The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Brian O. King. This current second edition chapter is a revision and update of the original authorís work.
A 25-year old woman and her husband are scheduled for a pre-conception appointment to discuss a family history of cystic fibrosis. The womanís brother, age 29 years, was diagnosed with mild cystic fibrosis at age 27 years, after two years of unsuccessfully attempting to have a child. He was determined to have two mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene (the gene associated with cystic fibrosis). The woman and her husband have been trying to conceive for four months. They have read information about cystic fibrosis online and would consider pre-implantation genetic diagnosis to determine if a future embryo is affected.
Variations of the genome, inherited or somatic, can result in disease. Variations include numerical (aneuploidy) or structural (e.g., translocations, inversions) chromosome disorders and single-gene mutations (errors in the DNA code). Gene-gene interactions and gene-environment interactions may also result in disease.
Genomic changes can alter the typical number of chromosomes within a cell. An example is nondisjunction during meiosis that results in gametes that have double the typical chromosomal complement or are missing a chromosome entirely. While none of the genes themselves may contain mutations, the additional or missing genetic material causes specific disorders, signs, and symptoms if that gamete successfully undergoes fertilization to form a zygote. An example of this type of genetic change, known as aneuploidy (numerical changes of chromosomes), is Trisomy 21 (Down syndrome). In this condition, there are three copies of chromosome 21 in each cell instead of the typical two copies. This is the most common trisomy in live births. In most cases, the meiotic nondisjunction occurred during maternal meiosis I.
Chromosome changes (structural rearrangements) and aneuploidy occur relatively often (7 of 1000 live newborns). Roughly half of spontaneous first-trimester pregnancy losses have a chromosome disorder. During DNA replication, chromosome segments may break and rearrange in an atypical location on the same or different chromosome. This is called a translocation. A translocation is considered "balanced" if all of the chromosomal material is present, without any extra (duplicated) chromosomal material. A translocation is considered "unbalanced", if the breakage and subsequent rearrangement results in some of the chromosomal material being duplicated or deleted. An example of a translocation is the Robertsonian translocation, in which two chromosomes become fused near the centromere, each losing their short arm. The most common structural chromosomal change in humans is the Robertsonian translocation involving chromosomes 13 and 14. This occurs in about 1 out of 1300 people and is typically a balanced translocation, meaning that carriers have a normal phenotype. However, they are carriers who produce gametes that have unbalanced allotments of chromosomal material, thus placing their offspring at risk for unbalanced translocations and abnormal phenotypes.
Single-gene changes cause genetic disease in roughly 2% of individuals over their lifetime. Human alleles at a particular genetic locus are classified as wild type (the most commonly found allele in the population), polymorphisms (genetic variations in a population, often implied to be more common than a mutation), variants (may be benign or of unknown significance), or mutations (which cause disease or abnormal phenotype). Mutations can occur on one pair of a chromosome set (heterozygous), on both pairs of a chromosome set (homozygous), or within the mitochondrial genome. An example of a single-gene mutation that causes disease occurs in the FGFR3 (fibroblast growth factor receptor 3) gene, the only gene thus far associated with achondroplasia. The vast majority of individuals with achondroplasia have a common mutation (1138G>A, a single substitution of guanine for adenine at the 1138 nucleotide position) in one copy of their FGFR3 gene. They are therefore heterozygous for a single-gene mutation that causes achondroplasia.
Somatic mutations occur by chance and are not inherited by offspring. These genetic changes are frequently seen in cancer tumors or tissue-specific mosaicism. However, germline mutations (be they genomic changes, chromosomal abnormalities, or single-gene mutations) occur in germ cells and can be inherited by offspring. An individual with a normal phenotype can have germline mosaicism, when a proportion of their germ cells contain a certain mutation. The result of germline mosaicism can be recurrence of an autosomal dominant condition in siblings of unaffected parents.
Single-gene disorders usually display characteristic inheritance patterns. The inheritance pattern of a particular genetic condition can often be identified through the creation of a pedigree with at least three generations of a family. Inheritance is dictated by whether the disease phenotype is dominant (i.e., a mutation of only one allele causes a disease phenotype), or recessive (i.e., both alleles must have a mutation for the disease phenotype to appear). The location of the genetic change also dictates inheritance. For example, a mutation can occur on an autosome or a sex chromosome. So, inheritance can be autosomal (dominant or recessive) or X-linked (dominant or recessive).
Autosomal dominant inheritance occurs when the genetic change is located on an autosome and the phenotype is expressed due to one allele having a mutation. An example of a condition with autosomal dominant inheritance is neurofibromatosis type 1. Each child of an affected parent has a 50% chance of inheriting the allele with the mutation and, therefore, also being affected.
Autosomal recessive inheritance occurs when the genetic change is located on an autosome and the phenotype is expressed due to both alleles having a mutation. An example of a condition with autosomal recessive inheritance is cystic fibrosis. Heterozygotes are carriers and do not have a disease phenotype. However, when two carriers have children together, there is a 25% chance that each fetus will inherit both mutated alleles and be affected. There is a 50% chance that each fetus will be a carrier (i.e., have one mutated allele), and a 25% chance that each fetus will inherit two normal alleles.
X-linked recessive inheritance occurs when the genetic change is located on the X chromosome and the phenotype is expressed due to both alleles having a mutation. An example of a condition with X-linked recessive inheritance is red-green color blindness. Since males only have one X chromosome, they are affected if their one X chromosome has the genetic change. Females, on the other hand, require two mutated alleles to be affected. A pedigree of a family with an X-linked recessive condition will show mostly affected males. Females with one copy of the genetic change have normal red-green color vision. Sons of female carriers have a 50% chance of being affected. Daughters of female carriers have a 50% chance of being carriers. Sons of affected males will not be affected, as they do not receive an X chromosome from their father. All daughters of an affected male will be carriers. Homozygous affected females are uncommon but can result from parents who are an affected father and a carrier heterozygous mother (50% probability) or an affected homozygous mother (100% probability).
X-linked dominant inheritance occurs when the genetic change is located on the X chromosome and the phenotype is expressed due to one allele having a mutation. An example of a condition with this type of inheritance is X-linked dominant Charcot-Marie-Tooth disease (a neuropathy of sensory and motor nerves). Individuals with this form of the disease can be male or female. All children of affected females have a 50% chance of also being affected. Daughters of affected males will all be affected, as they all inherit their fatherís X chromosome. Sons of affected males will not be affected, as they do not receive an X chromosome from their father. A pedigree will not show any male-to-male transmission of the disease.
In classic autosomal and X-linked recessive and dominant inheritance, a few generalizations often hold true. Enzyme deficiencies (e.g., Tay-Sachs disease; hexosamidase A deficiency)are almost always recessive, usually autosomal, but sometimes X-linked [e.g., glucose-6-phosphate dehydrogenase (G6PD) deficiency of red blood cells] because the heterozygous state with one normal allele generally results in sufficient enzyme activity to avoid the disease state. Coagulation factor deficiencies behave similarly because 50% factor activity is sufficient to prevent coagulopathy (Hemophilia A and B are both X-linked recessive). Lethal disease states that result in death before reproductive age are almost always recessive because if the condition was dominant, the allele would never be passed on and it would not exist in the gene pool. This is not 100% true since some dominant lethal conditions result from new mutations. Note that cystic fibrosis is inherited in an autosomal recessive fashion. While CF patients will survive into adulthood, this a contemporary result of medical advances. Without medical treatment, patients with CF died in childhood. The same is true of hemophilia. Disease states due to faulty structural genes are often inherited in an autosomal dominant pattern. The analogy is that if there are two alleles and one is making defective structural components, while the other is making normal structural components, the resulting structure containing both components will not be strong enough. Dominant inheritance classically shows vertical transmission in which one of the parents of an affected child will also have the disease state. Recessive inheritance lacks vertical transmission, but siblings are often affected (horizontal transmission). Osteogenesis imperfecta has many forms with different inheritance patterns. One severe form is autosomal recessive resulting in severe osteopenia and death during infancy due to chest deformities and respiratory failure. A milder autosomal dominant form is more occult and will often have a positive family history of frequent fractures in one of the parents.
There are no Y-linked diseases because the only functional gene on the Y chromosome is the determinant for testes. If this gene is mutated, then the person is infertile and hence, no inheritance is possible. In terms of X-linked recessive inheritance, the heterozygous female usually does not express the full phenotypic change because of the normal paired allele on the other X chromosome. However, because of random inactivation of one of the X chromosomes in females (a phenomenon known as Lyonization), there is a possibility for the normal allele to be inactivated in most cells, thereby permitting full phenotypic expression. (e.g., G6PD deficiency of red blood cells).
The inheritance of genetic information is not limited to the nuclear DNA. Mitochondria have their own genome that codes for the synthesis of certain proteins. Each mitochondrion contains hundreds to thousands of copies of the mitochondrial genome. The inheritance of this genetic material is termed mitochondrial inheritance. An example of a condition with mitochondrial inheritance is Leigh syndrome. This inheritance is maternal, since offspring receive their entire mitochondrial DNA from the oocyte. Accordingly, all offspring of a female with a change in her mitochondrial genome will inherit the change, while no offspring of a male with a change in his mitochondrial genome will inherit the change.
While the majority of single-gene disorders follow one of the typical patterns of inheritance mentioned above, there are exceptions. One exception, known as imprinting, is an example of epigenetics, which refers to inherited changes in gene expression without DNA sequence changes. Imprinting is a type of influence on gene expression, depending on whether the gene is transmitted from the father or the mother. Some genes or chromosomal regions are "labeled" (via methylation of the DNA) as maternal or paternal, and functionally silenced even before fertilization occurs, and remain labeled (with altered gene expression, e.g., being silenced) in a new embryo. For example, a mother may transmit a gene to her offspring, the expression of which depends on whether or not the DNA is methylated. The DNA itself has not changed or experienced a mutation, but methylation can cause the DNA to become inactive and the gene is not expressed (silenced). Perhaps the most well known example of imprinting involves two genetic conditions: Angelman syndrome and Prader-Willi syndrome. Both conditions occur due to changes in the chromosome 15q11-15q13 region, but the chromosome in which these changes occur (i.e., the chromosome inherited from the mother versus the chromosome inherited from the father) determines which phenotype is expressed. If there is a deletion in the 15q11-15q13 region in the maternally inherited chromosome, the individual only has genetic information from this region from his father (which has been methylated), and has a diagnosis of Angelman syndrome. If there is a deletion in the 15q11-15q13 region in the paternally inherited chromosome, the individual only has genetic information from this region from his mother (which has been methylated), and has a diagnosis of Prader-Willi syndrome. This example shows the importance of correct "labeling", or imprinting, as it relates to the expression of genetic material.
Multifactorial or complex conditions are caused by gene-gene and/or gene-environment interactions. These conditions affect over 60% of the population. Variations in several genes, with or without environmental factors, can result in or predispose an individual to a disorder or congenital abnormality. One example is late-onset Alzheimer disease (AD). Individuals who are homozygous for the e4 allele in the APOE (apolipoprotein E) gene on chromosome 19 are at an increased risk for developing AD earlier. However, some individuals homozygous for the e4 allele never develop AD, implying that there are other genetic and/or environmental factors contributing to the onset of disease. Another example of a complex condition is cleft lip with or without cleft palate. Offspring of individuals who are severely affected have a greater recurrence risk than offspring of individuals who are mildly affected, indicating that those with severe disease have a greater load of alleles that predispose to the malformation.
Individuals with the same genotype can have different phenotypic presentations. Variable expressivity refers to individuals with the same genotype but varying degrees of disease severity. For example, two family members with the same mutation in the NF1 (neurofibromin 1) gene (the gene that causes neurofibromatosis type 1) have a diagnosis of neurofibromatosis type 1, but they may experience signs and symptoms of the disease differently. One relative may have more severe disease (e.g., plexiform neurofibromas, severe tibial dysplasia) while another relative with the same mutation may have milder disease (e.g., uncomplicated neurofibromas and mild tibial dysplasia).
It is important to distinguish variable expression from the concept of penetrance, or the probability that an individual with a particular genotype will display any signs and/or symptoms associated with that genotype. If any signs and/or symptoms are present in an individual, this is considered "complete penetrance". If an individual with the genotype has no signs and/or symptoms, they are considered "non-penetrant". The proportion of individuals showing symptoms can sometimes be estimated based on pedigree analysis or published literature. For example, some people with an inherited mutation in the BRCA1 gene (a tumor supression gene that helps repair damaged DNA and when mutated or altered, DNA damage may not be repaired properly resulting in a higher risk of female breast and ovarian cancer) will develop breast cancer, while others will not. In fact, the chance that a woman with a BRCA1 mutation will develop breast cancer by age 70 years is about 65%. Thus, mutations in BRCA1 show reduced penetrance (less than complete penetrance).
A third way in which a difference in phenotype can be seen is called pleiotropy, or the phenotypic presentation of seemingly unrelated signs and/or symptoms (i.e., more than one effect of a mutated gene). For example, one individual with cystic fibrosis may experience lung involvement and pancreatic insufficiency, while another individual with cystic fibrosis may experience congenital absence of the vas deferens. Since there are many different mutations in the CFTR gene that cause cystic fibrosis, if both parents are carriers of different CF alleles that have different phenotypic expressions, pleiotropy further complicates the prognostic probabilities. Sometimes certain mutations within a given gene are associated with a specific phenotype, called genotype-phenotype correlation. Another good example is the RET proto-oncogene in which certain mutations are associated with the phenotype of multiple endocrine neoplasia (MEN) type 2B, while others have MEN type 2A or only medullary thyroid carcinoma.
Another important concept in the diagnosis of genetic conditions is heterogeneity. This applies when a given phenotype has more than one genetic cause. Hypertrophic cardiomyopathy is a good example of this. This phenotype can be caused by mutation in one of at least 14 different genes.
An understanding of the basic genetics principles, including inheritance patterns and factors that affect gene expression, is essential to recognizing and managing genetic conditions. Eliciting a three-generation pedigree will aid the healthcare provider in recognizing inheritance patterns and assess recurrence risks for the family.
1. In the case described, identify the inheritance pattern. Given that the proband (the person who initiates medical attention for a genetic disorder) is not affected, what is the chance that she is a carrier of a CFTR mutation?
2. What is the most common translocation in humans and why is this considered a balanced translocation?
3. In the case described, what is the probability of this womanís future children being affected, and explain how you would counsel the couple if they ask about an affected fetusí prognosis.
4. Why would it be important, when eliciting a family history, to determine the gender of those in a pedigree?
5. Using G6PD deficiency as an example of X-linked inheritance, how would it be possible for the son of an affected male to have G6PD deficiency?
6. A woman with an identified BRCA1 mutation (high risk for breast cancer) is considering a prophylactic double mastectomy. Why is it important to include a discussion about penetrance in your genetic counseling of this patient?
7. Name the type of genomic change exemplified by trisomy 21 and describe how this most often occurs.
8. List two other ways in which trisomy 21 can occur.
9. Name one striking feature of a pedigree of a family with a maternally inherited mitochondrial condition.
1. Nussbaum R, McInnes RR, Willard HF (eds). Thompson & Thompson Genetics in Medicine, 8th Edition. 2015. Elsevier, Philadelphia, PA.
2. Bull MJ and the Committee on Genetics. Health Supervision for Children with Down Syndrome. Pediatrics. 2011;128;393-406.
4. Pauli RM. (Updated: February 16, 2012). Achondroplasia. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
5. Trotter T and Hall J. Health Supervision for Children with Achondroplasia. Pediatrics. 2005;116:771-783.
6. Friedman JM. (Updated: May 3, 2012). Neurofibromatosis 1. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
7. Petrucelli N, Daly MB, and Feldman GL. (Updated: January 20, 2011). BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
8. Moskowitz SM, Chmiel JF, Sternen DL, Cheng E, and Cutting GR. (Updated: February 19, 2008). CFTR-Related Disorders. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
9. Bird TD. (Updated: March 28, 2013). Charcot-Marie-Tooth Neuropathy. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
10. Deeb SS and Motulsky AG. (Updated: September 29, 2011). Red-Green Color Vision Defects. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
11. DiMauro S and Hirano M. (Updated: May 3, 2011). Mitochondrial DNA Deletion Syndromes. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
12. Dagli AI and Williams CA. (Updated: June 16, 2011). Angelman Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
13. Driscoll DJ, Miller JL, Schwartz S, and Cassidy SB. (Updated: October 11, 2012). Prader-Willi Syndrome. In: GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed 4/5/2013.
Answers to questions
1. The inheritance pattern of cystic fibrosis is autosomal recessive. The chance that the proband is a carrier of a CFTR mutation is 67%. An unaffected sibling of an individual with an autosomal recessive disorder has 2/3 chance of being a carrier (there are only three possibilities left once we know they are not affected).
2. The most common translocation in humans is the chromosome 13 and 14 Robertsonian translocation (occurs in 1 out of 1300 people). This is considered balanced because a normal aount of genetic material is present and the individuals who carry this translocation have a normal phenotype.
3. If the woman and her husband are both carriers of a CFTR mutation, there will be a 25% chance that their offspring will be affected with cystic fibrosis. If they ask about prognosis in an affected child, genetic counseling should include a discussion of pleiotropy. The phenotypic presentation of the future child will depend upon the mutations inherited from his mother and father, and may not be the same phenotype as seen in his maternal uncle. There is genotype-phenotype correlation for many CFTR mutations.
4. It is important to identify the gender of those in a pedigree because this will help to identify the inheritance pattern. Families with X-linked conditions will show more males with disease phenotype and will generally not show male-to-male transmission.
5. His mother is a carrier (heterozygous) or affected with G6PD deficiency (homozygous). His mother passes an affected X chromosome to her son.
6. It is important to discuss penetrance when providing genetic counseling to a woman with a BRCA1 mutation who is considering a double prophylactic mastectomy because her risk of developing breast cancer is not 100%. She may want to consider other options, such as increased surveillance frequency or breast MRIs, given that she may not develop breast cancer. Even though she has a mutation in her BRCA1 gene, there is reduced penetrance of the breast cancer phenotype.
7. Trisomy 21 is an example of aneuploidy. This most often occurs due to nondisjunction (the failure of two chromosomes within a chromosome pair to separate from each other) during maternal meiosis I.
8. Two other ways in which trisomy 21 can occur include (1) a Robertsonian translocation between chromosome 21 and another acrocentric chromosome, or (2) mosaic trisomy 21, in which a population of the total cells in an individual have an extra chromosome 21, due to a post-fertilization error in DNA replication.
9. One striking feature of a pedigree of a family with a mitochondrial condition would be only maternal inheritance with both genders affected.