General aspects of X-linked diseases (2024)

Concepts of dominance and recessiveness were initially used for autosomal traits, and then applied to 'sex'-linked traits to distinguish X-linked recessive and X-linked dominant inheritance. The former was defined as vertical transmission in which carrier females pass the trait to affected sons, while the latter was defined as vertical transmission in which daughters of affected males are always affected; hence the trait can be transmitted to offspring of both sexes. However, X-linked disorders do not always fit these rules. In many of these disorders, the penetrance and severity index of the phenotype are high in males, while the severity index is low in females. However, in contrast with standard presentations of X-linked inheritance, penetrance appears highly variable in females and can be classified as high, intermediate or low. Classic definitions of X-linked recessive and dominant inheritance neither reflect the variable expressivity of X-linked disorders, nor take into account the multiple mechanisms that can lead to disease expression in females. The use of the terms X-linked recessive and dominant should probably be abandoned and all such traits simply described as following X-linked inheritance.

Introduction

More than 100 X-linked inherited human disorders or traits have now been identified (Table 1). Most of them are classified as recessive [1], a much smaller number as dominant [2] and a few as dominant and lethal in hemizygotes [3, 4]. Due to their particular mode of inheritance, X-linked diseases have a more significant place in genetic counselling than would be thought from the relative contribution of the X chromosome to the human genome. In this chapter, the issues associated with X-linked disease inheritance are discussed.

Table 1

Principal Mendelian disorders following X-linked inheritance.

Random X-chromosome inactivation

The words 'dominant' and 'recessive' should be used cautiously to describe X-linked disorders [5], as a much higher degree of variability in heterozygotes is observed than is the case with autosomal traits. Figure 1 shows left ventricular hypertrophy in a female patient with Fabry disease, exemplifying that high penetrance of the disease is possible in heterozygotes. This is largely due to random X-chromosome inactivation [6], which affects almost an entire X chromosome in human females. In a process known as Lyonization, one of the two X chromosomes is randomly inactivated during early embryonic stages and becomes visible as the Barr body under the nuclear membrane. As the descendants of each cell keep the same pattern of inactivation, a heterozygote for an X-linked disease will be a mosaic, with two cell populations, one of which will express the normal and the other the abnormal X chromosome. As a consequence, some disorders demonstrate 'mosaic' or 'patchy' symptoms in heterozygous females [4]. More often, variability in X inactivation can lead to a milder and more variable clinical and biochemical phenotype in females than in males [2].

Figure 1

Echocardiogram (TM mode) showing left ventricular hypertrophy (cardiac mass, 310 g) with increased septum (14 mm) and posterior wall (14 mm) thickness in a 60-year-old female heterozygote with Fabry disease. BPM, beats per minute.

Although inactivation applies to almost the entire human X chromosome, there are a few loci that escape inactivation. The short arm of the X chromosome is hom*ologous, in its terminal region, with part of the Y chromosome [7]. This allows pairing between the sex chromosomes during meiosis. A different region of the X chromosome, the X-inactivation centre, located on the proximal long arm, is involved in the control of the X inactivation process [8].

Identification of X-linked inheritance

In X-linked inheritance, the following simple rules apply to most genetic counselling issues [2].

Classic X-linked recessive pattern of inheritance

Recessive genes on the X chromosome have different consequences in males and females. A mutated recessive gene on the X chromosome tends to have little impact in a female because there is a second, normal, copy of the gene on the other X chromosome. By contrast, a mutated recessive X-linked gene will have an impact in a male because the genes on the Y chromosome are different from those on the X chromosome, and no second copy of the gene exists. The male must therefore pass the mutated X-linked gene to all of his daughters, but does not pass it to his sons, who all receive his Y chromosome.

Disorders where affected males do not reproduce

In cases of X-linked disorders in which the affected males do not survive to reproduce, the absence of male-to-male transmission cannot be tested. One-third of isolated cases of affected males are due to new mutations, whereas the mutation is inherited from a heterozygous mother in the remaining two-thirds of cases [12]. These proportions, however, may vary in disorders in which the mutation rate is different in the paternal and maternal lineages [2].

X-linked dominant inheritance

Classic X-linked dominant inheritance may be mistaken for autosomal dominant inheritance, but if descendants of affected males are considered, all sons are healthy while all daughters are affected. The excess of affected female heterozygotes may also be indicative of X-linked dominant inheritance.

X-linked dominant inheritance with lethality in the male

X-linked dominant disorders that are lethal in males in utero are, by definition, seen only in female heterozygotes, the affected (hemizygous) males appearing as an excess of spontaneous abortions. This situation is well known for several disorders, including incontinentia pigmenti [13] and Rett syndrome [14]. With regard to genetic counselling, it should be kept in mind that, leaving aside spontaneous abortions, one-third of the offspring of an affected woman will be affected; all the live-born males will be unaffected, as will half of the females. Two-thirds of all live offspring will be females.

Frequent X-linked mutations

If an X-linked mutation is frequent in a given population, misleading family trees may occur. For example, in European populations, it is not uncommon for both parents to carry the mutant gene leading to colour blindness (i.e. an affected male and a heterozygous female). In such cases, all female offspring will carry the mutant allele on one or both X chromosomes. In turn, the sons of the hom*ozygous female offspring will all be affected [2]. Such a pedigree pattern can also be observed with rarer traits in cases of consanguinity or endogamy [15].

Identification of individuals heterozygous for X-linked diseases

The risk of being a carrier

In inherited disorders, a carrier is often defined as an individual who is heterozygous for the gene responsible for an inherited disorder and who has no signs or symptoms of the disease at the time of investigation (but see Chapter 34). It is important to estimate by pedigree analysis the a priori genetic risk that a female relative of an affected individual is a carrier, in order to interpret correctly the information obtained from laboratory carrier testing.

X-linked recessive disorders are the most important diseases in terms of detecting carriers. Indeed, in X-linked disorders, carriers are usually healthy and will consequently be likely to reproduce, with the risk of giving birth to affected male offspring. In this context, the detection of women at high risk of being heterozygous for an X-linked disorder forms such an integral part of genetic counselling that it is often unwise to give a definitive risk estimate until information from testing is available [2].

In classic X-linked recessive diseases, a few heterozygous females may occasionally be clinically detectable, probably as a consequence of skewed X-chromosome inactivation, which results in a higher percentage of the X chromosomes bearing the mutant gene being expressed in the particular tissue of importance. In contrast, skewed inactivation can also result in carriers in whom a higher percentage of the X chromosomes bearing the normal gene are expressed. Such variability in symptom severity is characteristic of X-linked heterozygotes [5] and should be kept in mind when assessing and diagnosing potential patients. The most widely used phenotypic test for carrier detection in Fabry disease is an enzymatic assay that detects decreases in levels of α-galactosidase A in leukocytes. However, the enzymatic assay demonstrates a large overlap in values between normal individuals and heterozygotes, which makes it almost impossible to classify at-risk females dependably without genotyping [16]. DNA-based tests are not influenced by X inactivation, which is a key reason for their wide use in detecting X-linked heterozygotes.

Detection of female heterozygotes is feasible in some X-linked disorders. The spectrum of methods is wide and may be morphological, functional, biochemical or molecular. As a group, X-linked disorders are probably the most interesting in terms of our ability to identify the carrier state and, consequently, to prevent recurrence of the genetic disease in subsequent generations [2].

Isolated cases of an X-linked disorder

Any isolated case of an X-linked disease is a source of additional difficulty in detection of heterozygotes. There is huge uncertainty as to the percentage of cases that are due to denovo mutations and, correspondingly, the proportions of mothers who are heterozygotes. It is probable that this varies from one disease to another.

Conclusions

Standard definitions of X-linked recessive and dominant inheritance do not capture the variable expressivity of X-linked disorders or take into account the multiple mechanisms that can result in disease expression in females. These include skewed X inactivation [17, 18], clonal expansion [19] and somatic mosaicism [20, 21]. Use of the terms X-linked recessive and dominant should probably be discontinued and all such disorders simply described as following X-linked inheritance [5].

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