Grandparents, uncles, and aunts are added in similar fashion. Children of aunts and uncles also may be included. Ages or birthdays may be written next to or underneath each symbol. The proband (the patient who is the initial contact) is indicated with an arrow. Affected individuals are indicated by shading, or some other technique, which should be explained in a key. Carriers for a disorder (e.g., sickle cell disease) usually are indicated by a dot in the center of their symbol (Fig. 47-1).
Figure 47-1 Pedigree showing affected individuals and carriers.
To be useful, pedigrees should include representatives of at least three generations of family members.
If a single copy of a gene bearing a mutation is sufficient to cause disease and that gene is not on one of the sex chromosomes, that condition is inherited in an AD fashion (Table 47-1). In AD disorders, an affected parent has a 50% chance of passing the mutated gene to each child (Fig. 47-2; Table 47-2). Possessing one working gene and one nonworking gene is termed heterozygous. If both copies are the same, they are referred to as homozygous.
Some people who are obligate carriers of a mutation known to cause an AD disorder may not show clinical signsof the disorder, whereas other such individuals manifest symptoms. This phenomenon is referred to as penetrance.If all individuals who carry a mutation for an AD disordershow signs of that disorder, the gene is said to have complete penetrance. Many AD disorders show decreased penetrance.
Often, AD disorders show variability in symptoms expressed in different individuals carrying the same mutated gene. Some individuals have only mild clinical symptoms, whereas others have more severe disease. This phenomenon is referred to as variable expressivity.
AD disorders sometimes appear in a child of unaffectedparents because of a spontaneous mutation. Known in some cases to be associated with advanced paternal age(>35 years of age), spontaneous mutations may account formost individuals with some disorders. Approximately 80%of patients with achondroplasia have a spontaneous mutation in the fibroblast growth factor receptor type 3 (FGFR3)gene. The following are examples of autosomal dominantdisorders.
Table 47-1 Autosomal Dominant Diseases DISEASE FREQUENCY COMMENTS Achondroplasia Thanatophoric dysplasia Crouzon syndrome with acanthosis nigricans Nonsyndromic craniosynostosis ∼1:12,000 Mutations are in the gene for fibroblast growth factor receptor-3 on chromosome 4p16.3. 40% of cases are new mutations (different mutations in the same gene cause achondroplasia, thanatophoric dysplasia, Crouzon syndrome with acanthosis, and nonsyndromic craniosynostosis)
Neurofibromatosis 1 1:3500 About 50% of cases result from new mutations in the gene for neurofibromin, a tumor suppressor gene located at 17q11.2. Expression is quite variable
Huntington disease (HD) Variable in populations, The disease is caused by a (CAG) repeat expansion in the “Huntington” 1:5000–1:20,000 protein gene on chromosome 4p16.3
Marfan syndrome (FBN-1) 1:10,000 The syndrome is caused by mutations in the fibrillin 1 (FBN 1) gene on chromosome 15q21.1; there is variable expression
Caused by a defect in cartilage-derived bone, achondroplasia (ACH) is the most common skeletal dysplasia in humans. The bony abnormalities lead to short stature, macrocephaly, a flat midface with a prominent forehead, and rhizomelic shortening of the limbs. The disorder occurs in approximately 1 in 12,000 births.