Etiology and pathogenesis

The gene responsible for XLRS, RS1 (also known as XLRS1), was identified in 1997. So far, more than 160 inactivating mutations have been found. The mutations are predominantly missense and are clustered in exons 4-6, which encode the discoidin domain. Deletions, insertions and splice site mutations have also been described.

The RS1 gene is located on band Xp22 (Xp22.2-p22.1) and encodes a 224 amino acid protein retinoschisin that is expressed in photoreceptor and bipolar cells and is involved in cellular adhesion and cell-cell interactions within the inner nuclear layer as well as synaptic connection between photoreceptors and bipolar cells.
There is no genotype/phenotype correlation, suggesting that there may be other factors influencing disease severity, such as genetic modifiers or environmental factors.

Mode of inheritance

XLRS is inherited in an X-linked recessive manner and the risk to sibs depends on the carrier status of the mother. If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected. Female sibs who inherit the mutation will be carriers. Affected males will pass the disease-causing mutation to all of their daughters and none of their sons.

An unusual autosomal dominant retinoschisis with both macular and peripheral involvement has been reported in which male-to-male transmission was documented.
Genetic counseling should be offered to families to explain the X-linked inheritance pattern and recurrence risks in future offsprings. It is particularly important to explain the extreme variation in severity of the disease even within families.