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Copyright 1995 Information Access Company, a Thomson Corporation Company
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Copyright 1995 American Medical Association
JAMA, The Journal of the American Medical Association
June 7, 1995
SECTION: Vol. 273 ; No. 21 ; Pg. 1692; ISSN: 0098-7484
LENGTH: 1860 words
HEADLINE: Medical genetics.Contempo 1995
BYLINE: Korenberg, Julie R. ; Rimoin, David L.
BODY:
Medical genetics and the Human Genome Project 1 have come of age and
are now of prime importance for clinical medicine. lmportant advances
have been made, especially in the area of cancer. Rapid progress has been
made toward elucidation of the molecular basis of hereditary nonpolyposis
colon cancer, which is responsible for almost 15% of all colon cancers.
Mutations in four distinct mismatch repair genes, which play a key role
in maintaining fidelity during DNA replication and repair in bacteria and
higher organisms, have now been identified in patients with hereditary
nonpolyposis colon cancer. 2
Another landmark in cancer genetics in 1994 was the isolation of a
gene for breast and ovarian cancer susceptibility (BRCA1) that appears
to belong to the class of tumor suppressor genes. 3 An estimated 5% of
breast cancers are familial, and the majority of these cases are
attributable to two genes, BRCA1 (located at 17q12-q21) and BRCA2
(located at 13q12-q13). Some 40 different mutations in BRCA1 have been
identified to date, which presents technical problems for developing
generalized presymptomatic testing in families who carry the BRCA1 gene
and in individuals with sporadic disease. The observation that BRCA1 and
BRCA2 account for about 85% of all familial breast cancer suggests
these as candidates for at least some of the sporadic cases.
When will this new information be useful in clinical practice? In
view of the large number of genes and mutations involved in the cause of
these cancers, these tests can only be used safely and effectively by
the average clinician when well-controlled screening and prediction
studies are completed. However, similar to the development of successful
programs for the diagnosis of cystic fibrosis, these findings can
potentially be of great help in certain high-risk families if they are
performed under the guidance of, and interpreted by, an experienced
medical geneticist.
Many of the genes causing major monogenic diseases have been
cloned, and thefocus of research is turning to more complex common
diseases, such as coronary heart disease, diabetes, hypertension, and
psychiatric disease. The goal is to identify the large number of genes
involved in each one of these diseases and then to define the particular
gene sequences that are associated with an increased risk of developing
the disease. This may allow for the early detectionof predisposed
individuals, so that change in lifestyle and preventive therapy can be
offered on an individual basis. In addition, individuals identified in
high-risk families who do not carry the disease mutation will not have to be
screened regularly, resulting in major cost savings.
Major advances in molecular biology of the skeletal dysplasias
occurred in 1994. The most striking was the finding of a mutation in the
fibroblast growth factor receptor 3 gene on chromosome 4 in
achondroplasia, the most common form of dwarfism. 4 In contrast with
almost all other known human disease genes, more than 95% of the cases of
achondroplasia have the identical nucleotide substitution. This
represents the most common single base pair mutation known to exist in
humans, because more than 80% of cases of achondroplasia are sporadic
and represent new mutations. 5 Mutations in two of the other fibroblast
growth factor receptors have now been described in several
craniosynostotic disorders associated with abnormal cranial growth and
hand malformations, ie, Pfeiffer's syndrome and Jackson-Weiss syndrome
(fibroblast growth factor receptor 1) and craniofacial dysostosis
(fibroblast growth factor receptor 2). 6 It is clear that this family of
growth factor receptors will be found to be responsible for a number of
other skeletal dysplasias and dysostoses.
The growing list of unstable mutations caused by expansion of
trinucleotide repeats and characterized by anticipation (younger age at
onset in succeeding generations) has established this form of mutation as
the most common cause of autosomal dominant neurodegenerative disease.
7,8 Ten triplet expansions at disease or fragile site loci have been
found, including CGG expansions that cause hypermethylation and gene
repression resulting in mental retardation (fragile X syndrome); CAG
repeats that cause similar neurodegenerative diseases (eg, Huntington's
chorea, spinocerebellar ataxia type 1, and Machado-Joseph disease); and
the CAG repeat causing myotonic dystrophy. 7,8 This important mechanism
also may be responsible for other diseases, such as spinocerebellar
ataxia type 2 and possibly schizophrenia and manic-depressive psychosis. 8
High-resolution molecular cytogenetic techniques can now detect
submicroscopic chromosomal deletions and rearrangements in individuals
who were previously believed to have normal chromosomes. These are now
known to be the cause of isolated defects, such as cardiac conotruncal
malformations, in otherwise normal people as well as in genetic syndromes
9 that include Williams syndrome, Prader-Willi syndrome, Angelman's
syndrome, DiGeorge syndrome, and velocardiofacial syndrome. Molecular
cytogeretic markers have great potential for the diagnosis and prognosis
of the translocations, deletions, and other rearrangements seen in many
cancers.
These techniques have also led to our understanding of
nontraditional modes of inheritance, such as genomic imprinting, in
which the sex of the parent affects the clinical expression of the
disorder in the child. This phenomenon isdescribed in only a few regions
of the genome, and the parent-specific expression is established anew
during gametogenesis. In the Prader-Willi syndrome, the microdeletion is
at the proximal long arm of the paternal chromosome 15; in patients
without the deletion, both copies of chromosome 15 are maternally
inherited. These observations indicate the presence of a gene(s) in
proximal 15q that is expressed only from the paternal homologue. Their
absence, by deletion or by maternal uniparental disomy, leads to a
complete lossof function of this gene(s). Also reported are rare cases
of uniparental isodisomy, wherein a child inherits two copies of the same
chromosome from one parent, allowing a couple of whom only one is a
carrier to ave a child with a recessive disease. 10
The Human Genome Project has also had a profound effect on our
ability to perform early prenatal diagnosis of genetic disease. With the
definition of a specific mutation in an affected family member, prenatal
diagnosis at 10 to 12 weeks' gestation by chorionic villus sampling has
become routine. Even if the specific mutation in the family is unknown,
linkage analysis may be used for prenatal diagnosis in families with two
or more affected individuals available for analysis of the specific
polymorphic marker. The availability of polymerase chain reaction
amplification of DNA and in vitro fertilization has now made possible
preimplantation diagnosis of genetic disease. 11 This can be accomplished
by in vitro fertilization followed by removal of a single blastomere
(embryo biopsy), which is analyzed for the mutation. Embryos found
not to carry the mutation are then transferred tb the mother's uterus.
Couples at high risk of having a child with a single-gene disorder for
which the mutation is known can now potentially reproduce without the
fear of having an affected child or having to undergo a therapeutic
abortion. Advances also have been made in the isolation of fetal cells
from maternal blood, a technique that,when perfected, will lead to the
ability to perform noninvasive prenatal diagnosis of genetic disease.
Important progress has been made in human gene therapy for such
diseases as cystic fibrosis, including the first attempt at transferring
the cystic fibrosisgene to the lower airways of affected patients, and
for the lethal disorder homozygous familial hypercholesterolemia, in
which the recipient received transplantation of autologous hepatocytes
that were genetically corrected with recombinant retroviruses carrying
the low-density lipoprotein receptor. 12-14
The use of cord blood stem cells to transport the gene for adenosine
deaminase deficiency to patients with combined immunodeficiency disease
received a great deal of publicity in 1994, but the long-term success of
gene therapy still remains to be proved. This along with the problems of
viral airway inflammation with the adenovirus trial of cystic fibrosis
13 and the issues of patient choicein the hypercholesterolemia study 14
makes the point that gene therapy is still experimental. Major hurdles
in gene therapy include the development of "smart bombs" (vectors) to get
the gene to the appropriate tissue and specific "detonators" to turn the
gene on and off at appropriate times. The viral vectors for gene delivery
are improving and expanding (adenoviruses to transfect respiratory mucosa
for cystic fibrosis and specific targeting of endothelial cells for
atherosclerosis), as are nonviral vectors for gene delivery (coupling of
antibodies and viral coats to liposomes). New tissue-specific targeting
techniques will allow for treatment of genetic diseases and cancers.
Thus, gene therapy is moving rapidly, but many questions remain to be
answered before large-scale clinical trials should be undertaken.
1. Murray, JC, Buetow KH, Weber JL, et al. A comprehensive human
linkage map with centimorgan density. Science. 1994;265:2049-2054. 2.
Nicolaides NC, Papadapoulos N, Liu B, et al. Mutations of two PMS
homologues in hereditary nonpolyposis colon cancer. Nature.
1994;371:75-80. 3. Breaking down BRCA1. NatGenet. 1994;8:310.
Editorial. 4. Shiang R, Thompson L, Zhu YZ, et al. Mutations in the
transmembrane domain of FGFR3 cause the most common genetic form of
dwarfism, achondroplasia. Cell. 1994;78:335-340. 5. Francomano CA.
Thegenetic basis of dwarfism. N Engl J Med. 1995;332:58-59. 6. Davies
K. Receptormalfunction. Nature. 1994;372:202. 7. Mandel J-L.
Trinucleotide diseases on the rise. Nat Genet. 1994;7:453-455. 8.
Willems PJ. Dynamic mutations in double figures. Nat Genet.
1994;8:213-215. 9. Ledbetter DH, Ballabio, A. Molecular cytogenetics of
contiguous gene syndromes: mechanisms and consequencesof gene dosage
imbalance. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The
Metabolic and Molecular Bases of Inherited Disease. New York, NY:
McGraw-Hill International Book Co; 1995:811-8:39. 10. Engel E.
Uniparental disomy revisited: the first twelve years. Am J Med Genet.
1993;46:670-674. 11. Liu J,Lissens W, Silber SJ, Devroey P, Liebaers
I, Steirteghem AV. Birth after preimplantation diagnosis of the cystic
fibrosis delta 508 mutation by polymerase chain reaction in human embryos
resulting from intracytoplasmic sperminjection with epididymal sperm.
JAMA. 1994;272:1858-1860. 12. Culver KW. GeneTherapy: A Handbook for
Physicians. New York, NY: Mary, Ann Liebert Inc; 1994. 13. Alton E,
Geddes D. A mixed message for cystic fibrosis gene therapy. Nat
Genet. 1994;8:8-9. 14. Brown MS, Goldstein JL, Havel RJ, Steinberg D. Gene
therapy for cholesterol. Nat Genet. 1994;7:349-350.
IAC-NUMBER: IAC 17094154
LANGUAGE: ENGLISH
LOAD-DATE: August 02, 1995