X-linked inheritance is a less heard / spoken of phenomenon that could give rise to various genetic disorders. In order to understand the bigger picture, it would be useful to first familiarise with a few basics in genetics.

(The matter that follows might come across as a little extra, and possibly more technical than most other articles on this medium.  However, TBL has tried to keep it as simple as possible and hopes it interests the enthusiast.)

The genome (genetic material) of an organism comprises of its species-specific DNA (deoxyribonucleic acid). Chromosomes are thread-like structures made up of a tightly coiled length of DNA. Chromosomes are usually present in pairs (called homologous pairs) – one from the mother and one from the father. The number of chromosomes present in a cell depends on the species to which it belongs.

In humans, there are 46 chromosomes present in each cell of our body – 23 from the mother and 23 from the father. Of these, one pair of chromosomes is responsible for the sex (gender) of the offspring. These are referred to as ‘X’ and ‘Y’ chromosomes. The maternal chromosome is always an X chromosome, whereas the paternal chromosome could be X or Y. This paternal sex chromosome is therefore what determines the sex of the offspring – XX would be a female, XY would be a male.

A gene is a short length of DNA that is responsible for the expression of a particular characteristic (e.g. hair colour, eye colour, facial or body feature). An allele is a specific form of a gene that determines how a particular characteristic is expressed (e.g. black hair or blonde hair, blue eyes or brown eyes, pointed nose or round nose, long fingers or stubby fingers).

An allele, and hence its gene, is said to be dominant if the presence of only one of it (from only one parent) expresses its characteristic (referred to as its phenotype). An allele, and hence its gene, is said to be recessive if both parents are required to pass on that particular allele for the expression of its characteristic.

Now, back to our topic.

X-linked inheritance refers to the incidence of a genetic disorder when a mutation is present on and inherited via an X chromosome. Such mutations usually occur on only one X chromosome even in females.

There are two types of X-linked inheritance. However, a common trait for both types is that they cannot be passed on from father to son, i.e. no male-to-male transmission.

X-linked Recessive Inheritance

The significant difference with X-linked recessive inheritance is that since males have only one X chromosome, the presence of a faulty recessive allele on this single X chromosome gets expressed despite being recessive, resulting in male offspring becoming affected cases. In females, since there are two X chromosomes, the presence of a mutation on one X chromosome does not lead to an expressed character. They instead become a carrier for the disorder.

Let’s take a look at some Punnett Square tables, where X^R refers to the presence of a recessive mutation.

(R1) When the father is unaffected and the mother is a carrier, there is a 50% probability that male offspring would be affected, and a 50% probability that female offspring would be carriers.

(R2) When the father is affected and the mother is unaffected, there is no risk for male offspring as they get a Y chromosome from the paternal parent. However, the probability of female offspring being carriers is 100%.

In a mathematical sense, when the father is an affected individual and the mother is a carrier, there is a 50% chance of female offspring being affected. However, this is very rare and its incidence rate does not follow the science of probability in this case. For this reason, X-linked recessive inheritance disorders are largely considered to be male genetic disorders.

Common X-linked recessive inheritance disorders include:

• Daltonism (red-green colour blindness), which affects around 7-10% of the male population and around 0.5-1% females
• Haemophilia A (more common) and Haemophilia B, which are blood clotting diseases
• Duchenne Muscular Dystrophy, a rapidly progressive muscular degeneration disease which could lead to loss of skeletal muscle function, respiratory failure and death; and its milder form – Becker’s Muscular Dystrophy
• X-linked Ichthyosis, a steroidal enzyme deficiency disease

X-linked Dominant Inheritance

Unlike with recessive inheritance, there is no higher risk for males with X-linked dominant inheritance. Both or either gender may be equally affected by different disorders.

In the following Punnett Square tables, where X^D refers to the presence of a dominant mutation.

(D1) When the father is unaffected and the mother is affected, there is a 50% probability that male offspring would be affected, and a 50% probability that females would be affected.

(D2) When the father is affected and the mother is unaffected, there is no risk for male offspring as they get a Y chromosome from the paternal parent. However, the probability of female offspring being affected is 100%.

If both parents are affected, all female offspring would be affected, while 50% of male offspring are at risk of being affected. However, again, this is a very rare phenomenon.

Common X-linked dominant disorders include:

• Rickets related to Vitamin D deficiency, which softens and weakens bones in children
• Rett Syndrome, a brain disorder that usually affects females
• Fragile X Syndrome, an intellectual disability which affects more males than females
• Goltz Syndrome (Focal Dermal Hyperplasia), which causes skin and pigmentation disorders
• Incontinentia Pigmenti, which affects the CNS, skin, nails, hair and teeth

Since this discussion does not refer to a particular disease, but to a genetic disorder that can cause a range of diseases, prevention and treatment shall not be elaborated on. In fact, prevention is not much of an option for genetic disorders of this nature, except to refrain from reproducing if there are any such known conditions in either parent. Treatment should be sought for respective conditions if and when diagnosed.

Cover illustration from Listverse.