in which a female has a total of 45 chromosomes, including a single X chromosome. Nondisjunction events that lead to abnormal chromosome complements may occur in the egg or the sperm. However, in contrast to male sperm, which are produced throughout the lifespan, female egg cells are suspended in meiosis II since shortly after that female’s conception. These eggs are subject to aging over the female lifespan, and errors of nondisjunction are more likely to occur.
Triploidy and tetraploidy are the terms for the presence of one or two entire extra sets of chromosomes, leading to a total of 69 or 92 chromosomes, respectively. These anomalies, which usually are not viable in humans, are due to errors in fertilization such as dispermy (two sperm fertilizing an ovum) or failure of the ovum’s polar body to separate.
Inheritance Patterns in Mendelian Disease
Many of the traits Mendel studied in his peas were inherited in a simple dominant or recessive fashion, a manner in which many human traits and disease are also inherited. Characteristics of each of the different Mendelian inheritance patterns are summarized in Table 2.3. Pedigrees representing these well‐known patterns of inheritance are shown in Figure 2.10.
Autosomal Recessive
A condition described as autosomal recessive maintains that the causative gene is located on an autosome and that both copies of the gene must harbor a causative allele. In most cases of recessive conditions, it is correctly assumed that each parent of an offspring with the trait carries a single causative allele. Carriers for recessive conditions do not typically show phenotypic features. Recessive conditions occur more commonly in offspring of consanguineous unions or in populations with high frequency of carriers for a particular condition.
Autosomal Dominant
In a dominant condition, a genetic mutation in a single copy of a gene is sufficient to cause a disease or trait. Dominant conditions may be inherited through an affected parent or alternatively may have occurred as the result of a de novo genetic mutation. Some de novo dominant mutations have been shown to be associated with increased paternal age (Friedman 1981). Some dominant conditions may exhibit reduced penetrance, in which a person carries a causative gene but does not exhibit any manifestations of the condition. On the other hand, variable expressivity refers to the range of features that may be observed in individuals with the same condition. Codominance, in which a trait is expressed from both alleles, has also been observed in certain traits, for example, in AB blood type.
Table 2.3 Hallmarks of Mendelian inheritance patterns of different types.
| Inheritance pattern | Examples | Transmission features | Recurrence risk | Prevalence in population | Other critical features |
|---|---|---|---|---|---|
| Autosomal dominant | Marfan syndrome; neurofibromatosis; myotonic dystrophy | Transmitted from affected parent to affected offspring (vertical transmission) male‐to‐male possible transmission; de novo mutations may occur | For each offspring of affected parent, risk to child to inherit disease gene is 50% | p2 + 2pq | Reduced penetrance may be observed |
| Autosomal recessive | Sickle cell anemia; cystic fibrosis | Carrier parents generally unaffected | For carrier parents, risk for each subsequent child is 25% | q2 | Consanguinity considered |
| X‐linked | Duchenne muscular dystrophy; fragile X syndrome; hemophilia | No male‐to‐male transmission; de novo mutations may rarely occur | 50% of offspring of carrier female have trait (if male, affected, if female carrier); all female offspring of affected male are carriers | Females: q2; males: q | Females may show sub‐clinical, atypical, or fully penetrant features of the condition. Non‐random X inactivation may contribute to more severe female phenotype. |
| Y linked | Genes SRY and TDF, important in sex determination, are on the Y chromosome; no known diseases are located on Y | Exclusively male‐to‐male transmission | All sons of affected males are affected; no daughters of affected males are affected | Females: 0; males: q | Male‐determining genes are located just proximal to pseudoautosomal region on Y chromosome; faulty recombination in pseudoautosomal region can lead to errors in sex determination |
| Autosomal codominant | MN blood group; microsatellite repeat markers | Each allele confers measurable component to phenotype | Varies according to mating type | Genotypes expected to occur in Hardy–Weinberg proportions of p2, 2pq, and q2 | |
| Mitochondrial | Leber’s optic atrophy; KSS (Kearns–Sayre syndrome); MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes); | Exclusively maternal transmission through maternal mitochondria | All offspring of affected females are at risk to inherit mutation (may be affected or carrier). Proportion of affected offspring is variable based on maternal heteroplasmy. Offspring of affected male not at risk to inherit mutation. | Heteroplasmy may determine phenotypic severity. Majority of mitochondrial diseases are due to mutations in the nuclear genome rather than the mitochondrial genome and follow autosomal recessive inheritance pattern. |
Figure 2.10 Pedigrees consistent with (a) autosomal dominant inheritance, (b) autosomal recessive inheritance, (c) X‐linked recessive inheritance, (d) X‐linked dominant inheritance, and (e) mitochondrial inheritance. Here and elsewhere squares indicate males, circles indicate females, open symbols indicate unaffected individuals, and solid symbols indicate affected individuals.
X‐linked Inheritance
The majority of the genes located on the X chromosome do not have a complementary gene on the Y chromosome. Therefore, males are “hemizygous” at these loci because they have only a single copy of the gene. X‐linked conditions were historically described as “X‐linked dominant” or “X‐linked recessive.” In an X‐linked recessive condition, a single abnormal allele was sufficient to cause disease in a hemizygous male, while females needed two. On the other hand, in “X‐linked dominant” conditions, a single abnormal allele was sufficient to cause a condition in both males and females. Although these patterns of inheritance hold true for many
