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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. Of all newborns, 34% have a major congenital defect; by age 7 or 8 years, another 3-4% of children are discovered to have

Genetic Disorders


A variety of chromosome abnormalities can occur in association with a live birth. Most autosomal trisomies result from maternal 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 translocations may be sporadic or familial.

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. 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 age 35 should be offered prenatal genetic testing if their

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 47,XYY (in which it is paternal in origin). Women who have had a pregnancy complicated by fetal XXX or XXY should be offered prenatal testing in subsequent pregnancies because their recurrence risk for another fetal trisomy is estimated to be 1%. Although monosomy X (Turner's syndrome) and

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 translocation carrier's risk of having an aneuploid child should be estimated individually, taking into account the chromosomes involved, the

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

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 from fertilization with a diploid sperm. Such conceptions are usually partial hydatidiform moles and end spontaneously in the first trimester; the recurrence risk is minimal and genetic testing in future

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 aneuploid first-trimester loss increases the

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,


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

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

The number of single-gene disorders that can be diagnosed prenatally is increasing rapidly. The list of diagnosable diseases currently includes neurofibromatosis, myotonic dystrophy, congenital adrenal hyperplasia, adult polycystic kidney disease, Huntington's disease, osteogenesis imperfecta, cystic fibrosis, phenylketonuria and other enzyme deficiency diseases, hemophilia A, Duchenne muscular dystrophy, and fragile X syndrome. Any patient with a personal or family history of a monogenic disorder should be referred

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

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

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 um3. Those carriers found not to be iron deficient should have a hemoglobin A2 determination. Increased levels (>3.5%) indicate presence of the b-thalassemia trait, whereas normal levels should prompt a family study for the a-thalassemia trait. Prenatal diagnosis by molecular testing can identify all forms of a-thalassemia and approximately 20% of b-thalassemia.

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 carrier rate among Ashkenazi Jews for Tay-Sachs disease is 1 in 30,

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 screened for several monogenic diseases (population screening). Whether such screening is justified or useful is an area of great controversy. The legal, social, and health care implications of such screening have not been fully evaluated. The two conditions for which population screening has been considered in obstetrics are cystic fibrosis and fragile X syndrome.

More than 400 different gene mutations are known to cause cystic fibrosis. If a specific gene mutation has been identified in an affected family, individuals at risk can be screened for that particular deletion. In a low-risk family without affected members, the laboratory receives no guidance regarding the gene deletions

Fragile X syndrome is the most common form of familial mental retardation. It is related to an unstable DNA region on the X chromosome. The region is best described as a series of CGG (cytosine-guanine-guanine) repeats; the number of repeats determines the degree to which an individual is affected. Individuals carrying

Another nonclassical inheritance pattern involves germline mosaicism. Although it was previously believed that new autosomal dominant mutations occurred sporadically and had no recurrence risk (ie, osteogenesis imperfecta type II), it is now believed that some individuals carry two or more populations of germ cells, with one population carrying the new mutation. The risk of having another child with the new autosomal dominant mutation is therefore not zero, but somewhere between 1% and 7%.

Genomic imprinting describes a gene expression that differs according to the parent of origin. The differential expression is related to differences in DNA methylation patterns. The methylation patterns are not

Uniparental disomy is defined as a disomic (euploid) cell line in which both copies of one chromosome came from the same parent. The individual who has uniparental disomy therefore has two copies of certain genes