Opitz G/BBB syndrome

What causes Opitz G/BBB syndrome?

The X-linked form of Opitz G/BBB syndrome is caused by mutations in the MID1 gene. The MID1 gene provides instructions for making a specific protein called midline-1. This protein helps regulate the function of microtubules, which are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules help cells maintain their shape, assist in the process of cell division, and are essential for the movement of cells (cell migration). The MID1 gene is a member of a group of genes called the TRIM (tripartite motif) family. The proteins produced from this large family of genes are involved in many cellular activities. Primarily, TRIM proteins play a role in the cell machinery that breaks down (degrades) unwanted proteins. As part of its protein degrading function, midline-1 is responsible for recycling certain proteins, including phosphatase 2A (PP2A), integrin alpha-4 (ITGA4), and serine/threonine-protein kinase 36 (STK36). The recycling of these three proteins so they can be reused instead of broken down is essential because they are needed for normal cellular functioning. Mutations in the MID1 gene lead to a decrease in midline-1 function, which prevents this protein recycling. As a result, certain proteins are not recycled, and they buildup in cells. This buildup impairs microtubule function, resulting in problems with cell division and migration. Researchers speculate that the altered midline-1 protein affects how the cells divide and migrate along the midline of the body during development, resulting in the features of Opitz G/BBB syndrome.

Some people who have a family history of X-linked Opitz G/BBB syndrome have no detectable MID1 mutation. The reason for this is not yet known, although some researchers have suggested the involvement of other unknown genes.

The autosomal dominant form of Opitz G/BBB syndrome is caused by a deletion of a small piece of chromosome 22, specifically 22q11.2, which is why researchers consider this condition to be part of 22q11.2 deletion syndrome. It is not yet known which deleted gene(s) within this region of chromosome 22 specifically cause the signs and symptoms of Opitz G/BBB syndrome. In others with autosomal dominant Opitz G/BBB syndrome, the cause is related to a mutation in the SPECCIL gene.

Last updated on 05-01-20

How is Opitz G/BBB syndrome diagnosed?

The diagnosis of Opitz G/BBB syndrome is usually based on clinical findings. In order to differentiate the X-linked form from 22q11.2 deletion syndrome (the autosomal dominant form), the pattern of inheritance within the family may be assessed. Molecular genetic testing for mutations in the MID1 gene is available for confirmation. Between 15 and 45% of males with clinically diagnosed Opitz G/BBB syndrome are found to have a mutation in this gene.

Last updated on 05-01-20

How is Opitz G/BBB syndrome inherited?

Opitz G/BBB syndrome often has an X-linked pattern of inheritance. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes (the other sex chromosome is the Y chromosome). In most cases, males experience more severe symptoms of the disorder than females. This is because females have two different X chromosomes in each cell, and males have one X chromosome and one Y chromosome. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons, because fathers only pass a Y chromosome on to their sons (which is what makes them male). In some cases, an affected person inherits a mutation in the MID1 gene from an affected parent, while in other cases, it may result from a new mutation ( de novo ) in the affected individual. These cases occur in people with no history of the disorder in their family.

A female who has the X-linked form of Opitz G/BBB syndrome has a 25% (1 in 4) chance to have a daughter with the mutation, a 25% chance to have a son with the mutation, a 25% chance to have an unaffected daughter, and a 25% chance to have an unaffected son. This also means that there is a 50% chance, with each pregnancy, for the child to inherit the mutation. A male with the X-linked dominant form of Opitz G/BBB syndrome will pass the mutation on to all of his daughters and none of his sons.

Researchers have also described an autosomal dominant form of Opitz G/BBB syndrome caused by a deletion in one copy of chromosome 22 in each cell. In some cases, an affected person inherits the chromosome with a deleted segment from a parent, while in other cases, the condition results from a new deletion in the affected individual. These cases occur in people with no history of the disorder in their family. Males and females with the autosomal dominant form of Opitz G/BBB syndrome usually have the same degree of severity of symptoms. A male or female who has the autosomal dominant form of Opitz G/BBB syndrome has a 50% (1 in 2) chance with each pregnancy for the child (male or female) to inherit the genetic abnormality.

Last updated on 05-01-20

How can we be sure that this is the right diagnosis?

Genetic testing may help confirm the diagnosis. MID1 is the only gene in which mutations are currently known to cause X-linked Opitz G/BBB syndrome. Between 15 and 45% of males with clinically diagnosed Opitz G/BBB syndrome are found to have a mutation in this gene.

We strongly recommend that you work with a genetics professional who can help you better understand the role of genetic testing in the diagnosis of Opitz G/BBB syndrome.

Last updated on 05-01-20

What is Opitz G/BBB syndrome?

Opitz G/BBB syndrome is an inherited condition that affects several structures along the midline of the body. The most common features are wide- spaced eyes and defects of the larynx, trachea, and/or esophagus causing breathing problems and difficulty swallowing. Affected males usually have a urethra opening on the underside of the penis (hypospadias). Other features can include mild intellectual disability, cleft lip and/or a cleft palate, heart defects, an obstruction of the anal opening (imperforate anus), agenesis of the corpus callosum, and facial abnormalities. These features may vary, even among members of the same family.

There are two forms of Opitz G/BBB syndrome, which are distinguished by their genetic causes and patterns of inheritance. The X-linked form is caused by mutations in the MID1 gene. Autosomal dominant Opitz G/BBB syndrome is caused by a deletion of 22q11.2, and is often referred to as 22q11.2 deletion syndrome.

Treatment depends on the individual’s specific needs.

Last updated on 05-01-20

Is there a cure for Opitz G/BBB syndrome?

No. There is no cure for Opitz G/BBB syndrome.

Last updated on 05-01-20

How might Opitz G/BBB syndrome be treated?

Because of the wide range of signs and symptoms that may be present in affected individuals, management of Opitz G/BBB syndrome typically incorporates a multidisciplinary team consisting of various specialists. Treatment for the condition may include surgery for significant abnormalities involving the larynx, trachea and/or esophagus; surgical intervention as needed for hypospadias, cleft lip and/or cleft palate, and imperforate anus; therapy for speech problems; surgical repair as needed for heart defects; neuropsychological support; and special education services.

Last updated on 05-01-20

Name: CHASER (Congenital Heart Anomalies -- Support, Education & Resources, Inc.) 2112 North Wilkins Road
Swanton, OH, 43558, United States
Phone: 419-825-5575 Fax : 419-825-2880 Email: CHASER@compuserve.com Url: http://www.csun.edu/~hcmth011/chaser/contact.html
Name: About Face International 51 Wolseley Street Toronto, ON M5T 1A4
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Name: FACES: The National Craniofacial Association PO Box 11082
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Phone: 423-266-1632 Toll Free: 800-332-2373 Email: faces@faces-cranio.org Url: http://www.faces-cranio.org/
Name: The International 22q11.2 Foundation Inc. PO Box 532
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Phone: 877-739-1849 Email: info@22q.org Url: http://www.22q.org
Name: Ameriface PO Box 751112
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Phone: 702-769-9264 Toll Free: 888-486-1209 Email: info@ameriface.org Url: http://www.ameriface.org
Name: American Heart Association 7272 Greenville Avenue
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Phone: 214-570-5978 Toll Free: 800-242-8721 Email: https://www.heart.org/en/forms/general-questions-and-latest-research-information Url: https://www.heart.org
Name: ACPA Family Services 1504 East Franklin Street, Suite 102
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El-Ellaa SSA, El Gendya F, Tawfika MAM, Sobkyb EE, Khattaba A & El-mekkawya AM. Chromosome 22 microdeletion in children with syndromic congenital heart disease by fluorescent in situ hybridization (FISH) Egyptian Journal of Medical Human Genetics. October, 2012; 13(3). 313-32. Reference Link

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