The spectrum of methods is wide and may be morphological, functional, biochemical or molecular. DNA-based tests are not influenced by X inactivation, which is a key reason for their wide use in detecting X-linked heterozygotes.ĭetection of female heterozygotes is feasible in some X-linked disorders. 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. 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. Such variability in symptom severity is characteristic of X-linked heterozygotes and should be kept in mind when assessing and diagnosing potential patients. In contrast, skewed inactivation can also result in carriers in whom a higher percentage of the X chromosomes bearing the normal gene are expressed. 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 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. 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. X-linked recessive disorders are the most important diseases in terms of detecting carriers. 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. 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). More often, variability in X inactivation can lead to a milder and more variable clinical and biochemical phenotype in females than in males. As a consequence, some disorders demonstrate 'mosaic' or 'patchy' symptoms in heterozygous females. 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. 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. This is largely due to random X-chromosome inactivation, which affects almost an entire X chromosome in human females. Figure 1 shows left ventricular hypertrophy in a female patient with Fabry disease, exemplifying that high penetrance of the disease is possible in heterozygotes. The words 'dominant' and 'recessive' should be used cautiously to describe X-linked disorders, as a much higher degree of variability in heterozygotes is observed than is the case with autosomal traits. 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. 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. 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. 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, X-linked disorders do not always fit these rules. 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. 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.
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