Cause

The ASXL1 gene

Bohring-Opitz syndrome is caused by mutations in the ASXL1 gene. The ASXL1 gene (OMIM 605039) is located on the chromosome 20q11.21.

ASXL-related disorders, including Bohring-Opitz Syndrome, are epigenetic disorders. The ASXL gene provides instructions for making a protein that is involved in a process known as chromatin remodeling. Chromatin is the complex of DNA and proteins that packages DNA into chromosomes. Through its role in chromatin remodeling, the ASXL1 gene plays an important role in activating and deactivating many genes, including HOX genes. These HOX genes are essential for the development before birth of fertilized ovum to adult organism. ^[3]

The ASXL1 gene can increase the production of some proteins and decrease the production of others. Because the protein is involved in controlling the expression of many other genes, the syndrome can cause changes in many different parts of the body and organ systems, such as in the heart, brain, lungs, and kidneys. ^[4] Therefore, it leads probably to the neurological and physical features of this condition.

ASXL1 gene variants

The type of variant defines how a protein is made. Hereby proteins can be made incorrectly, made in excess, or not made at all. Bohring-Opitz Syndrome is caused by a truncating loss-of-function variant. In truncating variants, the DNA sequence is stopped prematurely which leads to a shorter, nonfunctional protein which leads to the serious functional consequences that cause the symptoms seen in ASXL-related disorders.^[6]

De novo and somatic mutation

The ASXL1 gene is already known to geneticists: a link with cancer has been established. There are two possible situations:

1. The de novo ASXL1 mutation: this causes Bohring-Opitz Syndrome. The gene mutates at conception, creating a developmental disorder that leads to Bohring-Opitz Syndrome.
2. The somatic ASXL1 mutation: The mutation occurs during later life. The patient has an increased risk of acute myeloid leukemia, a form of blood cancer (AML).^[5]