Various diagnostic modalities are available. Some genetic disorders involve chromosomes. Many chromosomal abnormalities are autosomal (not involving the sex chromosome); others are sex-linked (inherited through the sex chromosomes). In some cases there may be total or partial deletion of a chromosome, presence of an extra chromosome attached to a chromosome pair (trisomy), or translocation, when a portion of a chromosome breaks off and attaches to another chromosome. These disorders require chromosome analysis. Other genetic disorders are due to a defective or missing enzyme and are diagnosed by measurement of the enzyme responsible. Sometimes it is necessary to demonstrate that a normal quantity of enzyme does not produce its expected degree of activity. Finally, genetic abnormalities may be due to a gene defect not shown by standard chromosome analysis. In some of these cases, diagnosis can be made by methods using nucleic acid probes. This technique is described in Chapter 14. Briefly, a specific amino acid sequence is obtained from ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) using an enzyme known as “restriction endonuclease.” This probe fragment is spliced into a DNA strand (recombinant DNA) using an enzyme called “reverse transcriptase.” The probe is then used to identify patient DNA that contains the same amino acid sequence as the probe. It is also possible to construct a probe for certain gene deletions (chromosome regions where part of a gene area has been deleted) and for certain mutations (if the mutation has eliminated a restriction endonuclease cleavage site). In some cases the gene can be detected directly. This is generally the most sensitive and accurate technique. When this cannot be done, a technique known as gene linkage analysis using restriction fragment length polymorphism can be used. This refers to abnormal length of a DNA fragment produced by an enzyme (restriction enzyme) that cuts the DNA chain at a specific location near to the gene in question (an area closely linked to the gene location). This technique is said to be 94%-99% accurate.

Genetic diagnosis has been extended to the fetus by means of amniotic cells obtained through amniocentesis. This is usually carried out at 16-18 weeks’ gestation. It is also possible to obtain a small sample of chorionic villi from the fetal side of placenta at 9-12 weeks’ gestation (before the amniotic sac completely fills the uterine cavity) using suction from a catheter introduced through the cervix into the uterine cavity and then into the placenta with the guidance of ultrasound. There appears to be about a 2%-4% (range, 1%-6.4%) incidence of fetal death after the procedure. An impressive and continually increasing number of conditions can be diagnosed prenatally.

Neonatal genetic diagnosis is being increasingly mandated by state governments. Currently, for example, the state of Illinois requires neonatal screening for phenylketonuria (PKU), galactosemia, biotinidase deficiency, sickle cell hemoglobinopathy, congenital adrenal hyperplasia, and hypothyroidism. All of these disorders can be diagnosed using heelstick blood spotted on filter paper.