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Prenatal Diagnosis of Genetic Disorders

Genetic disorders have a tremendous potential adverse effect on reproductive-age women and their families. Of conceptuses, 8% (1/13) are chromosomally abnormal, accounting for 50% of all first-trimester abortions and 6-11% of all stillbirths and neonatal deaths gene therapy, genetic disorders, prenatal diagnosis of genetic disorders, down syndrome. Of all newborns, 34% have a major congenital defect; by age 7 or 8 years, another 3-4% of children are

Genetic Disorders

Chromosome Abnormalities

A variety of chromosome abnormalities can occur in association with a live birth (Table 4). Most autosomal trisomies resuk from matemal meiotic nondisjunction, a phenomenon that occurs more frequently with advanced maternal age. Numeric sex chromosome abnormalities can result from either maternal or paternal nondisjunction; inversions and

Trisomy. Most fetal trisomies result from an error in maternal meiosis I. Although any woman at any age can have a trisomic fetus, the frequency of meiotic errors and resulting fetal aneuploidy increases as women (and their eggs) age (Table 5). Traditionally, women who will be 35 years of age or older at the time of delivery are thought to be at great enough risk that fetal karyotype analysis by CVS or genetic amniocentesis is offered routinely. Women younger than

 Sex Chromosome Abnormalities. Sex chromosome abnormalities occur in 1 of every 300-500 births. The most common are 45,X; 47,XXY', 47,XXX; 47,XYY; and mosaicism (the presence of two or more cell populations with different karyotypes). The origin of the chromosome error may be either maternal or paternal in all cases except 

Translocations and Inversions. A translocation usually involves the reciprocal exchange of genetic material between two different (nonhomologous) chromosomes. A break occurs in one arm of each chromosome, and all the genetic material distal to each break point is exchanged.

In a balanced translocation, no genetic material is gained or lost, and the individual carrying such a rearrangement is usually phenotypically normal. However, a carrier of a balanced translocation may make unbalanced gametes, resulting in infertility, early pregnancy loss, or a structurally or developmentally abnormal fetus or child. The

A robertsonian translocation results from the centro-meric fusion of two acrocentric chromosomes. Acrocentric chromosomes (chromosomes 13, 14, 15, 21, or 22) have the centromere located very near one end. Because only

Inversions arise when two breaks occur in the same chromosome and the segment between the break points is inverted before the breaks are repaired. No genetic material is lost, but the gene sequence is altered. If both break points occur in the same arm of the chromosome (paracentric inversion), the centromere is not involved. The carrier

Triploidy. The word triploidy describes a conception in which three complete haploid (n = 23) chromosome complements are present (n = 69). This abnormality occurs in 12% of recognized pregnancies and in 15% of aneuploid abortuses. Most commonly, triploidy results from double fertilization of a normal haploid egg (dispermy) or

Spontaneous Pregnancy Loss. At least half of all early losses are due to fetal aneuploidy; the most common abnormalities are monosomy X, polyploidy (triploidy or tetraploidy), trisomy 16, and trisomies 13, 18, 21, and 22. Because recurrent abortions tend to be karyotypically normal, an aneuploid first-trimester loss does not increase the risk of having another early loss. Whether or not an aneu-plaid first-trimester loss increases the risk of having another aneuploid fetus surviving into the second trimester and beyond is controversial. Women who have had an 

Parental Aneuploidy. A parent with a numeric chromosome abnormality is at increased risk to have aneuploid offspring. Prenatal diagnosis should be offered in such cases. Women with trisomy 21 are fertile, and approximately 30% of their conceptions are trisomic. Men with trisomy 21 are almost always sterile.

Single-Gene Disorders

Single-gene disorders are diseases or phenotypic abnormalities either known or presumed to result from alteration of a single gene. It is currently believed that single-gene disorders are responsible for abnormalities in fewer than 1% of

Patient or Family History. Single-gene disorders are generally transmitted in autosomal dominant, autosomal recessive, or X-linked recessive fashion. An individual carrying a gene for an autosomal dominant disease generally has some features of that disease, as well as a 50% chance of passing on the affected gene with each conception. Individuals carrying a gene for an autosomal recessive disorder are usually not affected and are identified only after the birth of an affected child or because an affected family member has been identified. A couple whose child has an autosomal recessive disease has a 25% recurrence risk with each conception. Individuals identified as carriers of an autosomal recessive gene because of an affected family member are usually not at high risk of having an affected child, unless they are related to their partner (consanguineous). Women carrying an X-linked recessive gene are

Ethnic Groups at High Risk. Although single-gene disorders are generally rare, some ethnic groups are at higher risk of having certain diseases than others and should be counseled accordingly. Cystic fibrosis, a chronic pulmonary and exocrine pancreatic disease, is the most common mono-genic disorder in the white population. It is transmitted in autosomal recessive fashion and has a carrier frequency of 1 in 22. Patients with a family history of cystic fibrosis should be offered carrier testing, and all known carriers should be offered prenatal diagnosis. Whether carrier testing is worthwhile when there is no history of increased risk is controversial.

Sickle hemoglobin is the most common hemoglobin disorder in the United States; approximately 8% of African Americans carry the gene for sickle hemoglobin. It is found primarily in persons of African descent but is also reported in those of Mediterranean, Caribbean, Latin American, or Middle Eastern descent. Although universal screening is not indicated, the obstetrician should try to identify couples at risk for having offspring with the thalassemias or sickle cell disease. Because of the genetic basis of these disorders, carrier testing of both partners should be strongly recommended.

Individuals of Mediterranean or Asian origin are at increased risk of carrying the genes for a-thalassemia or b-thalassemia, gene deletion syndromes resulting in severe anemia. Carrier testing should be considered in all women with a mean erythrocyte volume of less than 79 Jim^3. Those carriers found not to be iron deficient should have

Patients of Jewish descent are at increased risk for carrying the genes for Tay-Sachs or Gaucher's disease, each of which is caused by a different enzyme deficiency (hexosaminidase A and lysosomal enzyme deficiency, respectively). These disorders have in common a rapidly progressive course resulting from a neurovisceral storage abnormality. The

Population Screening. Identification of the genes that are responsible for certain single-gene disorders has led, in many cases, to the development of a diagnostic or screening test. Therefore, low-risk individuals potentially can be

Nonmendelian Inheritance. It is now known that certain single-gene disorders are transmitted in nonclassical (nonmendelian) ways. For example, some inherited diseases occur as a result of a mutation in mitochondrial DNA (ie, Leber hereditary optic atrophy, Kearns-Sayre syndrome, myoclonus epilepsy with ragged red fibers). Because

Multifactorial Abnormalities

Multifactorial disorders are caused by a combination of factors, some genetic and some nongenetic (ie, environmental). Multifactorial disorders recur in families, but are not transmitted in any distinctive pattern. Many single-organ system congenital anatomic abnormalities are multifactorial, with an incidence in the general population of 1 per 1,000. Examples of multifactorial traits include the following:

• Cleft lip, with or without cleft palate

• Congenital cardiac defects

• Diaphragmatic hernia

• Hydrocephalus

• Mόllerian fusion defects

• NTDs

• Omphalocele

• Posterior urethral valves

• Pyloric stenosis

• Renal agenesis

• Talipes equinovarus

Because most of the defects on the above list may also occur as a result of a genetic syndrome, single-gene disorder, or chromosome abnormality, a thorough evaluation by a geneticist (or fetal pathologist in the case of a demise) may

• The risk to first-degree relatives (mother, father, brother, sister) is higher than in the general population. The most commonly quoted risk is an empiric risk, which is based on

• The risk is sharply lower (#1%) for second-degree relatives (aunt, uncle, niece, nephew,

• The recurrence risk is higher when more than one family member is affected, or when the

• If the trait is more common in one sex than in the other, the risk is higher if the affected

Amniocentesis

Amniocentesis for prenatal diagnostic testing is usually offered between 15 and 20 weeks of gestation. Under ultrasound guidance, a 20-22-gauge spinal needle is passed into the amniotic fluid. The initial aspirate of 1-2 mL of

Chorionic Villus Sampling

Indications for CVS are essentially the same as those for amniocentesis, except for analyses that require amniotic fluid rather than amniotic fluid cells. The primary advantage of CVS is that results are available much earlier in pregnancy, which decreases parental anxiety when results are normal and, when they are abnormal, allows earlier and safer methods of pregnancy termination. Earlier diagnosis may also be required for prenatal treatment (eg, prevention of

One disadvantage of amniocentesis is the need to culture cells for several days before karyotype analysis. Fluorescent in situ hybridization for the rapid detection of chromosomal aneuploidies in uncultured amniocytes has been reported. This method uses fluorescently tagged specific DNA probes to chromosomes 13, 18, 21, X, and Y. It can rapidly

Experience with preimplantation diagnosis (embryo biopsy) has been reported. After in vitro fertilization, a blastomere biopsy (at the eight-cell stage) is performed, with intrauterine transfer of the embryo and birth of a 

Trisomy 21 has been diagnosed in fetal cells from maternal blood obtained during the first trimester. Fetal cell sorting techniques may one day be developed (eg, for the diagnosis of fetal aneuploidy) by using methods such as