In contrast to genes on the autosomes, genes on the X and Y chromosomes are distributed unequally to males and females in families. The patrilineal inheritance of the Y chromosome is straightforward. However, there are very few strictly Y-linked genes, almost all of which are involved in primary sex determination or the development of secondary male characteristics, and they will not be considered here. Approximately 800 protein-coding and 300 noncoding RNA genes have been identified on the X chromosome to date, of which over 300 genes are presently known to be associated with X-linked disease phenotypes. Phenotypes determined by genes on the X have a characteristic sex distribution and a pattern of inheritance that is usually easy to identify and easy to distinguish from the patterns of autosomal inheritance we just explored.

Because males have one X chromosome but females have two, there are only two possible genotypes in males and four in females with respect to pathogenic alleles at an X-linked locus. A male with a pathogenic allele at an X-linked locus is hemizygous for that allele, whereas females may be a homozygote for the wild-type allele, a homozygote for a pathogenic allele, a compound hetero zygote for two different pathogenic alleles, or a heterozygous carrier of a pathogenic allele. For example, if XH is the wild-type allele for an X-linked disease gene and Xh , is the disease allele, the genotypes expected in males and females are as in Table1.

Table1. Genotypes and Phenotypes in X-Linked Disease

X Inactivation, Dosage Compensation, and the Expression of X-Linked Genes

As introduced in Chapters 3 and 6, X inactivation is a normal physiologic process in which most of the genes on one of the two X chromosomes in normal females, but not the genes on the single X chromosome in males, are inactivated in somatic cells, thus equalizing the expression of most X-linked genes between the two sexes. The clinical relevance of X inactivation in X-linked diseases is profound. It leads to females having two cell populations, which express alleles of X-linked genes from one or the other of the two X chromosomes. These two cell populations are thus genetically identical but function ally distinct, and both cell populations in human females can be readily detected for some disorders. For example, in Duchenne muscular dystrophy, female carriers exhibit typical mosaic expression of their dystrophin immunostaining (Fig. 1). Depending on the pattern of random inactivation of the two X chromosomes, two female heterozygotes for an X-linked disease may have very different clinical presentations because they differ in the proportion of cells that have the pathogenic allele on the active X in a relevant tissue (as seen in manifesting heterozygotes).

Fig1. Immunostaining for dystrophin in muscle specimens. (A) A normal female (×480). (B) A male with Duchenne muscular dystrophy (DMD) (×480). (C) A carrier female (×240). Staining creates the bright signals seen here encircling individual muscle fibers. Muscle from DMD patients lacks dystrophin staining. Muscle from DMD carriers exhibits both positive and negative patches of dystrophin immunostaining, representing fibers with either the normal or pathogenic allele on the active X. Images courtesy K. Arahata, National Institute of Neuroscience, Tokyo.

Recessive and Dominant Inheritance of X-Linked Disorders

As mentioned earlier in this chapter, the use of the terms dominant and recessive is different for X-linked conditions than for autosomal disorders. So-called X-linked dominant and recessive patterns of inheritance are typically distinguished on the basis of the phenotype in heterozygous females. Some X-linked phenotypes are consistently apparent clinically in carriers, at least to some degree; these are referred to as dominant. Other X-linked phenotypes are typically not observed in heterozygous females and are considered to be recessive. The difficulty in classifying an X-linked disorder as dominant or recessive arises because females who are heterozygous for the same pathogenic allele in a family may or may not demonstrate the disease, depending on the pattern of random X inactivation and the proportion of the cells in pertinent tissues that have the pathogenic allele on the active or inactive X.

Nearly a third of X-linked disorders are penetrant in some (but not all) female heterozygotes and cannot be classified as either dominant or recessive. Even for dis orders that can be so classified, they show incomplete penetrance that varies as a function of X inactivation pat terns, not inheritance patterns. Because clinical expression of an X-linked condition does not depend strictly on the particular gene involved, or even the particular pathogenic variant in the same family, some geneticists have recommended dispensing altogether with the terms recessive and dominant for X-linked disorders. Be that as it may, the terms are widely applied to X-linked disorders, and we will continue to use them, recognizing that they describe extremes of a continuum of penetrance and expressivity in female carriers of X-linked diseases.

X-Linked Recessive Inheritance

 The inheritance of X-linked recessive phenotypes follows a well-defined and easily recognized pattern (Fig. 2 and Box 1). An X-linked recessive trait is expressed phenotypically in all males who receive the variant allele, and, consequently, X-linked recessive disorders are generally restricted to males.

Fig2. Pedigree pattern demonstrating an X-linked recessive disorder such as hemophilia A, transmitted from an affected male through females to an affected grandson and great-grandson.

Box1. CHARACTERISTICS OF X-LINKED RECESSIVE INHERITANCE

Hemophilia A is a classic X-linked recessive disorder in which the blood fails to clot normally because of a deficiency of factor VIII, a protein in the clotting cascade. The hereditary nature of hemophilia and even its pattern of transmission have been recognized since ancient times, and the condition became known as the “royal hemophilia” because of its occurrence among descendants of Britain’s Queen Victoria, who was a carrier.

As in the earlier discussion, suppose Xh represents a pathogenic allele of factor VIII causing hemophilia A, and XH represents the normal allele. The sons of a male with hemophilia and a noncarrier female receive their father’s Y chromosome and a maternal X and are unaffected, but the daughters receive the paternal X chromo some with its hemophilia allele and are obligate carriers. Children of obligate carrier females have four possible genotypes, with equal probabilities (Table 2).

Table2. X-Linked Recessive Inheritance

The hemophilia of an affected grandfather, which did not appear in any of his own children, has a 50% chance of appearing in each son of his daughters. It will not reappear among the descendants of his sons, however. A daughter of a carrier has a 50% chance of being a carrier herself (see Fig. 2). By chance, an X-linked recessive allele may be transmitted undetected through a series of female carriers before it is expressed in a male descendant.

Affected Females in X-Linked Recessive Disease

 Although X-linked conditions are classically seen only in males, they can be observed in females under two circumstances. In one, a female can be homozygous for the relevant disease allele. This scenario is unlikely unless her parents are consanguineous; additionally the phenotype cannot have a reproductive fitness of 0 in males. However, a few X-linked conditions, such as X-linked color blindness, are sufficiently common and mild that such homozygotes are seen in female offspring of an affected father and a carrier mother.

More commonly, a female carrier of an X-linked allele who has phenotypic expression of the disease is referred to as a manifesting heterozygote. Whether a female carrier will be a manifesting heterozygote depends on a number of features of X inactivation. First, as we saw in Chapter 3, the choice of which X chromosome is to become inactive is random, but it occurs when there is a relatively small number of cells in the developing female embryo. By chance alone, therefore, the fraction of cells in various tissues of carrier females in which the normal or pathogenic allele happens to remain active may devi ate substantially from the expected 50%, resulting in unbalanced or skewed X inactivation. A female carrier may have signs and symptoms of an X-linked disorder if the skewed inactivation is unfavorable (i.e., a large majority of the active X chromosomes in pertinent tissues happen to contain the deleterious allele active).

Favorably unbalanced or skewed inactivation also occurs, in which the pathogenic allele is preferentially on the inactive X in some or all tissues of an unaffected heterozygous female. Such skewed inactivation may simply be due to chance alone, as we just saw (albeit in the opposite direction). However, in certain X-linked conditions, there is reduced cell survival (or a proliferative disadvantage) for those cells that originally had the pathogenic allele on the active X early in development. This results in a pattern of highly skewed inactivation that favors cells with the normal allele on the active X in relevant tissues. For example, highly skewed X inactivation is the rule in female carriers of certain X-linked immunodeficiencies, in whom only those early progenitor cells that happen to carry the normal allele on their active X chromosome can populate certain lineages in the immune system.

X-Linked Dominant Inheritance

 As discussed earlier, an X-linked phenotype can be described as dominant if it is regularly expressed in heterozygotes. X-linked dominant inheritance (Table 3) can readily be distinguished from autosomal dominant inheritance by the lack of male-to-male transmission, which is impossible for X-linked inheritance because males transmit the Y chromosome, not the X, to their sons.

Table3. X-Linked Dominant Inheritance

Thus the distinguishing feature of a fully penetrant X-linked dominant pedigree (Fig.3) is that all the daughters and none of the sons of affected males are affected; if any daughter is unaffected or any son is affected, the inheritance must be autosomal, not X linked. The pattern of inheritance through females is no different from the autosomal dominant pattern; because females have a pair of X chromosomes just as they have pairs of autosomes, each child of an affected female has a 50% chance of inheriting the trait, regardless of sex. Across multiple families with an X-linked dominant dis ease, the expression is usually milder in heterozygous females because the pathogenic allele is located on the inactive X chromosome in a proportion of their cells. Thus, most X-linked dominant disorders are incompletely dominant, as is the case with most autosomal dominant disorders (Box 2).

Fig3. Pedigree pattern demonstrating X-linked dominant inheritance.

Box2. CHARACTERISTICS OF X-LINKED DOMINANT INHERITANCE

X-Linked Dominant Disorders With Male Lethality

Although most X-linked conditions are typically apparent only in males, a few rare X-linked defects are expressed exclusively, or almost exclusively, in females.

These X-linked dominant conditions are lethal in males before birth (Fig. 4). Typical pedigrees of these conditions show transmission by affected females, who produce affected daughters, normal daughters, and nor mal sons in equal proportions (1:1:1); affected liveborn males are not seen.

Fig4. Pedigree pattern demonstrating X-linked dominant inheritance of a disorder that is lethal in males during the prenatal period.

Rett syndrome is a striking disorder that occurs nearly exclusively in females and meets all criteria for being an X-linked dominant disorder that is usually lethal in hemizygous males. The syndrome is characterized by normal prenatal and neonatal growth and development, followed by the rapid onset of neuro logic symptoms in affected girls. The disease mechanism is thought to reflect abnormalities in the regulation of a set of genes in the developing brain; the cause of male lethality is unknown but presumably reflects a requirement during early development for at least one functional copy of the MECP2 gene on the X chromosome.

X-Linked Dominant Disorders With Male Sparing

 Other disorders are manifest only in carrier females because hemizygous males are largely spared the consequences of the variant they carry. One such disorder is female-limited, X-linked epilepsy and cognitive impairment. Affected females are asymptomatic at birth and appear to be developing normally but begin to have seizures, generally in the second year of life, after which development begins to regress. Most affected females go on to be developmentally delayed, which can vary from mild to severe. In contrast, male hemizygotes in the same families are completely unaffected (Fig. 5). The disorder is due to loss-of-function variants in the protocadherin gene 19, an X-linked gene that encodes a cell surface molecule expressed on neurons in the central nervous system.

Fig5. Pedigree pattern of familial female epilepsy and cognitive impairment, demonstrating its X-linked dominant inheritance with sparing of males hemizygous for a premature termination variant in the PCDH19 gene.

The explanation for this unusual pattern of inheritance is not clear. It is hypothesized that the epilepsy occurs in females because mosaicism for expression of protocadherin 19, resulting from random X inactivation in the brain, disrupts communication between groups of neurons with and without the cell surface protein. Neurons in males uniformly lack the cell sur face molecule, but their brains are apparently spared cell-cell miscommunication by a different, compensating protocadherin.

Relationship Between New Mutation and Fitness in X-Linked Disorders

 Just as with autosomal dominant disorders, new mutations account for a significant fraction of isolated cases of many X-linked diseases. Males carrying variants causing X-linked disorders are exposed to selection that is complete for some disorders, partial for others, and absent for still others, depending on the fitness of the genotype. Males carrying pathogenic alleles for X-linked disorders such as Duchenne muscular dystrophy—a disease of muscle that affects young boys, do not reproduce. Fitness of affected males is currently 0, although the situation may change as a result of advances in research aimed at therapy for affected boys. In contrast, individuals with hemophilia also have reduced fitness, but the condition is not a genetic lethal. Affected males have, on average, ~70% as many offspring as unaffected males do, and fitness of affected males is therefore ~0.70. This fitness may also increase with improvements in the treatment of this disease.

When fitness is reduced, the pathogenic alleles that these males carry are lost from the population. In contrast to autosomal dominant conditions, however, pathogenic alleles for X-linked diseases with reduced fitness may be partially or completely protected from selection when present in females. Thus, even in X-linked disorders with a fitness of 0, less than half of new cases will be due to new mutations. The overall incidence of the disease, then, will be determined both by the transmittal of a pathogenic allele from a carrier mother and by the rate of de novo mutations at the responsible locus.

اخر الاخبار

اخبار العتبة العباسية المقدسة

30 قارئًا يشاركون بـ18 ختمة قرآنية رمضانية في محافظة الديوانية

الحوزة العلمية تقيم مجلس فاتحة الشهيد السيد علي الخامنئي (رضوان الله عليه)

تأهّل 5 مشاركين للمرحلة النهائية من جائزة العميد الدولية لتلاوة القرآن الكريم

محفل نهج البلاغة الأسبوعي في ذي قار يشهد تقديم المحاضرة الخامسة

المزيد

الآخبار الصحية

مركب طبيعي في القهوة يحمينا من التهابات اللثة

داء السكري لا يرفع السكر فقط.. بل يزيد خطر الإصابة بأمراض القلب!

اكتشاف سبب غير متوقع لضعف الذاكرة والتركيز

نصائح علمية لتقوية دماغك وتقليل التدهور العقلي

المزيد

الآخبار التكنلوجية

باحثون يرصدون أثر تغيّر المناخ في دم البشر

الجميع يحلم.. لماذا يتذكر البعض أحلامهم بينما ينسى آخرون؟

حرق الأمونيا.. كيف يساعد محطات الكهرباء في اليابان على إزالة الكربون؟

الشمس تقذف نتوءا عملاقا باتجاه قطبها الشمالي

المزيد

مواضيع ذات صلة

Preconception Genetic Screening and Testing

Problems in Prenatal Chromosome Analysis and Gene Sequencing

Introduction to Cytogenetics and Genome Analysis

Methods to Detect Fetal Chromosomal Abnormalities

The Origin and Frequency of Different Types of Mutation

Noninvasive Prenatal Screening by Analysis of Cell- Free Fetal DNA

Screening for Down Syndrome and Other Aneuploidies

Screening for Neural Tube Defects

Genetic Alterations Associated with Acromegaly

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

The Role of Epigenetics in Cancer