X-linked recessive inheritance

A male has only 1 copy of any X-linked gene and therefore is said to be hemizygous for the gene, rather than homozygous or heterozygous. Because there is no normal gene to balance a mutant X-linked gene in the male, its resulting phenotype, whether dominant or recessive, will always be expressed. A female may be heterozygous or homozygous for a mutant X-linked gene. X-linked traits are commonly called recessive if they are caused by genes located on the X chromosome, as these genes express themselves fully only in the absence of the normal allele. Thus, males (with their single X chromosome) are predominantly affected. All their phenotypically healthy but heterozygous daughters are carriers. By contrast, each son of a heterozygous woman has an equal chance of being unaffected or hemizygously affected.

Table 6-4 Characteristics of X-Linked Recessive Inheritance

A female will be affected with an X-linked recessive trait under a limited number of circumstances:

• She is homozygous for the mutant gene by inheritance (ie, from an affected father and a heterozygous [or homozygous] mother).

• Her mother is heterozygous and her father contributes a new mutation.

• She has Turner syndrome, with only 1 X chromosome, or a partial deletion of 1 X chromosome and therefore is effectively hemizygous.

• She has a highly unusual skewing of inactivation of her normal X chromosome, as explained by the Lyon hypothesis (discussed in the section Lyonization later in this chapter).

• Her disorder is actually an autosomal genocopy of the X-linked condition.

Table 6-4 summarizes the characteristics of X-linked recessive inheritance. X-linked recessive inheritance should be considered when all affected individuals in a family are males, especially when they are related through historically unaffected women (eg, uncle and nephew, or multiple affected half brothers with different fathers). Many X-linked RP pedigrees have been mislabeled as autosomal dominant because of manifesting female carriers. The key feature of an X-linked pedigree is no male-to-male transmission.

X-linked dominant inheritance

X-linked dominant traits are caused by mutant genes expressed in a single dose and carried on the X chromosome. Thus, both heterozygous women and hemizygous men are clinically affected. Females are affected nearly twice as frequently as males. All daughters of males with the disease are affected. However, all sons of affected males are free of the trait unless their mothers are also affected. Because only children of affected males provide information in discriminating X-linked dominant from autosomal dominant disease, it may be impossible to distinguish these modes on genetic grounds when the pedigree is small or the available data are scarce. Some X-linked dominant disorders, such as incontinentia pigmenti (Bloch-Sulzberger syndrome), may prove lethal to the hemizygous male. The characteristics of X-linked dominant inheritance are summarized in Table 6-5.

Table 6-5 Characteristics of X-Linked Dominant Inheritance

X-linked disorders

Females with X-linked diseases have milder symptoms than males. Occasionally, males may be so severely affected that they die before the reproductive period, thus preventing transmission of the gene. Such is the case with Duchenne muscular dystrophy, in which most affected males die before their midteens. In other disorders, males are so severely affected that they die before birth, and only females survive. Families with such disorders would include only affected daughters, unaffected daughters, and normal sons at a ratio of 1:1:1. Incontinentia pigmenti is one such lethal genetic disorder. In affected females, an erythematous, vesicular skin eruption develops perinatally, which progresses to marbled, curvilinear pigmentation. The syndrome includes dental abnormalities, congenital or secondary cataracts, retinal neovascularization with tractional retinal detachment, and pseudogliomas.

Among the most severe X-linked dominant disorders with lethality for the hemizygous males is Aicardi syndrome. No verified birth of a male with this entity has ever been reported. Females have profound cognitive disabilities and delays; muscular hypotonia; blindness associated with a characteristic lacunar juxtapapillary chorioretinal dysplasia and optic disc anomalies; and central nervous system (CNS) abnormalities, the most common characteristic of which is agenesis of the corpus callosum. No recurrences have been reported among siblings, and parents can be reassured that the risk in subsequent children is minimal. All instances of the disease appear to arise from a new X-dominant lethal mutation, and affected females do not survive long enough to reproduce. The distal end of the short arm of the X chromosome appears to be the crucial area, because some patients with a deletion in this region have also been shown to have features of Aicardi syndrome.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.