Chapter 063. Chromosome Disorders (Part 4) doc

Chromosome Disorders Part 4 Cytogenetic Testing in Prenatal Diagnosis The vast majority of prenatal diagnostic studies are performed to rule out a chromosomal abnormality, but cells ma

Chapter 063 Chromosome Disorders

(Part 4)

Cytogenetic Testing in Prenatal Diagnosis

The vast majority of prenatal diagnostic studies are performed to rule out a chromosomal abnormality, but cells may also be propagated for biochemical studies or molecular analyses of DNA Three procedures are used to obtain samples for prenatal diagnosis: amniocentesis, chorionic villus sampling (CVS), and fetal blood sampling Amniocentesis is the most common procedure and is routinely performed at 15–17 weeks of gestation On some occasions, early amniocentesis at 12–14 weeks is performed to expedite results, although less fluid

is obtained at this time Early amniocentesis carries a greater risk of spontaneous abortion or fetal injury but provides results at an earlier stage of pregnancy

The vast majority of amniocenteses are performed in the context of advanced maternal age, the best-known correlate of trisomy (see below) Additional reasons for amniocentesis referral include an abnormal "triple- or

quad-marker assay" and/or detection of ultrasound abnormalities In this assay, levels of human chorionic gonadotropin, α-fetoprotein, and unconjugated estriol (and, in the quad assay, inhibin) in the maternal serum are quantified and used to adjust the maternal age-predicted risk of a trisomy 21 or trisomy 18 fetus Specific ultrasound abnormalities, when detected at midtrimester, can also be associated with chromosomal defects When a nonspecific ultrasound abnormality is present, the estimated risk of a chromosomal defect is ~16% Associations of chromosomal abnormalities and specific types of abnormal ultrasound findings are listed in Table 63-1

Table 63-1 Frequency of Chromosome Abnormalities, Identified on the Basis of Abnormal Ultrasound Findings

Chromosomal Abnormalities (Frequency)

Ultrasound Finding

Average,

%

Range in Different Studies, %

Abnormal ultrasound

(nonspecific)

16 13–35

Omphalocele 39 26–54

Cystic hygroma 68 46–78

Congenital heart disease 30 8–40

Choroid plexus cyst 5 4–10

CVS is the second most common procedure for genetic prenatal diagnosis Because this procedure is routinely performed at about 10–12 weeks of gestation,

it allows for an earlier detection of abnormalities and a safer pregnancy termination, if desired CVS is a relatively safe procedure (spontaneous abortions,

<0.5–1%) Because there is an increased association of limb defects when the procedure is performed earlier (<10 weeks of gestation), CVS is applicable during

a narrow time frame of gestation CVS involves the use of a catheter inserted transvaginally; ~25 mg of villi are aspirated from the chorion frondosum (the fetal portion of the placenta) By adding colchicine directly to the rapidly dividing cytotrophoblasts, results can be obtained within 24–48 h Findings from these procedures should be confirmed by analyses of cultured mesenchymal cells, as they are more reliably derived from the fetus

Percutaneous umbilical blood sampling (PUBS) is a method for obtaining fetal blood during the second and third trimesters of pregnancy PUBS is usually performed when ultrasound abnormalities are detected late in the second trimester PUBS is also used when cytogenetic results from amniocentesis need clarification, such as in the detection of mosaicism

Chromosome Abnormalities

Chromosomes in Cell Division

To understand the etiology of chromosome abnormalities, it is important to review the movement of chromosomes during cell division In somatic tissues, chromosomes are replicated during the S-phase of the cell cycle, so that each replicated chromosome consists of two identical sister chromatids When the cell enters mitosis, each of the 46 chromosomes align on the metaphase plate, with the centromeres co-oriented toward opposite spindle poles (Fig 63-3) At anaphase the sister chromatids separate, with each of the daughter cells receiving one sister chromatid from each of the 46 chromosomes

Figure 63-3