X-Linked Inheritance More males than females show the recessive phenotype,but only males in some pedigrees

By Live Dr - Sun Jan 11, 12:53 pm

5. X-Linked Inheritance


Disorders due to abnormalities on the X-chromosome follow a characteristic clinical pattern due to the biology of this chromosome. The clinical manifestations are notable for their obligate expression in males (who have only a single X-chromosome and hence must express the genes on that chromosome). In females, the Lyon hypothesis predicts random inactivation of one of the X-chromosomes early in embryonic development. The lineage of each of the embryonic cells retains this X-inactivation pattern. Because the inactivation is initially random, females become mosaic in terms of which X-chromosome is expressed in which cell. This mosaicism means that the effect of a mutant allele on a single X-chromosome may be minimally detectable, not apparent at all, or obvious, depending on whether the X-chromosome carrying the mutant allele has been inactivated in the organ or organ system in which that gene is normally expressed. Obviously, the degree of involvement in females may be subtle and detectable only with detailed testing. This is important in terms of the general pattern of transmission of X-linked disorders.

Genes located on the  X chromosome are said to be X-linked, where as genes on the Y chromosome are said to be Y-linked. Males are hemizygous(only have one chromosome) for the x chromosome.For X-linked recessive genes the inheritance pattern(fig.6.4) is as follows:

X-linked recessive (XR)inheritance,

X-linked dominant (XD)inheritance,

Y-linked inheritance.

5.1  XR pedigree characteristics

⑴More males than females show the recessive phenotype,but only males in some pedigrees

⑵The disease is transmitted by a carrier  female, who is usually asymptomatic.

⑶If a mother is a carrier her sons have a 50% chance of being affected and her daughters a 50% chance  of being carriers.

⑷An affected male will usua11y have no affected offspring, but all the daughters will be carriers and,in turn,50% of their sons wi11 be affected.

⑸No sons of the affected male wi11 inherit the gene (i.e.there is no male-to-male transmission).Affected males may have unaffected parents but wi11 often have an affected maternal uncle or cousin.

Common XR diseases are Duchenne muscular dysfrophy and haemophilia A.

About 35% Of mutations in lethal X-linked recessive conditions are new. Women can be affected with X-linked recessive conditions if an affected male mate with a carrier female,if there is lyonization(inactivation) of a normal X chromosome in a skewed pattern,if there is X Chromosome autosome translocation,or if XO Turner’s syndrome) is present.

Figure 3.20

Figure 3.20 shows two pedigrees characteristic of X-linked inheritance.

Note that the symbol for a carrier female is the presence of a large dot within the circle. As before, affected males are marked by solid squares.

Several important observations are obvious:

■ Females are not affected as severely as males and, thus, may be considered normal on initial clinical encounters.

■ An affected male cannot transmit the trait to his sons, because the trait is on the X-chromosome, and the father must necessarily transmit his Y-chromosome to a son.

■ All of the daughters of an affected male must be carriers, because the only X-chromosome that the father can give to a daughter contains the mutation.

These features, which are direct consequences of the biology of the X-chromosome, impart a pattern to these pedigrees that some have called “diagonal.” This is because the affected males have only carrier daughters and unaffected sons. These sons are not at risk for further transmission of the mutant allele. The carrier daughters, however, are at 50% risk for having an affected son or a carrier daughter. Obviously, because carrier females may go undetected, many generations can pass with clinically silent transmission through females until an affected male appears. Testing then may demonstrate a pervasive(=to spread throughout) picture, of female carriers and significantly alter the known recurrence risks for other members of the kindred.

Unlike the situation seen in recessive conditions, the phenotype frequency in males equals the frequency of the mutant allele. This follows from the facts that in a two-allele system the mutant allele must be either present or absent, and, if present, it will be expressed.

The X-chromosome has been particularly well studied in many organisms. Because there is little opportunity for meiotic exchanges between the X- and Y-chromosomes (although a small amount of recombination can occur in isolated regions), the genes on the X-chromosome have been remarkably preserved in evolution. (This phenomenon has been called “Ohno’s law.”) This means that the complement of genes on the X-chromosome and much of their organization is similar in humans and other mammals, presenting many opportunities for comparative genetic, metabolic, and therapeutic studies.


Hemophilia A (OMIM # 306700) is a disorder of blood coagulation due to absence or abnormality of factor Ⅷ in the clotting cascade. It is one of the best-known X-linked conditions and has gained considerable notoriety.

The gene for factor Ⅷ is quite large and is located on the distal part of the large arm of the X-chromosome. Many mutations have been characterized in this gene, helping to explain the variations in clinical severity and in the presentations encountered in individuals with hemophilia A. The typical picture in hemophilia A is an otherwise healthy boy or young man with a history of either spontaneous hemorrhage or continued bleeding after minimal trauma. This bleeding may be into soft tissue, such as muscle, or it may be into joints, leading to the complication of hemarthrosis. Because the clotting factor is either defective or absent, these episodes of bleeding may be quite severe. In some episodes the bleeding stops slowly and spontaneously, presumably because the pressure of accumulated blood acts to tamponade it. Other situations may lead to life-threatening hemorrhage. These recurrent bleeding episodes are particularly disturbing to the patient and his family and can lead to anxiety, reduced mobility, and general avoidance of activities.

Because hemophilia A represents a deficiency of biologically active factor Ⅷ, it is treated by administering the active clotting factor. The quality and properties of the preparations used have changed from early treatment with fresh plasma, to cryoprecipitated plasma, to the point where recombinant factor Ⅷ has become available. These products arrest bleeding by replacing the defective clotting factor. Because clinical manifestations and severity differ, the treatment protocols differ as well.

Some individuals need prophylactic administration of relatively small doses, while others do not need treatment except after trauma that causes bleeding. These management protocols are usually established relatively early in life. For many reasons, including diagnostic confusion and because the individuals themselves are less able to avoid minor trauma, the symptoms of hemophilia A are more often severe in younger boys than in adolescents and adults.

The mutant allele for hemophilia A is passed through asymptomatic carrier females. It can pass through many generations. A particularly notable pedigree developed from the fact that Queen Victoria of England was a carrier and had one affected son (Leopold, Duke of Albany) as well as a several carrier daughters. One of her granddaughters, Alexandra, also a carrier, married Nicholas II, the last Romanoff Czar in Russia the illness of their son, born with hemophilia A, created considerable intrigue and political difficulties toward the end of the Romanoff era.

5.1.2 Fragile X chromosome omit

It has been known for many years that a disproportionate number of males have mental retardation. The complete basis for this has not been established, but recent studies have helped to clarify an entire group of disorders.

Among mentally retarded males there is a population whose karyotypes often show broken chromosomes when their cells are cultured in media lacking folic acid. This is usually due to fragmentation (failure to condense during mitosis) of the X-chromosome at a specific location, Xq27 (see Figure 3.21) this “fragile site” is the FMR-1 gene. Despite the ability to detect this important chromosomal landmark, little progress was made until the nature of the underlying genetic change was clarified.

Figure 3.21

Fragile X syndrome (OMIM #309550) was the first disorder characterized by a triplet repeat in the DNA. We already have considered the implications of such repeats in our review of myotonic dystrophy. Fragile X syndrome involves expansion of a CGG trinucleotide 5′ to the coding region of the FMR-1 gene. No gene product is produced in this amplified situation. Fragile X syndrome is remarkably common, affecting about one in 1500 males. However, unlike the situation in hemophilia A, one third of females with the expansion are mentally impaired (although usually not severely so).

An additional anomaly in Fragile X syndrome is seen in its transmission (see Figure 3.22). A

threshold exists, with individuals who have 50-200 repeats being considered to have premutations. A male with such a premutation is usually clinically normal and called a “normal transmitting male.” His daughters (who must inherit the premutation) are usually asymptomatic as well and have little change in their repeat numbers.


Both male and female children of these females are at risk for receiving greatly increased numbers of repeats (250-4000 the “full” mutation), as well as symptoms. Thus, expansion of this triplet repeat is largely confined to female meioses (since clinically affected males rarely reproduce). It is not quite as clear, however, whether clinical severity is related to the degree of expansion of the repeat sequence.

The degree of mental retardation varies, but the average IQ of affected males is about 40. Males with the full mutation can show behavior changes resembling those of autism, with delayed language skills and poor coordination. These males generally have coarse facial features, with elongation and a thickened bridge and filtrum of the nose, as well as large testicles. Unfortunately, however, the visual impression of males with Fragile X syndrome is not always distinctive thus, the presence of mental retardation in a male justifies a search for Fragile X. Evaluation of kindreds once a male with a full mutation has been detected often identifies individuals who have triplet expansions to premutation levels but are unaffected themselves. There currently is no treatment for affected individuals, so detection through prenatal and presymptomatic studies can be useful for families.

5.1.3  Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) (OMIM # 3102( 0) is the most common form of muscular dystrophy in males. It has a relatively early age of onset, usually before age 6. Affected boys exhibit problems with walking and a waddling gait, sometimes mistaken for clumsiness. This apparent clumsiness or weakness may appear anomalous, because of muscular enlargement, particularly early in the disease this has been termed “pseudohypertrophy.” Weakness of pelvic, paraspinal, and shoulder girdle musculature is often present early as well. Knee and hip extensor weakness makes rising from a seated position difficult. To accomplish this maneuver, affected individuals usually flex their hips and push themselves up by placing their hands on their knees and moving them up the thighs (Gowers’sign).

These problems are progressive, with the development of muscular atrophy leading to flaccid limbs and prominence of bones as the overlying muscles become thinner. Involvement of the heart muscle is common, and congestive heart failure is frequent as a terminal event in those few individuals who live beyond the third decade. Some patients show a decline in IQ, but this is not usually severe. In general, those developing symptoms earliest have the worst prognosis.

There is a remarkably high apparent spontaneous mutation rate for DMD as many as 1 in 3000 to 4000 liveborn males are affected. This may reflect the fact that the gene itself is very large (~2.3 mb), presenting a large target for mutations. The gene is located on the short arm of the X-chromosome (Xp21.2). This gene encodes an enormous protein called dystrophin (>400 kDa), found in cardiac and skeletal muscle. It is now possible to measure dystrophin levels in muscle biopsies of individuals suspected of having the condition.

A broad range of mutations has been found in individuals with DMD about 60 to 70% of affected individuals show a deletion in the gene. Some of these mutations present as what has been called “Becker type muscular dystrophy,” but this is now recognized to be part of the milder aspects of the clinical and mutational spectrum of DMD.

The progressive weakness and lack of mobility of affected males gives them reduced reproductive fitness. However, the carrier status of their mother and other female relatives is an important piece of information for the entire family. For most of these families, a specific DNA-based study can establish the presence of the underlying gene change in female carriers as well as in pregnancies and presymptomatic boys. Interestingly, a few carrier females have muscle weakness, presumably due to some expression (or lack thereof) of the mutant gene in muscles through lyonization.

As proposed many years ago on the basis of population studies, DMD behaves like an X-linked lethal disorder, because affected males do not reproduce. Haldane formulated an instructive relationship in regard to such disorders. He noted that in a population of 2n persons at equilibrium, there should be 3n X-chromosomes. About one-third of all DMD mutations will be found on the n X-chromosomes of affected males, and about two-thirds would be on the 2n X-chromosomes of carrier females. The mutations on the n male X-chromosomes would be lost in each generation because of the genetic lethality. Thus, to maintain equilibrium in the distribution of mutations across 3n X-chromosomes, about one-third of the mutations must arise per generation to replace those lost. This formulation permits an estimate of the mutation rate, because about one-third of affected males should represent new mutations. Therefore, obviously, the other two-thirds of patients have mothers who are carriers. This high number of carriers means that family screening studies can be valuable in counseling unsuspecting and clinically unaffected females who are at risk for having affected sons.

Although there is no effective treatment currently, isolation of the gene and characterization of the dystrophin protein have led to attempts at gene replacement in order to restore muscle function. This area of research has not yet proved useful clinically but has considerable promise for affected individuals.

5.1.4  Glucose-6-phosphate dehydrogenase(G6PD) deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency (OMIM # 305900) is an enzyme defect associated with nonspherocytic hemolytic anemia. G6PD deficiency occurs worldwide and has been recognized and studied for many years. There is remarkable variation in its clinical spectrum, undoubtedly reflecting the fact that over 300 different genetic variants of the G6PD protein are known. Males deficient for the enzyme have reduced resistance to oxidative stress this leads to altered erythrocyte stability. The most frequent form of oxidative stress is due to drug exposure. The characteristic picture is that an individual is given the drug and within several days develops an episode of acute hemolysis, with its characteristic pain, anemia, and urinary abnormalities. Interestingly, such hemolysis usually is confined to the older red cells in the circulation, because of the relative resistance of younger red blood cells to oxidative stress.

G6PD deficiency represents an important interaction between the host and the environment. G6PD deficiency is largely a drug sensitivity.

There are several important categories of drugs to which deficient individuals are particularly susceptible some of these drugs are indicated in Table 3.2. Exposure to any of these agents can lead to acute hemolysis. Rarely, some individuals present with chronic hemolysis without any identifiable environmental cause. Some individuals have sensitivities to food an Italian population was identified whose hemolysis developed after eating fava beans. Their condition was known as “favism,” but it was really just a special case combining G6PD deficiency with exposure to a dietary oxidant.

Table 3.2. Drugs and chemicals causing problems in individuals with G6PD deficiency


Acetanilide  Niridazole  Doxorubicin Nitrofurantoin Furazolidone Phenazopyridine Methylene blue Primaquine Nalidixic acid Sulfamethoxazole nonspherocytic hemolytic anemia Acetaminophen Isoniazid Quinidine Ascorbic acid Phenacetin Quinine Aspirin Phenylbutazone Streptomycin Chloramphenicol Phenytoin Sulfamethoxypyridazine Chloroquine Probenecid Sulfisoxazole Colchicine Procainamide Trimethoprim Diphenhydramine Pyrimethamine Tripelennamine

G6PD deficiency is undoubtedly the most common hemolytic anemia throughout the world, but the broad range of variants makes its clinical manifestations hard to predict. In addition to favism, notable in Italian communities, large populations of individuals in areas endemic for malaria, particularly in Africa and Southeast Asia, have hemolysis induced by primaquine. Interestingly, G6PD deficiency received more attention following racial integration of the U.S. armed forces some African-American GIs in the Korean War developed hemolysis after receiving malaria prophylaxis. Table 3.2 emphasizes that a broad range of drugs must be considered when treating sensitive individuals. Despite this, there also is a large group of agents that are safe to use. The obvious treatment for individuals deficient in G6PD is to avoid contact with inducing agents. This certainly requires circumspection in prescribing and also some dietary considerations. Because acute hemolysis can be severe, it is important to document G6PD deficiency in any individual once it has been identified so that future problems can be avoided. Testing for G6PD deficiency is usually based on enzyme activity, which is detected by a simple laboratory test DNA-based diagnosis is not commonly used. (Again, there is a broad range of mutations in the responsible gene.)

5.2 X linked dominant inheritance pattern

The X linked dominant inheritance pattern is rare and difficult to distinguish from AD except that affected males have normal sons,but all daughters are affected,for example Xg blood group, X-linked hypophosphataemic rickets, Rett syndrome (X-linked dominant and only seen in females as lethal in males).

XD pedigree hallmarks:

⑴Affected males have no normal daughters and no affected sons.

⑵Affected heterozygous females transmit the condition to half their children of either sex.

⑶Transmission by females follows the same pattern as an AD inheritance cannot be distinguished from AD inheritance by the progeny of affected females, but only by the progeny of affected males.

⑷Affected females are more common than affected males, but as they are almost always heterozygotes they usually have milder (but Variable) expression.

⑸Passed in a vertical fashion with no skipping.

5.2.1  Hypophosphatemic rickets

There is a group of disorders whose genes are found on the X-chromosome but for whom the transmission pattern differs from those discussed above. These have been called “X-linked dominant” disorders to distinguish their pedigree patterns. In this group of conditions, both males and females are affected and can transmit the trait to offspring. Pedigrees for X-linked dominant traits show that females transmit the trait to 50% of both sons and daughters. (Each has a 50% chance of receiving the mutant X-chromosome.) Males, however, transmit the trait to none of their sons and all of their daughters.

One of the best-studied examples of this transmission pattern is seen in X-linked hypophosphatemic rickets (OMIM #307800), the most common inherited form of rickets in the United States. Affected individuals are usually short, with bowed legs and osteomalacia. They often develop ankylosis of the spine and large joints and can have hearing loss. Because of defective renal phosphate transport, patients have phosphate wasting and low serum phosphate levels. They also have abnormal metabolism of 1,25-dihydroxyvitamin D. Treatment with both phosphate and vitamin D often leads to improvement in bone abnormalities.

The responsible gene (called PEX) is located at Xp22.1 and shows homologies to endopeptidases, but its exact function has not been determined. As might be expected because of the conservation of genes on the X-chromosome (recall Ohno’s law) a homologous gene has been found on the X-chromosome of the mouse.

6. Y-linked inheritance

Y-linked (holadric ) inheritance is very rare (eg,hairy ears)。

7.  Non-mendlian inheritance

7.1 Imprinting(as mentioned above)

This is differential expression of genetic materia1 at chromosomal or allelic level, depending upon which parent(male or female) it has been inherited from lt can be thought of as selective inactivation of genes (probably through methylation) according to the paternal or maternal origins of the chromosomes Hydatidiform moles(it means that any of numerous burrowing mammals found in temperate regions and having minute eyes often covered with skin.) illustrate the different roles of paternal and maternal genomes:

⑴A complete mole(46 XX) has chromosomes that are a11 paterna1 in origin (both X chromosomes being of paternal origin,ie extra paternal set,but no materna l set), and results in either no fetus or a normal placenta with severe hyperplasin of the cytotrophoblast.

⑵A partial mole (69) is an triploid with an extra of  chromosomes of maternal or paternal origin. An extra paternal sef(diandric)results in abundant trophoblast but poor embryonic development.An extra maternal set(digynic) results in severely retarded embryonic development with a small fibrotic plancenta.

7.2. Dynamic mutation(as mentioned above)

7.3. Mosaicism(discussed in next chapter)

7.4.  Mitochondrial inheritance

Mitochondria have their own DNA and are inherited only from the mother, as ova have an abundant cytoplasm containing mitochondria; the sperm contributes no mitochondria to the zygote.

Mitochondria are distributed randomIy in daughter cells,so these may contain normal mitochondral DNA and mutant DNA, or a mixture of both.There is,therefore,variable expression of disease due to mutation in mitochondral DNA, depending upon the relative propotion of normal to mutant DNA.

A peculiar condition known as Leber hereditary optic neuropathy (LHON OMIM #535000) appears related to mitochondrial integrity as well. This is an optic nerve degeneration usually seen in young adults and can be associated with peripheral neuropathy and cardiac arrhythmias. LHON has a maternal pattern of inheritance, but more males than females are affected according to clinical studies. At least 19 different mitochondrial DNA mutations have been characterized in LHON, five of which appear essential in leading to illness. Interestingly, these five mutations are associated with different degrees of clinical severity some cause other neurologic symptoms as well. Not all maternal relatives of individuals with LHON have visual loss, and not all individuals with the same mitochondrial mutation have the same clinical course. It is likely that the clinical outcome is affected by other variations in the mitochondrial DNA, the proportion of heteroplasmy, the status of nuclear-encoded genes related to mitochondrial function, and the age and sex of the patient. Because of the small size and complete characterization of the mitochondrial genome, it is possible to establish the nature of any genetic changes with certainty. Specialized laboratories can thus proceed directly to mitochondrial DNA analysis in equivocal cases so that the diagnosis can be based on precise molecular information.


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