2.1. Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann syndrome, a condition characterized by overgrowth and other signs and symptoms that affect many parts of the body, can result from changes that affect the IC1 region. In some people with this condition, the maternally inherited copy of the IC1 region is methylated along with the paternally inherited copy. Because the IC1 region controls the genomic imprinting of the H19 and IGF2 genes, this abnormality disrupts the regulation of both genes. Specifically, abnormal methylation of the IC1 region leads to a loss of H19 gene activity and increased IGF2 gene activity in many tissues. A loss of H19 gene activity, which normally restrains growth, and an increase in IGF2 gene activity, which promotes growth, together lead to overgrowth in people with Beckwith-Wiedemann syndrome.

In a few cases, Beckwith-Wiedemann syndrome has been caused by deletions of a small amount of DNA from the IC1 region. Like abnormal methylation, these deletions alter the activity of the H19 and IGF2 genes.

2.2. Russell-Silver syndrome

Changes in methylation of the IC1 region are also responsible for some cases of Russell-Silver syndrome, a disorder characterized by slow growth before and after birth. The changes are different than those seen in Beckwith-Wiedemann syndrome and have the opposite effect on growth.

In Russell-Silver syndrome, the paternally inherited copy of the IC1 region often has too few methyl groups attached (hypomethylation). Hypomethylation of the IC1 region leads to increased activity of the H19 gene and a loss of IGF2 gene activity in many tissues. An increase in H19 gene activity, which restrains growth, and a loss of IGF2 gene activity, which normally promotes growth, together lead to poor growth and short stature in people with Russell-Silver syndrome.

2.3. Wilms Tumor

Changes in methylation of the IC1 region have also been found in some cases of Wilms tumor, a rare form of kidney cancer that occurs almost exclusively in children.

In some people with Wilms tumor, the maternally inherited copy of the IC1 region is methylated along with the paternally inherited copy. Abnormal methylation of the IC1 region leads to a loss of H19 gene activity and increased IGF2 gene activity in kidney cells. A loss of H19 gene activity, which normally restrains cell growth, and an increase in IGF2 gene activity, which promotes cell growth, together lead to uncontrolled cell growth and tumor development in people with Wilms tumor. As this mechanism is similar to the one that causes Beckwith-Wiedemann syndrome (described above), it is thought that individuals with Wilms tumor caused by changes in IC1 methylation may later be diagnosed with Beckwith-Wiedemann syndrome.

In most cases, abnormal methylation of IC1 and subsequent changes in H19 and IGF2 gene activity are somatic, which means that they are acquired during a person's lifetime and present only in the some tissues. Rarely, these changes are germline, which means they are present in all of the body's cells.