(Table of Contents- Lesson 2) (Next) (Glossary)

As you learned in Lesson 1, genetic conditions are classified according to the type of genetic lesion causing the problem such as chromosome abnormalities, single gene or Mendelian disorders and polygenic or multifactorial disorders. All have characteristic inheritance patterns.

CHROMOSOME ABNORMALITIES

As a rule, chromosome abnormalities occur sporadically when the gametes are formed. Therefore, it is not unusual to find only one affected individual in a family. Most individuals with chromosome abnormalities are diagnosed because they have obvious physical abnormalities, short stature, failure to thrive, a history of developmental delay or mental retardation.

Individuals who carry a balanced translocation chromosome, however, are physically and intellectually normal. These individuals are usually identified following the birth of a child with a chromosome abnormality or because of a history of multiple miscarriages. It is for this reason that recording miscarriages becomes important when taking a family history. Individuals who have a history of three or more pregnancy losses should be referred to a genetic service for counseling and evaluation.

SINGLE GENE DISORDERS

Single gene disorders can be divided into autosomal dominant, autosomal recessive and X-linked conditions. As you will recall from Lesson 1, the term "autosome" refers to chromosomes 1 through 22. These chromosomes are inherited in pairs in both males and females.

The 23rd pair of chromosomes, or the sex chromosomes, differ between the sexes. Women inherit two copies of the X chromosome and, therefore, two copies of each gene on the X chromosome. Men, on the other hand, inherit one X chromosome and a smaller Y chromosome.

The presence of a single gene abnormality can sometimes be inferred from a patient's family history.

AUTOSOMAL DOMINANT INHERITANCE

An autosomal dominant disorder is one in which the abnormal phenotype is evident when a mutation is present in one autosomal gene of a pair. Individuals with an autosomal dominant disorder such as Marfan syndrome may have a parent with the same condition. Further analysis of the family may reveal that there are other affected aunts and uncles or a grandparent.

The following are characteristics of an autosomal dominant pedigree:

• Affected individuals are usually present in each generation, creating a vertical pattern of inheritance.
• Approximately 50% of the children born to an affected individual will be affected, providing the partner is unaffected.
• Both males and females can be affected, therefore, male to male transmission is possible.

Examples of autosomal dominant single gene disorders include: Marfan syndrome, achondroplasia, neurofibromatosis, and retinitis pigmentosa.

Fig. 2.3. A typical autosomal dominant pedigree

When analyzing a pedigree it is important to keep in mind the following:

• Some autosomal dominant disorders exhibit reduced penetrance or appear to "skip" generations because the disorder is not expressed in some individuals who inherit the gene. Therefore, collecting information about aunts, uncles and grandparents may be necessary to make a diagnosis or identify at-risk individuals.
• An autosomal dominant disorder cannot be ruled out just because there is only one affected family member. Isolated cases of dominant disorders may be the result of a new mutation.
• Some dominant genes code for late onset disorders. For this reason, it is important to update a patient's family history on a regular basis, as a pattern may begin to emerge over time.
• Given that wide variability in clinical expression is common in many autosomal dominant disorders, careful examination of a child's parents is important. Severely affected offspring may be born to minimally affected adults.

AUTOSOMAL RECESSIVE INHERITANCE

An autosomal recessive disorder is one which is fully expressed only when a mutation is present in both genes of a pair. The characteristic features of an autosomal recessive pedigree include:

• The parents of an affected child are usually clinically normal and, as a rule, they are not aware that they carry a recessive gene until after the birth of an affected child.
• It is highly unusual to find other affected individuals in preceding or succeeding generations. The disorder is generally found only in sibs, thus resulting in a horizontal pattern of inheritance.
• Either sex can be affected, on average in equal numbers.
• When both parents are carriers, there is a 25% chance with each pregnancy of having an affected child.
• Consanguinity is noted more often among the parents of individuals with rare recessive disorders. A consanguineous relationship noted in the parents of a patient with an unidentified genetic disorder suggests the possibility of an autosomal recessive single gene disorder.

Examples of autosomal recessive single gene disorders include: albinism, cystic fibrosis, mucopolysaccharidosis, and phenylketonuria.

Fig. 2.4. A typical autosomal recessive pedigree

X-LINKED INHERITANCE

An X-linked disorder is one in which the altered gene is located on the X chromosome. The characteristics of X-linked inheritance are as follows:

• The hallmark of X-linked inheritance is that there is no male to male transmission, since males pass on Y chromosomes to their sons.
• Unaffected males cannot transmit the disorder because they do not carry the abnormal X-linked gene.
• Affected males have clinically normal offspring. Their sons receive a Y chromosome and are free of the trait. Their daughters receive an X chromosome and are normal, but obligate carriers.
• Carrier females have a 50% chance, with each pregnancy, of passing on the abnormal gene. Sons who inherit the gene will be affected and daughters will be carriers like their mothers.
• Female carriers may be mildly symptomatic due to unequal inactivation of the X chromosomes.
• Although unlikely, a female can express an X-linked disorder if her father is affected and her mother is a carrier. Even rarer is an affected female with Turner syndrome (females who have only one X chromosome).
• Females are considered obligate carriers if they have more than one affected son, or an affected son and another affected male relative.

Examples of X-linked single gene disorders are: color blindness, Duchenne muscular dystrophy, hemophilia, and Hunter syndrome.

Fig. 2.5. A typical X-linked pedigree

Keep in mind when recording family history information that:

• An isolated case of an X-linked disorder may be the result of a new mutation in the affected male individual or his mother. It could also be the result of a germline mosaicism in which only some of his mother's eggs carry the mutation.
• Rarely are X-linked conditions expressed in both males and females. In such cases the inheritance pattern may resemble the pattern seen in autosomal dominant single gene disorders but with no male to male transmission.

POLYGENIC MULTIFACTORIAL INHERITANCE

Many disorders that occur in families are known to have a genetic component but do not follow clear Mendelian patterns of inheritance. These disorders, as discussed in Lesson 1, are referred to as polygenic or multifactorial disorders because they are believed to be caused by the interaction between a variety of genes as well as environmental factors.

Examples of multifactorial disorders include cleft lip and palate, neural tube defects and pyloric stenosis. Individuals who have a first or second degree relative with such a disorder should be referred for counseling, given that their risk of having an affected child is increased above the general population risk. The recurrence risk to sibs or the offspring of an affected individual is approximately 3 to 5%. The recurrence risk increases, however, when more family members are affected or the parents are related.

Figure 2.6 shows a pedigree suggestive of a polygenic or multifactorial pattern of inheritance.

Fig. 2.6. Polygenic or multifactorial pattern of inheritance

SPORADIC CASES

In most cases, analysis of a patient's family history will reveal that he or she is the only affected member in the family. However, when dealing with sporadic cases it is not safe to assume that the disease is not genetic. As you know, sporadic disorders can be caused by de novo chromosome abnormalities, new dominant mutations, autosomal recessive genes, uniparental disomy, germline mosaicism or exposure to a teratogenic agent. In such cases, further investigation of the patient's medical and developmental history may reveal clues to the etiology of his or her disease. A history of delayed physical or cognitive development, major or minor malformations or exposure to a known teratogenic agent are all appropriate reasons for referral, especially if the family has questions about why a particular problem occurred.

SUMMARY

If you are working with a patient or family with a possible chromosome abnormality, a single gene disorder, a history of three or more miscarriages, or other similarly affected family members, consider referral for evaluation. Individuals who belong to high-risk ethnic groups or who are in a consanguineous relationship might also benefit from a genetic evaluation and counseling.

When dealing with a patient with an isolated abnormality you cannot rule out a genetic disease. For this reason you should consider collecting additional information in an effort to determine if a genetics referral is appropriate.

PRACTICE ACTIVITY 1

1. Analyze the following pedigree and state the most likely inheritance pattern, your reason for the choice and an example of the disease/condition.

Pattern of Inheritance

Rationale

Example

2. Analyze the following pedigree and state the most likely inheritance pattern, your reason for the choice and an example of the disease/condition.

Pattern of Inheritance

Rationale

Example

3. Analyze the following pedigree and state the most likely inheritance pattern, your reason for the choice and an example of the disease/condition.

Pattern of Inheritance

Rationale

Example

Use a T or F to show whether this statement is true or false.

4. If there are no other affected family members, it is safe to assume that the condition is not genetic.

PRACTICE ACTIVITY 1: ANSWERS

1. X-linked

Only males are affected, inherited through their mothers

Hemophilia, Duchenne muscular dystrophy

2. Autosomal recessive

Horizontal pattern of inheritance, parents are second cousins

PKU, sickle cell anemia

3. Multifactorial

Multiple affected family members

Neural tube defect, pyloric stenosis, cleft lip/palate

4. False Isolated abnormalities may be the result of a new mutation, nontraditional pattern of inheritance or autosomal recessive single gene disorders.

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