SNP Shot: Genomic Insights

Norrie disease is a genetic eye disorder, passed down through families, that typically causes blindness in male infants, either at birth or shortly thereafter. The disease disrupts the normal development of the retina, the light-sensitive layer at the back of the eye responsible for vision. This disruption leads to a buildup of immature retinal cells. A key sign of Norrie disease is leukocoria, where the pupils appear white when light is directed into the eye. Over the initial months of life, the irises (the colored part of the eye) or the entire eyeball can shrink and degrade. Cataracts, or clouding of the eye's lens, may also eventually occur.

Approximately 30% of individuals with Norrie disease experience progressive hearing loss. Furthermore, between 30% and 50% exhibit developmental delays affecting motor skills, such as sitting and walking. Additional potential complications include mild to moderate intellectual disability, sometimes accompanied by psychosis, as well as irregularities in circulation, breathing, digestion, excretion, or reproduction.

Inheritance:

Norrie disease follows an X-linked recessive inheritance pattern. X-linked conditions arise when a mutated gene causing the disorder resides on the X chromosome, one of the sex chromosomes. Males, possessing only one X chromosome, are affected if they inherit a single altered copy of the gene in their cells. Females, with two X chromosomes, require a mutation in both copies of the gene to develop the condition. Consequently, X-linked recessive disorders are significantly more prevalent in males than in females. A hallmark of X-linked inheritance is that fathers cannot transmit X-linked traits to their sons.

In X-linked recessive inheritance, a female carrying one altered copy of the gene on one of her X chromosomes is considered a carrier. While she can pass the gene to her offspring, she generally doesn't display the disorder's signs or symptoms. However, in rare instances, carrier females may exhibit some retinal abnormalities or mild hearing loss associated with Norrie disease. These instances occur due to a process called X-inactivation. Early in a female embryo's development, one of the two X chromosomes is permanently deactivated in somatic cells (all cells except egg and sperm). This X-inactivation ensures that females, like males, have only one active X chromosome per cell. The X-inactivation process is typically random, resulting in each X chromosome being active in approximately half of the body's cells. Therefore, in females with an NDP gene mutation (the gene associated with Norrie disease), the X chromosome containing the mutated NDP gene is active in about half of the cells, while the X chromosome with the normal NDP gene is active in the other half. Because this leads to some cells producing functional norrin protein (the protein coded by the NDP gene) and some cells not, females can sometimes exhibit features of Norrie disease.