Monogenic diseases Genetic terminology used inheritance

By Live Dr - Sun Jan 11, 12:50 pm

1.  Genetic terminology used inheritance.

Monogenic disorders

Monogenic disorders/Single gene disorders,Which are due to one or more mutant alleles at a single locus, follow simple Mendelian inheritance


One of the variant forms of a gene at a particular locus, or location, on a homogenous cs. Different alleles produce variation in inherited characteristics such as hair color or blood type.


The variant forms of a gene at a particular locus, or location, on a homogenous cs. ,for example, A, a.

Multiple alleles

Any of a set of three or more alleles, only two of which can be present in a diploid organism.


This is the genetic constitution of an individual and is also used to refer to the alleles present at one locus.


This is the observed biochemical physiological or morphological characteristics of an individual that are determned by the genotype and the environment in which it is expressed.


These are chromosomes other than sex chromosomes.

Autosomal inheritance

This involves any chromosome other than the sex chromosomes.


Where a genetic lesion finds expression in some individuals,but not in others; penetrance is expressed as the proportion of individunls with the disease gene that have symptoms.

⑴lf a genetic lesion is completely penetrant(100%) all the individuals with that altered gene express it(e g.Huntington’s chorea).

⑵.About 75% Of women with certain mutationss in the BRCAl gene develop breanst or ovarian cancer(i.e. the mutations have a penetrance of 75%).

Variable expressivity

This occurs when a genetic lesion produces a range of  phenotypes:for example,tuberous sclerosis can be asymptomatic with harmless kidney cysts, but in the next generation may be fatal owing to  the presence of  brain malformations.


This is an individual or genotype with two different alleles at a given locus on a pair of homologous chromosomes.


This is an individual or genotype with identical alleles at a given locus on a pair of homologous chromosomes.

Pedigree Charts

These are used to illustrate inheritance(fig.3.1)

Mende1ian inheritamce

Mendelian inheritance follows specific pantterns, which determine risk to relatives.Single gene disorders,which are due to one or more mutant alleles at a single locus, follow simple mendelian inheritance.

2.  Symbols in pedigree

Pedigrees are diagrammatic representations of family structures. They provide a quick picture of the location of an affected individual within a larger kindred and/or of the spread of a problem (or any genetic trait or marker) through the kindred. Because pedigrees contain so much information, it is useful to use a common set of symbols to simplify studies and comparisons. The conventional symbols are shown in Figure 3-1. A given family is represented by a series of symbols, the oldest individual in a generation, or sibship, being on the left. By convention, males in an individual mating are on the left and females are on the right. Sometimes it is useful to simplify a kindred and present only an outline. This can be particularly helpful if one is tracing a long lineage and if all of the details are not known. The inclusion of a carefully assembled and drawn pedigree in a clinical note can communicate a great deal of information quickly. It also can be simpler than long verbal descriptions of the same relationships.

Figure 3-1

■ Symbols make the pedigree more complete and gives a better picture of the pattern of this condition.

■ The pedigree pattern may identify others who are at risk for a particular problem and who might benefit from further study.

Identifying other affected family members may provide information critical for establishing the diagnosis in a given individual.

■ Considering the manifestations of a given problem in some family members may help explain the prognosis for others.

■ Assembling large kindreds can be essential for performing linkage studies and other diagnostic testing.

3. Autosomal Dominant Conditions

3.1 Overview

A dominantly inherited condition is detectable in an individual who has only one altered gene of a pair. Such a person is called a “heterozygote.” Because having only a single aberrant copy of the gene is sufficient to develop a recognizable clinical phenotype, the transmission pattern of autosomal dominant conditions is very characteristic. The chance that any individual germ cell will contain the chromosome with the abnormal gene is obviously 50%, because there is a 50% chance of receiving either of the chromosomes of any autosomal pair. This means that the chance for an affected individual to transmit the abnormal gene is 50% with each conception. In general, the aberrant gene is detectable clinically in all individuals carrying it, and thus it is expected that an average of one-half of the offspring of an affected individual also will be affected. Two autosomal dominant pedigrees are shown in Figure 3.1. Certain conspicuous features can be derived from these patterns other aspects are important as well:

Careful questioning(inquest) may reveal multi-generational family histories of problems, establishing what has been termed the “vertical transmission pattern.”

■ The sexes arc involved equally, because there is no sex limitation for manifesting the aberrant gene (although some manifestations in males may differ from those in females).

■ Some individuals present with recognizable clinical pictures that reflect new mutations. Although there is no antecedent family history in these individuals, subsequent transmission of the trait will follow the predictable pattern, with a 50% chance of transmitting the trait with each conception. Often this idea of having new mutational events establish the potential for subsequent, predictable Mendelian transmission is difficult for families and individuals to understand.

■ Because dominant conditions are detectable in the presence of the normal allele of the responsible gene (on the unaffected chromosome), their physiologic bases often, but not always, are related to aberrant structural or developmental problems. Only a relatively small number of dominant conditions (acute intermittent porphyria being an excellent example) reflect enzymatic or metabolic blockades.

■ Dominant transmission includes the mechanism of so-called triplet repeat disorders. This relatively newly recognized phenomenon has added particularly valuable insight into certain neurologic disorders and what have been considered anomalous aspects of their transmission.

■ Dominant disorders often show “pleiotropy.” This means that multiple, overtly unconnected biologic and clinical changes may develop from a single mutation. Pleiotropic effects often involve multiple organ systems. With improved biochemical and physiologic understanding, such effects are found to be consistent with the biology of change.

■ The severity or prominence of a particular aspect of a dominant disorder may be unpredictable, despite the obvious presence of the mutation. This has been termed “variable expressivity.”

■ So-called dominant tumor syndromes provide clinical support for the Knudson hypothesis. Consideration of several dominantly inherited conditions will point out the operation of these individual principles.

3.2 AD pedigree characteristics

A dominant gene is phenotypically expressed in homozygotes and heterozygotes for that gene.

Each affected individual has one affected parent. Unaffected family members do not transmit the trait to their children.

50% of sibs are affected.  Males and females are affected with equal probability. The occurrence and transmission of the trait are not influenced by sex .

50% of offspring are affected. Any child of an affected person has a 50% risk of inheriting the trait.

Passed in a vertical fashion with no skipping.

Common autosomal dominant diseases are achondroplasia, Huntington’s disease,retinoblastoma and neurofibromatosis type 1.

Homozygotes for the trait are rare. in some AD conditions,new mutations account for a substantial proportion of cases(e.g.Huntington Disease,Marfan syndrome,etc.).AD genes can show.

3.3 Huntington Disease (HD)

A progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years after onset. Inherited in an autosomal dominant manner. Offspring of an individual with a mutant allele have a 50% chance of inheriting the disease-causing allele.


3.4 Marfan syndrome

Individuals with Marfan syndrome (OMIM # 154700) show many of the characteristic features of dominant inheritance discussed earlier. Pleiotropism is notable, with multiple system involvement. Variable expressivity is prominent, with different degrees of clinical change in different individuals. The remarkable variation of features in individuals with Marfan syndrome was very difficult to rationalize until molecular studies provided an understanding of the underlying genetic changes.

Marfan syndrome is characterized by changes in growth of bones and supporting tissues. Excessive height is prominent(US/LS=upper strength/lower strength(ratio of growth). The growth of long bones and the long, slender, gracile fingers and toes lead to arachnodactyly. The long fingers permit overlapping of the thumb and fifth finger around the circumference of the opposite wrist, the so-called wrist sign, or Walker-Murdoch sign. The length of the thumb also often permits it to protrude from the clenched hand, the so-called thumb sign, also called the “Steinberg thumb sign”. Bone growth also can be associated with torsion in the spine and the development of scoliosis. Usually detected during childhood and worsening during adolescent growth, scoliosis is an important complication that needs pros- pective management. In addition to increased bone length, laxity of joints and supporting tissues can be prominent, leading to joint instability, dislocations, and weakness, particularly in joints involved with weight bearing, such as the ankle.

Another area of complications in Marfan syndrome is the eye, where laxity of the zonular fibers supporting the lens leads to spontaneous lens dislocation, or “ectopia lentis.”. The fiber laxity and consequent lens mobility lead to iridodonesis, a waving motion of the iris upon movement of the eye that often can be appreciated with the hand-held ophthalmoscope. The ocular dimensions also can change, leading to a longer globe measured from front to back. This puts excessive tension on the retina and establishes the potential for retinal detachment.

The most life-threatening features for many individuals with Marfan syndrome are related to blood vessels. Here, the laxity of supporting tissues leads to progressive dilation of the aorta. This is most prominent at the proximal aorta just above the aortic valve and produces a characteristic series of changes progressing from valvular regurgitation through aneurysm formation to dissection. Other valves also may be involved in Marfan syndrome. Mitral valve prolapse is common. Aortic aneurysms also develop beyond the proximal aorta and may even appear in the abdomen.

On first glimpse, these three areas of change-bones and supporting tissues, eyes, and large blood vessels and heart valves-appear to have relatively little relation to one another. Yet they clearly are different manifestations of the same genetic problem, characteristic of pleiotropy.

In addition, variable expressivity may lead to different degrees of prominence in different individuals. This perplexing situation is sometimes manifested within extended kindreds. For instance, a father may have blindness but no aortic difficulties at all, while a son has serious scoliosis and a daughter has aortic regurgitation, although both children have relatively normal vision. While the identical gene mutation is present in all three individuals, the expressivity differs considerably.

Another reason for differences in manifestations between kindreds comes from the broad spectrum of genetic abnormalities that underlie the syndrome. These genetic changes occur in the gene for the protein fibrillin, which is found on chromosome 15. The spectrum of mutations is remarkable, ranging from various point mutations to deletions and truncations of the encoded protein. The changes in fibrillin are important to consider from the pathophysiologic perspective. Clearly, one allele of the gene remains intact and is presumably responsible for producing normal fibrillin protein. Fibrillin, a 350-kDa glycoprotein, is a structural component of microfibrillar fibers, threadlike filaments that serve as scaffolding during elastin deposition. Because a fibrillin molecule interacts with other copies of the same molecule during elastogenesis, the notion has developed that the presence of both normal and abnormal proteins causes changes in the integrity, length, and/or physical properties of elastin in supporting tissues. There is no consistent way to predict what the consequences of any of these changes will be, however, and this obviously contributes to at least some of the clinical variation. What is consistent is that fibrillin is involved in forming elastin-containing tissues in the eye, in the aortic wall and heart valves, and in tendons and joints. All of these areas are at risk for change in individuals with Marfan syndrome.

In the clinic, individuals with Marfan syndrome must be treated prospectively, and many management techniques have been developed for individual complications. Joint laxity may be approached both with strengthening exercises and with bracing. Obviously, scoliosis can be managed through bracing, which is best begun early to minimize the need for surgery (while recognizing that it still may be required in certain cases). Ectopia lentis is helped by removing the ectopic lens and making appropriate optical corrections. Early ophthalmologic evaluation also is useful to detect and manage retinal detachment.

New approaches to managing cardiovascular complications in Marfan syndrome patients have been developed. Formerly, there was an important risk of lethal aortic dissection, but this has been reduced by preventive strategies and new surgical techniques. The echocardiogram provides noninvasive measurements of aortic valve function and aortic root dimensions. Additional and more detailed information can be obtained through magnetic resonance imaging. Combined with clinical follow-up observations, these noninvasive approaches permit detection of aortic enlargement as it occurs and before it threatens dissection. While measuring aortic and valvular changes is important, efforts to prevent or minimize these changes also have been studied. The most effective of these is the use of β-blocking drugs. The rationale of this approach is that reducing the contractile force of the left ventricle minimizes the stress on the aortic valve and proximal aorta. β -Blockade can slow the progression of aortic root enlargement and delay the need for surgical repair. This treatment is well tolerated and provides a physiologically rational approach to minimizing the consequences of the underlying tissue defect. Reliable surgical intervention to replace the aortic valve and proximal aorta has been developed. The approach recognizes the abnormal properties of the tissue and thus differs from similar repairs performed in individuals without Marfan syndrome. Because of the connective tissue laxity, it is important to minimize a situation in which the result depends on a single suture line connecting the prosthesis to the aortic tissue of the host. This approach makes the insertion of a prosthesis combining both valve and proximal aorta into the existing aorta of the individual. It maintains the linear integrity (such as it is) of the patient’s own aortic wall, permitting longitudinal strengthening of the wall, preventing further dilation, and solving the problem of valvular regurgitation. Aortic surgery for individuals with Marfan syndrome can be offered prophylactically-before aortic enlargement reaches dangerous dimensions. This, combined with the use of β-blockade, has been an important advance in the long-term care of these individuals. Because the mitral valve also is involved frequently, Marfan syndrome patients may need multiple valve replacements.

Women with Marfan syndrome present important considerations during pregnancy and delivery. The increased blood volume that normally develops during pregnancy places the mother at risk for aortic dissection, particularly in the immediate postpartum period. Fortunately, the use of β-blockade and noninvasive measurement of aortic dimensions and valve function have minimized maternal complications.

The pleiotropic manifestations of fibrillin defects make individuals with Marfan syndrome remarkably complex in their presentation. Managing the various clinical problems requires coordinating different medical specialties. In addition, there currently is no way to predict all potential manifestations reliably. Also, it is not currently possible to relate specific fibrillin gene changes to specific clinical manifestations.

However, even within kindreds, where the mutation is necessarily the same, both the pleiotropy and the variable expressivity are puzzling and challenging. Individuals with Marfan syndrome thus present a remarkable contrast to those with achondroplasia in regard to both clinical and underlying gene changes. They also present a contrast to individuals with VRNF, in whom, although the gene changes vary widely, the problems generally remain confined to supporting tissues of the nervous system. Thus, the clinical consequences of individual mutations cannot be separated from the underlying physiologic function(s) of the genes and gene products involved.

US/LS=upper strength/lower strength(ratio of growth)

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