Birth Defects

An example of an autosomal dominant disorder is achondroplasia, the most common form of short-limbed dwarfism in humans. Achondroplasia displays complete penetrance (everyone with the genetic defect also has the disorder), and it occurs in 1 out of 25,000 births. Most cases are sporadic rather than inherited.

Achondroplasia is a growth disorder caused by a mutation of the gene that encodes the fibroblast growth factor receptor 3 (FGFR3), and it is characterized by short limbs, malformed hands, a disproportionately large head, and abnormal facial features. Medical problems are due to abnormally configured bones and related structures, leading to hydrocephalus, problems of the spine, frequent sinus and ear infections, and orthopedic problems. If one parent is affected with achondroplasia, there is a 50 percent risk that an offspring will also be affected. If both parents are affected, there is a 25 percent chance that an offspring will inherit two gene copies and develop severe, life-threatening features. Two known mutations in FGFR3 account for 98 percent of all achondroplasia cases. This makes early identification, even prenatal diagnosis, relatively easy.

Another autosomal dominant condition is Marfan syndrome, which results from a defect in the synthesis, secretion, or utilization of the protein fibrillin, an important component of connective tissue throughout the body. The gene for Marfan syndrome is fibrillin 1 (FBR1). Marfan syndrome features are variable, including cardiovascular, skeletal, and ocular defects.

Marfan syndrome's most serious medical complication is the risk of sudden death from aortic dissection, a tear in the inner wall of the major artery leading from the heart. Approximately 75 percent of individuals with Marfan syndrome have a family history of the disease, with the rest occurring as new mutations. Because the syndrome is autosomally dominant, affected indviduals have a 50 percent risk of passing the mutated gene to their off-spring. The condition has full penetrance; therefore, all individuals who inherit this mutation will express some features of Marfan syndrome.