3

Patterns of Inheritance

Objectives

1.   Differentiate between various patterns of inheritance including autosomal dominant (AD), autosomal recessive (AR), X-linked dominant, and X-linked recessive

2.   Utilize appropriate online resources to assist in learning inherited genetic conditions

26How Can Genetic Disorders Be Inherited?

Patterns of Inheritance—AD

AD inherited disorders are attributed to a single-gene mutation located on the autosomes or any one of the first 22 chromosomes (see Figure 2.1). Only one deleterious gene mutation located on its designated autosome is needed for disease occurrence, and this inheritance can occur at the time of conception from either the mother or father. Because of this dominance of inheritance, there is a 50% chance of transmission of the affected gene to the offspring with each pregnancy (Figure 3.1). This 50% probability often leads to multiple generations being affected in the family, depending upon the number of offspring. Examples of AD disorders include most hereditary breast cancer syndromes like hereditary breast and ovarian cancer (HBOC) due to mutations in the BRCA genes; Huntington’s disease, Marfan syndrome, neurofibromatosis, achondroplasia, retinoblastoma, familial hypercholesterolemia, and most inherited colon cancer syndromes.

Patterns of Inheritance—AR

Like that of AD, AR disorders occur on the autosomes. Disorders that are AR require the genetic mutation to occur on both chromosomes, unlike AD disorders where only one chromosome with the gene mutation may lead to disease occurrence. Therefore, for an AR disorder/disease to occur, the offspring must inherit the mutation from both the mother and father. This requires that each parent must be at least a carrier of one affected chromosome with the gene mutation. Parents who are carriers of an AR disorder often will be without symptoms of the genetic disorder unless one of them has the affected disorder (e.g., both chromosomes with the gene mutation).

AR disorders are a result of Mendelian inheritance. If both parents are carriers of the genetic mutation, there is a 25%, or one in four, chance that the offspring will inherit the affected gene from each of the parents, resulting in disease. This probability of inheritance can occur with each pregnancy. There is also a 50% probability with each pregnancy that a child will be a carrier of the disorder (one normal gene and one mutated gene) and a 25% chance that the offspring is born without a gene mutation (both genes normal). Examples of recessive genetic disorders include, but are not limited to, sickle cell disease, cystic fibrosis, hemochromatosis, thalassemias (e.g., alpha thalassemia, beta thalassemia), albinism, Tay–Sachs disease, phenylketonuria (PKU), and polycystic kidney disease. In fact, most of the newborn screening (NB) tests that are mandated by public health programs are AR disorders (see Chapter 10 for information on NB screening). Figure 3.2 provides a depiction of gene transmission due to AR disorder.

Patterns of Inheritance—X-Linked Dominant

The sex chromosomes, specifically the X chromosome, are the causative factors for X-linked genetic disorders. For females, who have two X chromosomes, one affected gene mutation on the X chromosome is sufficient for disease occurrence; because men only have one X chromosome, if the affected gene is transmitted by the mother to the son, then the male will also have the genetic disorder. In X-linked disorders, the following patterns of inheritance for disease transmission can occur with each pregnancy:

In an affected mother:

1.   A 50%, or one in two, chance of transmission of the deleterious gene mutation to the female or male offspring with each pregnancy leading to the disease or condition.

2.   A 50%, or one in two, chance that the male or female offspring will not inherit the mutated gene and will be without the disease or condition.

29In an affected father:

1.   A 100% transmission of the disease to the female offspring occurs.

2.   No (0%) transmission to the male progeny occurs as the father only contributes the Y chromosome to male offspring.

Figure 3.3 depicts an X-linked dominant pattern of inheritance through an affected mother or father to their offspring.

There are few X-linked dominant disorders. Examples of X-linked dominant disorders include Rett syndrome, a neurodevelopmental disorder that affects primarily females (National Institute of Neurological Disorders and Strokes, 2015); hypophosphatemic rickets a disorder related to low levels of phosphate in the blood that is essential to normal bone and teeth formation (U.S. National Library of Medicine [NLM], 2017b); and incontinentia pigmenti, a disorder associated with abnormal skin changes (usually hypopigmentation) as well as numerous other conditions including alopecia, dental abnormalities, and changes of the fingernails and toenails (U.S. NLM, 2017c).

30Fragile X syndrome is another condition that results from an X-linked dominant pattern of inheritance. The prevalence of the condition is higher in males (1/4,000) compared to females (1/8,000; Jorde, Carey, & Bamshad, 2016). The syndrome is associated with intellectual, behavioral, and learning disabilities as well as numerous physical characteristics that include long face, prominent forehead and jaw, large protruding ears, connective tissue problems (e.g., hyperflexible joints; flat feet), and macroorchidism after puberty in males. Although the characteristics can be observed in both genders, males are often more severely affected by the disorder compared to females (National Fragile X Foundation, n.d.; U.S. NLM, 2017a). Figure 3.4 provides a fragile X phenotype.

Patterns of Inheritance—X-Linked Recessive

X-linked recessive disorders warrant that both genes on the female’s X chromosome are affected; however, in the male, given that the offspring only has one X chromosome, a mutation on that chromosome will lead to disease. For this pattern of inheritance to cause disease, the following must occur:

1.   In female offspring, both X chromosomes must be affected. This inheritance must occur from both parents (mother who is a carrier or affected and a father who is affected); thus, X-linked recessive disorders are rare in females.

2.   In an affected male parent with an unaffected female parent:

      a.   None (0%) of the male offspring will develop the disease.

      b.   All daughters (100%) will be carriers but unaffected with the disease.

3.   In a female carrier (only one X chromosome affected) with an unaffected male:

      a.   A 50% chance that her son will be affected

      b.   A 50% chance that her son will be unaffected

      c.   A 50% chance that her daughter will be an unaffected carrier

      d.   A 50% chance that her daughter will be unaffected and a noncarrier

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