Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter IV.7. Basic Genetic Principles
Bryan O. King, MS
November 2002

Return to Table of Contents

Dr. G, the pediatric chief resident, rushes to the delivery room to assist with a resuscitation being attended by a first year resident and a medical student. The newborn has low Apgar scores and is not breathing well. Endotracheal intubation and ventilation results in improvement. The newborn is transferred to the NICU. A chest X-ray demonstrates severe demineralization of all the bones and multiple rib fractures. A skeletal survey demonstrates severe osteopenia and multiple fractures with crumpling of the long bones. Osteogenesis imperfecta (OI) is diagnosed. This infant dies at about one month of age due to respiratory failure. There is no family history of previous neonatal deaths or bone problems.

On the pediatric floor, there is a teenager with "osteogenesis imperfecta" who has sustained a tibia fracture. The father, aunt and two uncles of this patient also have OI. The house staff and medical students ask Dr. G to explain why one case of OI can be so severe, while another case can be relatively mild. Also, why does one case have a negative family history, while the other case has a positive family history? A second year resident mentions that this is similar to muscular dystrophy in which some cases are very severe (with no family history) and other cases are milder with a teen or adult onset (and sometimes with a positive family history).

A significant proportion of human illnesses have a genetic basis. The topic of genetic diseases is therefore broad and encompasses both inherited diseases as well as somatic diseases caused by spontaneous mutations. This chapter covers the mechanisms of gene and chromosome mutation and their relevance to both inherited and somatic diseases. Mendelian genetics and chromosome disorders associated with a variety of clinical conditions will also be reviewed.

Genetic mutations occur anytime there is a permanent change in the primary nucleotide DNA sequence. Mutations can be lethal, deleterious, or confer an evolutionary advantage. Genes and chromosomes can mutate in either somatic or germinal tissue. Somatic mutations can occur during embryogenesis or in dividing somatic tissue. A single somatic cell that mutates will be the progenitor for a clonal population of cells known as the mutant sector. This "patch" of developing mutant cells tends to stay close together and is phenotypically distinct from the surrounding population of normal somatic cells. If the mutation is compatible with cell survival, phenotypic variations can be visualized such as the pigmented lesions seen in McCune-Albright Syndrome. Somatic mutations are often associated with cancer because they can offer growth advantages. Cancer mutations occur in a special category of genes called proto-oncogenes, many of which regulate cell division. When mutated, such cells enter a state of uncontrolled division, forming a cluster of cells known as a tumor.

A germinal mutation occurs in germ cells which are specialized tissue that is set aside during development to form sex cells. If a mutant sex cell participates in fertilization, then the mutation will be passed on to the next generation. It is possible for mosaic germline mutations to occur in which case the mutation can be transmitted to some progeny but not others. This causes confusion when attempting to determine patterns of inheritance.

Mutations may be classified into three categories: genome, chromosome, and gene. Genome mutations involve the loss or gain of whole chromosomes, giving rise to monosomy or trisomy. These mutations are infrequently transmitted to the next generation because they are often incompatible with survival or at least result in reduced fertility. Thus, most monosomies and trisomies are the result of spontaneous events (new mutations). Chromosome mutations result from rearrangement of genetic material and result in structural changes to the chromosome (e.g., translocations, which will be discussed later). The most common type of mutations associated with hereditary diseases are gene mutations, the mechanisms of which will be briefly reviewed here.

Point mutations (single base substitutions) within coding sequences may alter the DNA in such a way that the new mutated sequence encodes a different amino acid. Because these mutations alter the meaning of the genetic code, they are called missense mutations. Sickle cell anemia is a classic example of a coding sequence point mutation which affects the beta-globin chain of hemoglobin. The nucleotide triplet CTC, which codes for glutamic acid, is changed to CAC, which codes for valine. This single amino acid substitution causes the formation of structurally abnormal hemoglobin resulting in a clinically significant hemoglobinopathy.

Point mutations can also change amino acid coding sequences into chain terminating stop sequences. Because these new stop sequences do not code for amino acids, they are known as nonsense mutations. An example of this occurrence again involves the beta-globin gene in a severe form of anemia known as beta-thalassemia. In this condition a point mutation affecting the codon for glutamine (CAG) creates a stop codon (UAG) leading to premature termination of beta-globin chain translation.

Mutations within noncoding sequences can also interfere with protein synthesis at various levels. Point mutations or deletions affecting promoter and enhancer sequences may suppress gene transcription. Such is the case in certain forms of hereditary hemolytic anemias. Lastly, deletions and insertions can cause frame-shift mutations unless the number of base pairs involved is three or a multiple of three.

All Mendelian disorders are the result of expressed mutations in single genes with a noticeable phenotypic effect. The number of these disorders is great with some estimates listing more than 5000 disorders. As the name implies, most of these conditions follow classic Mendelian patterns of inheritance. Although gene expression is usually described as dominant or recessive, in some cases, both of the alleles of a gene pair may be fully expressed in the heterozygote, a phenomenon known as codominance. Histocompatibility and blood group antigens are good examples of condominant inheritance.

In autosomal dominant (AD) disorders, if an affected heterozygous person marries an unaffected person, every child they have, carries a 50% chance of having the disease. AD disorders are generally compatible with survival until reproductive age since this is the only way that the mutation would be able to remain in the gene pool (i.e., if the condition were not compatible with reproduction, then the mutation would not be passed on). AD disorders are manifested in the heterozygous state so that at least one parent of an index case is usually affected (along with aunts/uncles on the affected parent's side of the family). However, every AD disorder has cases where neither parent is affected. In these cases, the disease is caused by new mutations of the egg or sperm. Also, the clinical features of a particular AD disorders can vary. For instance, some individuals inherit the mutant gene but are phenotypically normal. This is referred to as reduced penetrance, a termed that is expressed mathematically as the percentage of patients that phenotypically express their genotypic mutations. On the other hand, variable expressivity occurs when a trait is seen in all individuals carrying a mutant gene, but is expressed differently.

Autosomal dominant disorders usually do not involve diseases where there is a loss of function of an enzyme (i.e., enzyme deficiency states are almost never autosomal dominant). Because a 50% reduction of most enzymes can be compensated by the 50% that remain viable (i.e., the person is phenotypically normal), heterozygous enzyme mutations usually do not present with an autosomal dominant pattern of inheritance. Instead, autosomal dominant disorders usually affect non-enzyme proteins that can be divided into two categories.

The first involves proteins that are involved in the regulation of complex metabolic pathways that are subject to feedback inhibition (e.g., regulator genes). For example, patients with familial hypercholesterolemia carry a loss of function mutation in the gene encoding the LDL receptor. As a result, there is a loss of feedback control of plasma cholesterol levels due to the fact that the liver is less capable of clearing circulating plasma LDL. Additionally, a reduction of LDL receptors on the liver reduces LDL entry into the liver which disrupts the negative feedback regulation of hepatic cholesterol synthesis. As a consequence of these receptor abnormalities, cholesterol levels are elevated and induce premature atherosclerosis resulting in increased risk of heart disease.

The second type of non-enzyme proteins that are affected by autosomal dominant disorders are certain structural proteins. The detrimental effects of reducing levels of a structural protein by 50% become clearer when considering that the abnormal products from a mutant allele can interfere with the assembly of a functionally normal multimeric complex. For example, the collagen molecule is a trimer in which the three collagen chains are arranged in a helical configuration. Each of the three collagen chains in the helix must be normal in order to produce a stable collagen molecule. Even a single mutant collagen chain disrupts the integrity of the trimeric complex. The effects of these autosomal dominant structural protein disorders are seen in conditions such as osteogenesis imperfecta (occult types), Marfan syndrome, and Ehlers-Danlos syndrome. A simplistic way of looking at this is to consider structural protein mutations like a wall of bricks composed of 50% normal bricks and 50% defective bricks (from the abnormal allele). Such a wall is likely to be very weak and eventually collapse.

Disease states with an autosomal recessive inheritance pattern comprise the largest category of Mendelian disorders. Most of these disorders are enzyme or protein factor deficiency states (e.g., hexose amidase deficiency, factor 10 deficiency). Because autosomal recessive disorders require that both parents have the mutant allele, such disorders are characterized by the following features: 1) the trait does not usually affect the parents, but siblings may show the disease, and 2) siblings have one chance in four of being affected with a recurrence risk of 25% for each subsequent birth.

In contrast to autosomal dominant disorders, the following features generally apply to autosomal recessive disorders: 1) The expression of the defect tends to be more uniform than in autosomal dominant disorders. 2) Complete penetrance is common. 3) Onset is frequently early in life. 4) Many autosomal recessive conditions result in defective non-functional enzymes (i.e., loss of enzyme function). 5) Autosomal recessive disorders include almost all inborn errors of metabolism. 6) Many of these disorders are incompatible with life.

All sex-linked disorders are X-linked, and most are X-linked recessive. 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 remote possibility for the normal allele to be inactivated in most cells, thereby permitting full phenotypic expression. (e.g., G6PD deficiency). An enzyme deficiency such as RBC G6PD deficiency is compatible with a relatively normal life span. Therefore, an affected male may pass on the abnormal X allele to his daughter, who may also receive an abnormal X allele from her unaffected heterozygous mother. Thus, this is another mechanism that a female could be affected by an X-linked recessive disorder. This is not possible if the affected condition is incompatible with survival to reproductive age.

There are only a few X-linked dominant conditions. They are caused by dominant disease alleles on the X chromosome. These disorders are transmitted by an affected heterozygous female to half her sons and half her daughters and by an affected male parent to all his daughters but none of his sons. Vitamin D-resistant rickets is an example of this type of inheritance.

The aberrations underlying chromosome disorders may take the form of an abnormal number of chromosomes or alterations in the structure of one or more chromosomes. In humans, the normal complement of chromosomes in a haploid cell is 23. A cell with any multiple of the haploid number is called euploid. Aneuploidy refers to conditions where errors occur during meiosis or mitosis that result in the formation of cells with a set of chromosomes that are not a haploid multiple. The most common causes of aneuploidy are nondisjunction and anaphase lag.

Nondisjunction occurs when homologous chromosomes fail to separate during meiosis I or when sister chromatids fail to separate during meiosis II. During gametogenesis, the consequence of nondisjunction during either meiosis I or II is that gametes formed have either an extra chromosome (n+1) or one less chromosome (n-1). Subsequently, fertilization of such gametes by normal gametes yields a trisomic zygote (2n+1) or a monosomic zygote (2n-1) respectively. In anaphase lag, one homologous chromosome in meiosis or one chromatid in mitosis lags behind, is left out of the cell nucleus and eventually undergoes degeneration. Anaphase lag is similar to nondisjunction except that the chromosome or chromatid gets lost, so that one daughter cell has the right number of chromosomes and one daughter cell has one less than normal. This can occur in either of the gametes before fertilization or in the zygote. In the former case, fertilization with a normal gamete will form a zygote with one less chromosome yielding a true monosomic zygote. In the latter case, if anaphase lag occurs after the zygote has already formed, a mosaic, composed of normal cells and monosomic cells, is produced.

Monosomy or trisomy involving sex chromosomes (XXY syndrome, Turner syndrome, Klinefelter syndrome, Multi-X females) are compatible with life and are usually associated with a range of severity of phenotypic abnormalities. Autosomal monosomy generally involves the loss of too much genetic information to permit live birth or even embryogenesis. Conversely, a number of autosomal trisomies do permit survival such as Down syndrome (trisomy 21). With the exception of trisomy 21, all other trisomies yield severely handicapped infants that usually die at an early age.

Mosaicism is a condition characterized by the formation of aneuploid cells that arises when mitotic errors in early development give rise to two or more distinct populations of cells in the same individual. These errors usually occur during the cleavage of the fertilized ovum or in somatic cells. Mosaicism affecting the sex chromosomes is relatively common. For example, in a dividing fertilized ovum, a mitotic error may lead to one of the daughter cells receiving three sex chromosome while another receives only one and can be represented as a 45,X/47,XXX mosaic. All descendent cells from these two precursor cells will accordingly have either a 47,XXX or a 45,X makeup. Depending on the percentage of 45,X cells, this person can potentially further develop to become a mosaic variant of Turner syndrome. Autosomal mosaicism, on the other hand, appears much less commonly than sex chromosome mosaicism. An error during early mitosis that affects the autosomes usually forms a nonviable mosaic with autosomal monosomy. Trisomy 21 is an exception to this rule. Approximately 1% of Down syndrome patients are mosaics, usually having a mixture of cells with 46 and 47 chromosomes. This mosaicism results from mitotic nondisjunction of chromosome 21 during early embryogenesis. Symptoms in such cases are usually milder, depending on the proportion of abnormal trisomic cells.

A separate category of chromosomal aberrations is associated with changes in the structure of chromosomes. Such alterations occur spontaneously at a low rate that is increased by exposure to environmental mutagens. In addition, several rare autosomal recessive genetic disorders (Fanconi anemia, Bloom syndrome, ataxia-telangiectasia) are highly associated with chromosomal instability and are therefore known collectively as chromosome-breakage syndromes. Also, there is a significantly increased risk of cancers in all these conditions.

Common forms of alterations in chromosome structure include deletions, ring chromosomes, inversions, isochromosomes, and translocations. Deletions refer to loss of a portion of chromosome that may involve either the terminal or interstitial regions. A ring chromosome is produced when a deletion occurs at both ends of a chromosome with fusion of the damaged ends. This might be expressed as 46,XY,r(14). Inversion is a rearrangement that involves two breaks within a single chromosome with inverted reincorporation of the segment. An inversion of only one arm is known as pericentric while breaks on opposite side of the centromere are known a paracentric. Isochromosome formation results when one arm of a chromosome is lost and the remaining arm is duplicated, resulting in a chromosome consisting of only two short arms or of two long arms. In translocations, a segment of one chromosome is transferred to another. In one form, called balanced reciprocal translocation, there are single breaks in each of the two chromosomes, with exchange of material. For example, a balance reciprocal translocation between the long arm of chromosome 2 and the short arm of chromosome 5 would be written 46,XX,t(2;5)(q31;p14). Because there is no loss of genetic material, the individual is phenotypically normal. However, a balance translocation carrier is at increased risk for producing abnormal gametes. Subsequently, fertilization between a carrier and a normal person could lead to the formation of an unbalanced zygote, resulting in spontaneous abortion or birth of a malformed child.

Robertsonian translocations result when the two long arms of acrocentric chromosomes (those with the centromere very near to one end) fuse at the centromere, losing the two short arms, forming a single chromosome (with twice the genetic material), thus having a karyotype with only 45 chromosomes. Common Robertsonian translocations are confined to the acrocentric chromosomes 13, 14, 15, 21, and 22, because the short arms of these chromosomes contain no essential genetic material. Individuals with these translocations are phenotypically normal and carry 45 chromosomes in each of their cells. Their offspring, however, may either be normal and carry the fusion chromosome or they may inherit a missing or extra long arm of an acrocentric chromosome. About 4% of Down syndrome patients have 46 chromosomes, one of which is a Robertsonian translocation between 21q and the long arm of an acrocentric chromosome (usually chromosomes 14 or 22). The translocation chromosome replaces one of the normal acrocentrics but gains an additional chromosome 21 which yields a total of 46 chromosomes with trisomy 21. The karyotype of a Down syndrome patient with a Robertsonian translocation between chromosomes 14 and 21 is 46,XX or XY,rob(14,21),+21. Unlike trisomy 21 caused by nondisjunction, there is no relation between maternal age and the incidence of rob(14,21). However, there is a relatively high recurrence risk in families when the parent, especially the mother is a carrier of the translocation.

Lyonization (X chromosome inactivation): Females have two X chromosomes while males have only one. Thus, one might expect that females should have twice the level of X chromosome proteins and enzymes than males. Empirically, however, this does not happen. The levels are equal in men and women. The reason for this is that in the cells of a human female, one and only one X chromosome is active. The other X coils and condenses into a small ellipsoid structure that is called a Barr body and is functionally deactivated and the genes on that chromosome are not transcribed. The geneticist Mary Lyon hypothesized this almost 40 years ago, so the phenomenon is often called Lyonization. During the very early embryonic development of a female, both her maternal and paternal X chromosomes are active. After 12 days of development, when the embryo has about 5,000 cells, one of these chromosomes is randomly deactivated in all the cells. Once a chromosome is inactive in a given cell, all its daughter cells will have the same chromosome deactivated. That is, if "cell number 23" has the paternal X deactivated, then all descendants of cell 23 will also have the paternal X deactivated. The particular X chromosome deactivated in the original cell is random. Consequently, half of a female's cells will express her paternal X chromosome while the other half will express her maternal X. Thus, females are genetic mosaics.

The gene responsible for X chromosome inactivation, the XIST locus, has recently been localized to the long arm of the X, but the precise mechanism for achieving inactivation is not totally understood. Certain data suggest that the major reason for Lyonization is "dosage compensation"-making certain that the same levels of proteins and enzymes are expressed in males and females. Females with Turner's syndrome (only one X chromosome) do not have Barr bodies, females with three X chromosomes have two Barr bodies in each cell, and males with Klinefelter syndrome (two X chromosomes and one Y chromosome) have one Barr body. It appears that the process evolved to guarantee that one and only one X chromosome is active in any given cell. However, inactivation is not totally complete. A few loci of the chromosome comprising a Barr body remain active, most notably those loci homologous to the pseudoautosomal region of the Y chromosome. The fact that inactivation is incomplete is used to explain the phenotypic irregularities for Turner, XXX, and Klinefelter syndrome.

In summary, understanding some common genetic principles permits a better understanding of most genetic disorders. To summarize the case that was initially described, osteogenesis imperfecta (see chapter on connective tissue disorders) is the name given to a group of several different disorders. The severe infantile type is autosomal recessive (an enzyme deficiency) and incompatible with life. The milder adult type is autosomal dominant (a heterozygous structural protein mutation) and compatible with life beyond reproductive age. The autosomal dominant form will probably have a positive family history in one of the parents, and aunts/uncles on the affected parent's side of the family, while the autosomal recessive form will only have a positive family history in siblings. Similarly, Duchenne muscular dystrophy, which is severe, has an early onset, and is often incompatible with reaching reproductive age, is X-linked recessive due to deficiency of the dystrophin protein. Fascioscapulohumeral dystrophy, which is milder, has a later onset, and is compatible with life beyond reproductive age, is autosomal dominant. A positive family history in a parent, aunts, and uncles is likely to be present.


1. A genetic condition which is lethal in infancy is most likely to be:
. . . . . a. An X-linked structural protein.
. . . . . b. An autosomal recessive enzyme deficiency.
. . . . . c. An autosomal dominant enzyme deficiency.
. . . . . d. An autosomal dominant structural protein abnormality.

2. An enzyme deficiency condition can only be inherited in one of two ways:
. . . . . a. Autosomal dominant.
. . . . . b. Autosomal recessive.
. . . . . c. X-linked dominant.
. . . . . d. X-linked recessive.
. . . . . e. Spontaneous new mutation.

3. The cytologic mechanism(s) by which trisomy 21 (Down Syndrome) can occur include:
. . . . . a. Nondisjunction
. . . . . b. Robertsonian translocation
. . . . . c. Mosaicism
. . . . . d. Two of the above
. . . . . e. All of the above

4. If there is a family history of genetic disorders, knowing the gender of an unborn child can be important because:
. . . . . a. Male children are more likely to have autosomal defects show up in their phenotypes.
. . . . . b. Female children are more likely to have autosomal defects show up in their phenotypes
. . . . . c. Male children are more likely to have X-linked traits show up in their phenotype
. . . . . d. a and c

5. An exchange of fragments of chromatids between non-homologous chromosomes may occur during the first meiotic division. This chromosomal structural abnormality is called:
. . . . . a. Deletion
. . . . . b. Inversion
. . . . . c. Nondisjunction
. . . . . d. Segregation
. . . . . e. Translocation


1. Griffiths AJF. An Introduction to Genetic Analysis, 7th edition. 2000, New York: W.H. Freeman and Co.

2. Braunwald E. Harrison's Principles of Internal Medicine, 15th edition. 2001, New York: McGraw-Hill.




Answers to questions

1. b. An autosomal dominant condition which is lethal in infancy is not going to survive in the gene pool. Such conditions must be autosomal recessive to survive in the gene pool. Most autosomal recessive conditions are enzyme deficiencies. An X-linked enzyme deficiency is also a possible answer, but this is less likely and it is not one of the choices given.

2. b,d. Enzyme deficiencies must be homozygous for the condition to manifest, because a 50% reduction of the enzyme level is generally sufficient to carry out the biochemical reaction involved, such that no clinical disease results. The observed inheritance pattern is autosomal recessive. Enzymes on the X-chromosome such a RBC G6PD are not present on the Y-chromosome, so enzymes can also be inherited in an X-linked recessive fashion. An enzyme deficiency is not likely to manifest from a spontaneous new mutation, because it would have to coincidentally occur in both alleles for this to occur.

3. e. Trisomy 21 results from meiotic nondisjunction in about 95% of patients. About 4% have a Robertsonian translocation. A small percentage of patients are mosaic. An even rarer cause of trisomy 21 is the 21q21q translocation, a chromosome comprised of two chromosome 21 long arms. It is thought to originate as an isochromosome.

4. c. There is a far greater probability of males expressing recessive alleles in their phenotypes if they are carried on X chromosomes. For females to have such traits, they would have to inherit the recessive allele for them on both of their X chromosomes.

5. e. An exchange of fragments of chromatids between non-homologous chromosomes during the first meiotic division is termed a translocation.

Return to Table of Contents

University of Hawaii Department of Pediatrics Home Page