X-linked diseases 16/4/03. By Richard Twyman Single gene disorders caused by defective genes on the X chromosome.

X-linked diseases are single gene disorders that reflect the presence of defective genes on the X chromosome. This chromosome is present as two copies in females but only as one copy in males.

The inheritance patterns of X-linked diseases in family pedigrees are complicated by the fact that males always pass their X chromosome to their daughters but never to their sons, whereas females pass their X chromosomes to daughters and sons with equal.

Figure 1: The Y chromosome makes you male. Therefore, fathers pass their Y chromosome exclusively to their sons and their X-chromosome exclusively to their daughters. This is why men affected by X-linked diseases never pass the disease to their sons.

Like autosomal single gene disorders, X-linked diseases can be either recessive or dominant. X-linked recessive diseases include red-green colour blindness, haemophilia and the Duchenne and Becker forms of muscular dystrophy (both of which involve mutations in the DMD gene). These diseases are much more common in males than females because two copies of the mutant allele are required for the disease to occur in females, while only one copy is required in males.

The inheritance pattern of an X-linked recessive disease has the following characteristics:

Figure 2: A family pedigree for an X-linked recessive disease such as red-green colour blindness, where affected males can reproduce. Note the prevalence of affected males and the absence of male to male disease transmission.

• The vast majority of affected individuals are male.
• Affected males never pass the disease to their sons because there is no male-to-male transmission of the X chromosome.
• Affected males pass the defective X chromosome to all of their daughters, who are described as obligate carriers. This means they carry the disease-causing allele but generally show no disease symptoms since a functional copy of the gene is present on the other chromosome.
• Female carriers pass the defective X chromosome to half their sons (who are affected by the disease) and half their daughters (who are therefore also carriers). The other children inherit the normal copy of the chromosome.
• The overall pattern of the disease is therefore characterised by the transmission of the disease from affected males to male grandchildren through carrier daughters, a pattern sometimes described as a 'knight's move'.
• Affected females, with two deficient X chromosomes, are the rare products of a marriage between an affected male and a carrier female. However, manifesting carrier females (with one deficient X chromosome and one normal one) may arise if there is a chromosome disorder or a problem with X-chromosome inactivation.

X-linked dominant diseases are very uncommon, but some inherited forms of rickets are transmitted in this manner. Unlike the recessive diseases discussed above, the frequency of X-linked dominant diseases is similar in males and females. However, the absence of male-to-male transmission distinguishes X-linked dominant diseases from autosomal dominant diseases, in which both sexes are also equally affected.