If two diferent alleles in a gene pair are both expressed in the phenotype, they are considered to be codominant. Blood type, for example, is determined by expression of dominant A and B red-cell antigens that can be expressed simultaneously. Another example of codominance is the group of genes responsible for hemoglobin production. An individual with one gene directing production of hemoglobin S and the other directing production of hemoglobin C will produce both Siand C hemoglobin (Chap. 56, p. 1082).
Paternal age older than 40 is associated with increased risk for spontaneous genetic mutations, particularly single base substitutions. This may result in ofspring with new autosomal dominant disorders or X-linked carrier states. In particular, advanced paternal age has been associated with mutations in the ibroblast growth actor receptor 2 (FGF2) gene, which may cause craniosynostosis syndromes such as Apert, Crouzon, and Pfei fer syndromes; mutations in the FGF3 gene, which may result in the ET proto-oncogene, which may cause multiple endo crine neoplasia syndromes Qung, 2003; Toriello, 2008). Using whole genome sequencing, described later (p. 272), Kong and utes to a rise in the rate of single-nucleotide polymorphisms among ofspring. his rate is approximately two mutations for each year of paternal age. Because individual autosomal domi nant disorders are uncommon, the actual risk for any speciic condition is low, and no screening or testing is speciically rec ommended.
Advanced paternal age has also been associated with a structural abnormalities (Grewal, 2012; Toriello, 2008; Yang, 2007). It is not generally considered to pose an elevated risk for other aneuploidies, probably because the aneuploid sperm cannot fertilize an egg.
Recessive diseases develop only when both gene copies are abnormal. Many enzyme deficiency diseases display autosomal recessive inheritance, and enzyme activity in the carrier is usually about half of normal. Unless carriers are screened for a specific disease, such as cystic ibrosis, they usually are recognized only after the birth of an afected child or the diagnosis of an afected family member (Chap. 14, p. 289). If a couple has a child with an autosomal recessive disease, the recurrence risk is 25 percent for each subsequent pregnancy. hus, 1/4 of ofspring will be homozygous normal, 2/4 will be heterozygous carriers, and 114 will be homozygous abnormal. In other words, three of four children will be phenotypically normal, and 2/3 of phenotypically normal siblings are actually carriers.
A heterozygous carrier of a recessive condition is only at risk to have afected children if his or her partner is heterozygous or homozygous for the disease. Genes for rare autosomal recessive conditions have low prevalence in the general population. Thus, the likelihood that a partner will be a gene carrier is small, unless there is consanguinity or the partner is a member of an at-risk group. Heterozygous carriers are usually undetectable clinically but may have biochemical test abnormalities that can be used for carrier screening. Other recessive conditions can be identified only by molecular genetic testing (Chap. 14, p. 288).
Inborn Errors of Metabolism
Most of these autosomal recessive diseases result from absence of a crucial enzyme, leading to incomplete metabolism of proteins, lipids, or carbohydrates. The metabolic intermediates that build up are toxic to various tissues and may result in intellectual disability or other abnormalities.