in the
even if present in the UC blood donor (infant), would not
transplant recipient. Examples are hemoglobin C, hemoglo-
become manifest in the hematopoietic stem-cell recipient.
bin E, sickle cell disease (HbS), glucose-6-phosphate
Based on the potential consequences in the hematopoietic
dehydrogenase (GGPD) deficiency and pyruvate kinase
stem-cell transplantation setting, we have classified genetic
(PK) deficiency. Molecular and/or other laboratory testing
diseases into four categories and present a proposed test (or
for each of these diseases is available and economically
non-test) strategy for each. This information is summarized
feasible. All US States have newborn-screening programs for
in Table 1, along with examples of ‘common’ genetic
HbS, the results of which are usually sent to the infant’s
disorders within each category.
physician and medical record. Hemoglobin electrophoresis,
The first category includes those diseases which would
which is routinely used for the laboratory diagnosis of HbS,
not be expected to have a clinical effect on the recipient of
also detects other common hemoglobinopathies, b-thalasse-
a hematopoietic cell transplant (e.g. Factor V Leiden,
mia and combinations of the two. Thus, additional testing
Duchenne muscular dystrophy). Testing for these diseases
for the most common diseases in this group can be avoided
is not indicated.
by reviewing the potential donor’s medical records.
The second category includes those genetic diseases that
In contrast to previously mentioned hemoglobino-
are treated by BM transplantation. This involves primarily
pathies, definitive testing for a-thalassemia, which is
inherited metabolic diseases. Obviously, if the UC blood
molecular-based, is time- and labor-intensive. Thus, rather
donor and recipient are affected with the same metabolic
than screening for this disorder, testing would be indicated
disease, transplantation would be of no benefit. Thus, when
only in specific situations, such as where the ethnic back
Correspondence to: Myra Wick, Assistant Professor, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA ß 1999 ISHAGE
275
276
M Wick et al.
Table 1. Genetic screening of banked cord blood Disease
Disease frequency
Affected tissue/ organ
Category 1 Diseases unlikely to affect recipient Cystic fibrosis 1/2500 Lung/pancreas Fragile X 1/2000 males Brain Hemochromatosis 1/2000–1/5000 Many organs (European)
Duchenne muscular dystrophy Factor V Leiden
Gaucher disease
1/10 000 males
Muscle fibres
2/100–13/100
Predeposition to thrombophilia
1/600 Ashkenazi Jewish, CNS, spleen, bone rare in others
Category 2 Diseases treated by transplantation MPS I–VII Ranges from rare to All cells 1/25 000 B cells XLA (Bruton) 1 in 105
X-linked SCID
Rare
ADA deficiency
Fairly rare, > 200 familiesLymphocytes documented 1/500000 T and B cell dysfunction
Wiskott Aldrich
T and B cell deficiency
Category 3 Diseases for which testing is recommended Sickle cell Prevalent in Africa, India, RBC Mediterranean and Middle East a-thalassemia High frequency in Asian, RBC Mediterranean and African population Hemoglobin E Common in Eastern RBC India to SE Asia, portions of China, Thailand and the Malay peninsula
Potential effect on BMT recepient
Pathology involves abnormal intestinal iron absorption Effect on BMT recipient should be minimal
Availability of genetic testing þ þ þ
þ Protein synthesized by þ hepatocytes and endothelial cells. Effect on BMT recipient should be minimal ? (Recipient enzyme may be þ adequate)
Presence of recipient enzyme For most types is adequate ? Deficient enzyme is ecto-5- þ prime-nucleotidase; recipient enzyme may be adequate þ ? Abnormal expression of HLA molecules due to defective synthesis of an abnormal transacting regulatory gene located outside the major histocompatibility complex; presence of recipient gene may be adequate ? Recipient enzyme may be Research adequate ? WAS protein believed to þ play a role in lymphocyte and platelet regulation; presence of recipient protein may be adequate þ
þ
þ
þ
Heterozygous state is not þ associated with clinical disability, but does have effects in compound heterozygotes for HbE and b-thal
Genetic testing of banked umbilical cord blood
277
Table 1. Continued Disease
Disease frequency
Affected tissue/ organ
Potential effect on BMT recepient
Hemoglobin C
Gene frequency in African Americans is 0.01–0.02
RBC
G6PD deficiency
Varies; most common in Erythrocyte: Africa, Middle East, hemolytic anemia subtropical Asia PK deficiency is 1/ Erythrocyte: 20 000; all others are rarehemolytic anemia
HbC heterozygotes have no clinical disability; HbC/HbS and HbC/b-thal compound heterozygotes have clinical symptoms ? (Recipient enzyme may be adequate)
Erythrocyte enzymopathies
Category 4 Diseases for which effect on receipient is unknown Huntington’s disease 1/10 000 Neuronal cells Spinocerebellar 1/50 000 Neuronal cells ataxias (SCA 1, 2, 3, 6, 7)
Availability of genetic testing þ
þ
? (Recipient enzyme may be adequate)
þ
?? ??
þ þ
ground of donor and recipient suggested a high frequency of
a framework within which testing of UC blood for inherited
the disease (Asian, Mediterranean, or African). Both
diseases could be approached, if other ethical, practical,
biochemical and direct DNA analysis are available for the
technologic and economic factors were resolved.
detection of PK and G6PD deficiencies. It is recommended
In the framework described here, genetic screening of
that biochemical analysis be used to screen for these two
UC blood units selected for transplantation would include
disorders and molecular studies used for confirmation of
the following disorders: hemoglobin E, HbS (based on
positive biochemical results.
results of newborn-screening by public health agencies),
The fourth category of inherited disorders comprises
G6PD or PK deficiency. Testing for a specific metabolic
those diseases for which the effects on the recipient are as yet
disorder is indicated when the patient is receiving the
unknown. Of greatest concern are autosomal dominant
transplant for treatment of that disorder. The list of genetic
diseases which are caused by a mutant ‘gain of function’
disorders for which screening of UC blood is indicated will
protein. The most familiar of these are the neurodegenera-
change as we gain experience with UC blood transplantation
tive ‘CAG repeat disorders’, such as Huntington’s disease
and as we acquire a greater understanding of the molecular
and the Spinocerebellar ataxias (SCA1, 2, 3, 6 and 7). The
pathogenesis of genetic diseases. Finally, if genetic testing is
pathology of each of these diseases is attributed to novel
to be done, there are many complex issues that remain to be
mutant proteins, which interfere with the normal function of
resolved.
other neuronal proteins. It is not known whether transplantation of hematopoietic stem cells carrying these abnormal
References
genes would affect the recipient. Although transgenic mice
1
expressing the abnormal gene demonstrate the disease phenotype [4], it seems unlikely that postnatal transplantation would adversely affect an individual with a normal
2
neurologic system. Thus, screening for these diseases is not recommended. Genetic testing of UC blood donated to an allogeneic bank is a sensitive and complex issue. This letter does not address many important considerations. We have proposed
3 4
McCullough J, Clay ME, Fautsch S, et al. Proposed policies and procedures for the establishment of a cord blood bank. Blood Cells 1994;20:609–26. Sugarman J, Reisner EG, Durtzberg J. Ethical aspects of banking placental blood for transplantation. J Am Med Assoc 1995;274:1783–5. Haley R, Harvath L, Sugarman J. Ethical issues in cord blood banking workshop. Transfusion. In press. Mangiarini L, Sathasivam K, Mahal A, et al. Instability of highly expanded CAG repeats in mice transgeneic for the Huntington’s disease mutation. Nature Genet 1997;15:193–200.