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The Human Genome

New Opportunities in Prenatal Diagnosis: Practical Benefits From the Human Genome Project

Marion S. Verp, MD

In the past 10 years, the Human Genome Project,¹ together with other geneticist-investigators, have identified genetic mutations that explain many disorders whose etiology was previously unknown. For example, it is now known that both the Prader-Willi and Angelman syndromes result from a deletion on chromosome 15 in the q11-q13 region. Moreover, the deletion in Prader-Willi patients has been localized to the paternally inherited chromosome 15, whereas Angelman patients have a deletion on the maternally inherited chromosome 15.² These discoveries in turn supported another new concept: genomic imprinting, ie, that it matters in certain disorders whether a deletion is on the maternally or paternally inherited chromosome.

This new knowledge has created both an opportunity and a responsibility for physicians who care for pregnant women. Given an understanding of inheritance patterns that were previously obscure and the development of molecular diagnostic tools, it is now possible to offer prenatal diagnosis for many conditions that were undetectable in utero before.

INDICATIONS FOR TESTING

General Screening

Prenatal screening and diagnosis involves three groups: the general pregnant population, patients with a specific ethnic background or personal/family history featuring a genetic disorder, and patients with a fetal anomaly identified on ultrasonography. Screening tests are routinely offered to all patients in the first group, irrespective of family or personal history. These tests include assays of maternal serum alpha-fetoprotein (AFP) for detection of neural tube defects, and of various combinations of maternal serum analytes (eg, AFP, unconjugated estriol, human chorionic gonadotropin) for estimation of Down syndrome risk. All patients who present for care prior to 20 weeks’ gestation are eligible for this form of population screening.

Known Personal/Familial Risk Factors

Targeted screening/testing applies to patients with an identified risk factor. For example, advanced maternal age is a known risk factor for a child with a chromosomal abnormality, so mothers aged 35 years and older are offered chromosome analysis by amniocentesis or chorionic villus sampling (CVS). Initial chromosome analysis can now be performed more quickly with fluorescent in-situ chromosome-specific hybridization (FISH) probes, allowing rapid diagnosis of common aneuploidies (eg, trisomies 21, 13, 18).³

More recently, investigators have identified mutations associated with specific genetic disorders. Families that have had a child with one of these disorders can now be offered DNA analysis of a prenatal specimen to determine whether a fetus carries the same mutation as the affected child. For example, spinal muscular atrophy (SMA) is a relatively common autosomal-recessive condition resulting in loss of alpha motor neurons in the spinal cord and progressive weakness, with onset in infancy or early childhood. The etiology of SMA has now been traced to the absence of a portion of the survival motor neuron gene (SMN1) located on chromosome 5.⁴ Once the genetic defect is demonstrated in DNA from an affected child, CVS or amniocentesis can be performed in the parents’ future pregnancies to obtain fetal DNA for diagnosis.

Preimplantation diagnosis may also be possible following the identification of a familial genetic disorder. In fact, preimplantation diagnosis is now available for a number of conditions (eg, cystic fibrosis,β-thalassemia, hemophilia) as a direct result of research into genetic defects and improvements in molecular diagnostic techniques.

New mechanisms for inherited diseases have been recognized in the last several years. Fragile X syndrome, myotonic dystrophy, Huntington disease, spinocerebellar ataxia, and other conditions are all the result of an abnormal number of copies (repeats) of a normal trinucleotide genetic sequence. In these disorders, one parent has a slightly higher number of repeats with no adverse effects. However, in the process of gametogenesis, the repeat region can become unstable and expand, increasing the number of repeats in the fetal genome. Beyond a certain number, the excess repeats interfere with normal cellular function, resulting in manifestations of disease.⁵ Now it is possible to test individuals with a personal or family history of a triplet repeat disorder, predict the likelihood of expansion in the next generation, and offer prenatal diagnosis of these conditions if desired.

Another benefit of prenatal identification of genetic mutations associated with specific conditions is that prenatal treatment may be possible. For example, congenital adrenal hyperplasia is an autosomal-recessive disorder, resulting in deficiency of the 21-hydroxylase enzyme, failure of glucocorticoid and adrenocorticoid output and overproduction of androgens, with virilization of female fetuses in utero. The resultant ambiguous genitalia ultimately require surgical repair. However, if the family is known to be at risk because they already have an affected child, maternal treatment with steroids to suppress excess fetal androgen production can be initiated soon after conception. Chromosome and DNA diagnosis can then be performed and the treatment continued throughout pregnancy if an affected female fetus is identified, reducing the chance of a severe genital anomaly.⁶

Intervention is also possible in pregnancies with maternal sensitization to Rh or Kell antigens. Fetal DNA obtained with amniocentesis or CVS can be tested to determine whether the fetus carries the antigen in question. If not, there is no reason to subject the mother or fetus to further diagnostic testing (eg, amniocentesis for optical density at 450 nm, serial ultrasonography for fetal hydrops, percutaneous umbilical cord sampling).⁷ Mutations for certain genetic disorders common to specific ethnic groups have also been identified. The most common mutations causing cystic fibrosis (CF) in whites have been delineated, allowing screening for CF carrier status and prediction of fetal risk in any couple. The same is true for a variety of disorders in the Ashkenazi Jewish population (eg, Canavan disease, Tay-Sachs disease, Niemann-Pick disease type A, Bloom syndrome, Fanconi anemia type C, familial dysautonomia, mucolipidosis IV); Mediterranean groups (β-thalassemia); Asian groups (α- or β-thalassemia); and blacks (sickle cell anemia).

Ultrasonographic Anomalies

In the face of an unexpected ultrasonographic finding, genetic tests can be selected based on the ultrasonographic phenotype. Defects in the fibroblast growth factor receptor 3 (FGFR3) gene can result in thanatophoric dysplasia, achondroplasia, and hypochondroplasia.⁸ All of these can be detected using fetal DNA obtained from amniocentesis or CVS. Analysis of FGFR3 mutations is appropriate for a fetus with certain ultrasonographically detected skeletal defects, and may provide useful information about prognosis. A fetus with an ultrasonographically detected cardiac anomaly, particularly a conotruncal defect, may warrant studies with a probe specific for region 11.2 on the long arm of chromosome 22. A deletion in this region is frequently found in fetuses with conotruncal defects, and suggests the presence of other abnormalities (eg, thymic/ parathyroid hypoplasia, facial dysmorphism) consistent with DiGeorge syndrome).⁹

Likewise, a fetus with multiple anomalies may have a chromosomal syndrome, eg, thickened nuchal fold, duodenal atresia, and cardiac defect (trisomy 21); growth restriction, cardiac defect, and omphalocele (trisomy 18); midline facial defects, holoprosencephaly, cardiac defects, and abnormal kidneys (trisomy 13); and growth restriction, cardiac defects, and large, hydropic-appearing placenta (triploidy).¹⁰ These four conditions can be diagnosed rapidly with chromosome-specific DNA FISH probes, allowing parents to obtain information and make decisions about their pregnancies as quickly as possible. Conversely, in the presence of “soft signs” of fetal aneuploidy (eg, pyelectasis, echogenic intracardiac focus), a FISH chromosome screen can be very reassuring to worried parents.

CONCLUSION

Ultimately, the goal of prenatal diagnosis is to prevent the severe consequences of genetic mutations. Knowledge acquired from the Human Genome Project has provided a better understanding of the nature of genetic defects, and is likely to lead to additional and more successful drug and gene therapies.

References

1. McKusick VA. The anatomy of the human genome. A neo-Vesalian basis for medicine in the 21st century. JAMA. 2001;286:2289-2295.
2. Handel MI, Wevrick R. The role of genomic imprinting in human developmental disorders. Lessons from Prader-Willi syndrome. Clin Genet. 2001;59:156-164.
3. Eiben B, Trawicki W, Hammans W, Goebel R, et al. Rapid prenatal diagnosis of aneuploidies in uncultured amniocytes by fluorescence in situ hybridization. Evaluation of >3,000 cases. Fetal Diagn Ther. 1999;14:193-197.
4. Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155-165.
5. Mandel JL. Questions of expansion. Nat Genet. 1993;4:8-9.
6. Travitz J, Metzger Dl. Antenatal treatment for classic 21-hydroxylase forms of congenital adrenal hyperplasia and the issues. Genet Med. 1999;1:224-230.
7. Bennett PR, Le Van Kim C, Colin Y, et al. Prenatal determination of fetal RhD type by DNA amplification. N Engl J Med. 1993;329:607-610.
8. Tavormina PL, Shiang R, Thompson LM, et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. 1995;9: 321-328.
9. Wilson DI, Goodship JA, Burn J, et al. Deletions within chromosome 22q11 in familial congenital heart disease. Lancet.1992;340:573-575.
10. Bianchi DW, Crombleholme TM, D’Alton ME. Fetology: Diagnosis and Management of the Fetal Patient. New York, NY: McGraw-Hill; 2000.
    

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