3 Genetic Disorders John W. Bachman In family medicine, knowledge of genetics is useful in evaluating the risk a patient may have for a genetic disorder and to counsel patients about possible risks associated with any future childbearing. Today’s family physician assumes many roles in managing genetic issues (Table 3.1). The explosion in science centering on genetics requires all primary care physicians to be aware of the pragmatic advances in this field. The Basic Science of Genetics There are 50,000 to 100,000 genes located in the 46 chromosomes of the human cell. Each gene is composed of one copy originating from the paternal side and the other from the maternal side. Genes are composed of DNA, and the ultimate products of most genes are proteins. The coding for a gene is its genotype. The physical result in the organism is its phenotype. It may not necessarily mean that the organism with the gene is expressed by its phenotype (recessive gene). Most changes in the DNA of genes do not result in a disease; these are called polymorphisms. A change in the DNA of a gene that re- sults in an abnormal protein that functions poorly or not at all is called a mutation. The same mutation in a gene does not necessarily pro- duce the same physical findings in affected persons. This difference is called gene expression. Alleles are alternative forms of a gene at a specific location on a chromosome. A single allele for each locus 36 John W. Bachman Table 3.1. The Roles of Family Physicians in Genetic Medicine Identify individuals who are at increased risk for genetic disorders or who have a disorder Use common prenatal genetic screening methods and effectively use genetic testing to care for individuals Recognize the characteristics of common genetic disorders Provide ongoing care for individuals with genetic disorders by monitoring health and coordinating referrals Provide informed options about genetic issues to patients and their families Be aware of genetic services for patients with various genetic disorders for appropriate referral is inherited from each parent. Damage to DNA is corrected by DNA repair genes. Mutations of repair genes lead to an increased risk for cancer. Types of Testing Indirect Analysis–Linkage Analysis This type of testing is used when the location of a gene is not known or it is too difficult to test for directly. It is used primarily in fami- lies and requires that one affected person be tested to determine whether the gene is located near some genetic material that can be measured, such as another gene or a segment of DNA. If a marker is found, it can be used in other family members to assess whether they might have the gene. (You find the gene by knowing the com- pany it keeps.) A geneticist might order this testing in a patient if there is a clustering of a disease in the family. Direct Mutation Analysis This type of genetic analysis involves looking for the specific muta- tion on the gene by one of several techniques. Common ones include Southern blot analysis, multiplex polymerase chain reaction, and di- rect sequencing of the gene. It does not rely on testing other mem- bers of the family. A family physician or geneticist ordering this type of testing is looking for a specific mutation on a gene, usually be- cause of observing a patient’s phenotype. A limitation of this tech- nique is that a disease may be caused by multiple mutations. An ex- ample is cystic fibrosis, which is the result of the loss of phenylalanine 3. Genetic Disorders 37 at position 508 in about 70% of cases. The other 30% of cases are caused by hundreds of other mutations on the gene. Therefore, it is unrealistic to check for all of them when screening an individual. An- other issue is that sometimes more than two genes are involved and account for the same phenotype. Molecular Cytogenetic Analysis Chromosome rearrangements can be detected by fluorescence in situ hybridization (FISH). The technique involves preparing a fluorescent probe that identifies either the abnormal region (a visible color ap- pears on examination) or a normal region (no color appears). The technique is quick but often requires follow-up studies. Types of Genetic Disorders The types of genetic disorders that the patients of family physicians may have can be classified as follows: 1. Chromosome disorders: These disorders are caused by the loss, gain, or abnormal arrangement of one or more chromosomes. Their frequency in the population is about 0.2%. 2. Mendelian disorders: These disorders are single-gene defects caused by a mutant allele at a single genetic locus. The transmis- sion pattern is divided further into autosomal dominant, autoso- mal recessive, X-linked dominant, and X-linked recessive. Their frequency is about 0.35%. 3. Multifactorial disorders: These disorders involve interactions be- tween genes and environmental factors. The nature of these in- teractions is poorly understood. It includes cancers, diabetes, and most other diseases that develop during a patient’s life. The risks of transmission can be estimated empirically, and their estimated frequency in the population is about 5%. 4. Somatic genetic disorders: Mutations arise in somatic cells and are not inherited. They often give rise to malignancies. Although the mutation is not inherited, it often requires a genetic predisposition. 5. Mitochondrial disorders: These disorders arise from mutations in the genetic material in mitochondria. Mitochondrial DNA is trans- mitted through only the maternal line. Each of these groups of disorders, except mitochondrial disorders, is discussed below. 38 John W. Bachman Chromosome Abnormalities Down Syndrome The most frequent chromosome disorder (1 in 800 births in the United States) is the one associated with Down syndrome. Down syndrome is caused primarily by nondisjunction during development of the egg, with failure of a chromosome 21 pair to segregate during meiosis. The event is random. Another cause (3–4% of cases) is a robertson- ian translocation, in which chromosome 21 attaches to another chro- mosome. Although the amount of genetic material is normal, the num- ber of chromosomes is 45 instead of 46. The offspring of a parent with a robertsonian translocation have a 25% chance of having a Down syndrome karyotype. Karyotyping is required for all newborn children with Down syndrome to rule out robertsonian translocation. Another cause of Down syndrome (1–2% of cases) is nondisjunction after conception that leads to a mosaic pattern of inheritance, in which some cells are trisomy 21 and others are normal. A normal karyotype initially in a child with classic Down syndrome is possibly explained by mosaicism and requires chromosome analysis of other tissue. Down syndrome can be diagnosed during the prenatal period. The definitive tests are amniocentesis and chorionic villus sampling. In- dications for either procedure are as follows1: 1. Robertsonian translocation and previous birth of a child with Down syndrome: For women younger than 30 years, the risk for recurrent Down syndrome is about 1%. For those older than 30, the risk is the same as that for other women of their age. The risk for recurrence in a patient with a robertsonian translocation is high. 2. Increasing maternal age: The risks for Down syndrome and other chromosome disorders according to maternal age are listed in Table 3.2. Prenatal diagnosis should be offered to women older than 35 years, who in fact comprise the largest group referred for genetic testing prenatally. About 25% of all Down syndrome births can be detected when age is used as a criterion. 3. Low serum levels of maternal ␣-fetoprotein: When testing for neural tube defects, another subset of pregnant women can be iden- tified as being at risk for having a child with Down syndrome. Because the liver of a fetus with Down syndrome is immature, ␣- fetoprotein levels are lower than normal. Another 20% of fetuses with Down syndrome can be identified with this test (amniocen- tesis rate of 5% of a pregnant population being tested). The test also can be used to adjust patients older than age 35 years into a lower risk group. 3. Genetic Disorders 39 Table 3.2. Chromosome Abnormalities in Liveborn Infants, by Maternal Agea Maternal Risk for Total risk for age Down chromosome (years) syndrome abnormalitiesb 20 1/1667 1/526 21 1/1667 1/526 22 1/1429 1/500 23 1/1429 1/500 24 1/1250 1/476 25 1/1250 1/476 26 1/1176 1/476 27 1/1110 1/455 28 1/1053 1/435 29 1/1000 1/417 30 1/952 1/385 31 1/952 1/385 32 1/769 1/322 33 1/602 1/286 34 1/485 1/238 35 1/378 1/192 36 1/289 1/156 37 1/224 1/127 38 1/173 1/102 39 1/136 1/83 40 1/106 1/66 41 1/82 1/53 42 1/63 1/42 43 1/49 1/33 44 1/38 1/26 45 1/30 1/21 46 1/23 1/16 47 1/18 1/13 48 1/14 1/10 49 1/11 1/8 aBecause sample size for some intervals is relatively small, 95% confi- dence limits are sometimes relatively large. Nonetheless, these figures are suitable for genetic counseling. b47,XXX excluded for ages 20 to 32 years (data not available). Source: Simpson,16 by permission of Bailliere Tindall. 4. Triple test: The risk for Down syndrome can be ascertained by measuring the serum levels of ␣-fetoprotein, estrogen, and human chorionic gonadotropin (hCG). The serum hCG level is higher and that of unconjugated estriols is lower in a pregnant woman whose 40 John W.