Familial Dysautonomia -- Dysautonomia Foundation

Dysautonomia Foundation, Inc

Genetics

The following page provides basic information about the field of genetics as it relates to Familial Dysautonomia. We address how FD is inherited, the discovery of the FD gene, and the availability of genetic testing.

This Page Includes:
How Familial Dysautonomia Is Inherited
Discovery of the FD Gene
Genetic Testing Information and Locations


How Familial Dysautonomia Is Inherited
Familial Dysautonomia is a genetic condition that occurs almost exclusively among people of Eastern European (Ashkenazi) Jewish descent. In this population it is estimated that one in 27 individuals is a carrier of the FD gene. FD is transmitted in a recessive gene fashion.


All parents of children with FD are carriers of the recessive gene that transmits the disease. The affected child has received a double dose of recessive genes – one from the mother and one from the father. For a child to be affected, he or she must inherit two copies of the FD gene.

A parent has no symptoms or warning signs of being a carrier. When two carriers produce a baby, there is a 25% chance with each pregnancy that the recessive genes will pair and produce FD in the child. Thus the first clue for most individuals that they are carriers is the birth of a child with FD.

Discovery of the FD Gene

In 1993 the FD gene was localized to the long arm of chromosome 9 (9q31) and flanking genetic markers (benign variants of DNA) were discovered. This information made possible prenatal diagnosis and carrier genetic testing for people with a family history of FD or whose spouses had a history.

In 2001, the FD gene was identified as IKBKAP. Two mutations in this gene can cause FD.

The most common mutation is in intron 20; >99% of FD individuals have two copies of this mutation (or are are homozygous for this mutation). The result of this mutation is that some of the IKBKAP gene message is not expressed. More specifically, it results in skipping of exon 20 which results in a smaller than normal gene product (a mutant IKAP protein). This skipping mutation is tissue specific which means it affects some tissue types more than others, for example brain tissue cells are affected more than white cells in the blood.

The second mutation is a missense mutation on exon 19 (G to C change). This may result in disrupting a phosphorylation site on IKAP and decreasing its effectiveness.

As of Spring 2001, general population screening for people without a family history of FD became available.

Genetic Testing Information and Locations

How is genetic testing performed?

Genetic testing is performed on a small sample of blood from the interested individual. The DNA is examined with a special probe designed to detect the two known specific mutations. The reliability of the test is greater than 99%.

Who should be tested?

Any individual with Ashkenazi Jewish (Eastern European) origin has a 1 in 27 risk of being a carrier and should consider screening

Any individual who has a family history of FD has an increased risk of being a carrier and should consider a screening test.

If your partner is a carrier, then you should be tested.

How is prenatal diagnosis done?

If both members of a couple are shown to be carriers by genetic testing, prenatal diagnosis by amniocentesis (14-17 weeks) or chorionic villus sampling (10-11 weeks) is possible.

Where is testing performed?

Please see our list of Genetic Testing Locations.

Please see our "Get Tested for FD" poster.

The Dysautonomia Foundation's designated genetic counseling center is at NYU School of Medicine. Israelis may receive genetic counseling at Hadassah Medical Center.

Genetic tests are performed only with an individual's consent. Other genetic tests will not be performed in the absence of consent. However, from a single blood sample it is possible to test for other conditions that also affect Ashkenazi Jewish children. These include Tay-Sachs disease, Canavan disease, cystic fibrosis, Gaucher disease, Bloom's syndrome, Fanconi Anemia A, and Niemann-Pick disease.

To accommodate families interested in prenatal diagnosis and carrier testing, the Dysautonomia Foundation created the Dysautonomia Genetic Counseling Center. The Dysautonomia Genetic Counseling Center works in conjunction with three Molecular Diagnostic Reference Laboratories: Mount Sinai Medical Center in New York under the direction of Dr. Robert Desnick; New York University Medical Center under the direction of Dr. Harry Ostrer; and at Hadassah-Mt. Scopus in Jerusalem, Israel. Testing is performed only after the interested person has received genetic counseling to clarify the benefits and limitations.

copyright (c) 2004, Dysautonomia Foundation, Inc. last modified 2/19/04

	Dysautonomia Foundation, Inc Genetics The following page provides basic information about the field of genetics as it relates to Familial Dysautonomia. We address how FD is inherited, the discovery of the FD gene, and the availability of genetic testing. This Page Includes: How Familial Dysautonomia Is Inherited Discovery of the FD Gene Genetic Testing Information and Locations
	How Familial Dysautonomia Is Inherited Familial Dysautonomia is a genetic condition that occurs almost exclusively among people of Eastern European (Ashkenazi) Jewish descent. In this population it is estimated that one in 27 individuals is a carrier of the FD gene. FD is transmitted in a recessive gene fashion. All parents of children with FD are carriers of the recessive gene that transmits the disease. The affected child has received a double dose of recessive genes – one from the mother and one from the father. For a child to be affected, he or she must inherit two copies of the FD gene. A parent has no symptoms or warning signs of being a carrier. When two carriers produce a baby, there is a 25% chance with each pregnancy that the recessive genes will pair and produce FD in the child. Thus the first clue for most individuals that they are carriers is the birth of a child with FD.
	Discovery of the FD Gene In 1993 the FD gene was localized to the long arm of chromosome 9 (9q31) and flanking genetic markers (benign variants of DNA) were discovered. This information made possible prenatal diagnosis and carrier genetic testing for people with a family history of FD or whose spouses had a history. In 2001, the FD gene was identified as IKBKAP. Two mutations in this gene can cause FD. The most common mutation is in intron 20; >99% of FD individuals have two copies of this mutation (or are are homozygous for this mutation). The result of this mutation is that some of the IKBKAP gene message is not expressed. More specifically, it results in skipping of exon 20 which results in a smaller than normal gene product (a mutant IKAP protein). This skipping mutation is tissue specific which means it affects some tissue types more than others, for example brain tissue cells are affected more than white cells in the blood. The second mutation is a missense mutation on exon 19 (G to C change). This may result in disrupting a phosphorylation site on IKAP and decreasing its effectiveness. As of Spring 2001, general population screening for people without a family history of FD became available.
	Genetic Testing Information and Locations How is genetic testing performed? Genetic testing is performed on a small sample of blood from the interested individual. The DNA is examined with a special probe designed to detect the two known specific mutations. The reliability of the test is greater than 99%. Who should be tested? Any individual with Ashkenazi Jewish (Eastern European) origin has a 1 in 27 risk of being a carrier and should consider screening Any individual who has a family history of FD has an increased risk of being a carrier and should consider a screening test. If your partner is a carrier, then you should be tested. How is prenatal diagnosis done? If both members of a couple are shown to be carriers by genetic testing, prenatal diagnosis by amniocentesis (14-17 weeks) or chorionic villus sampling (10-11 weeks) is possible. Where is testing performed? Please see our list of Genetic Testing Locations. Please see our "Get Tested for FD" poster. The Dysautonomia Foundation's designated genetic counseling center is at NYU School of Medicine. Israelis may receive genetic counseling at Hadassah Medical Center. Genetic tests are performed only with an individual's consent. Other genetic tests will not be performed in the absence of consent. However, from a single blood sample it is possible to test for other conditions that also affect Ashkenazi Jewish children. These include Tay-Sachs disease, Canavan disease, cystic fibrosis, Gaucher disease, Bloom's syndrome, Fanconi Anemia A, and Niemann-Pick disease. To accommodate families interested in prenatal diagnosis and carrier testing, the Dysautonomia Foundation created the Dysautonomia Genetic Counseling Center. The Dysautonomia Genetic Counseling Center works in conjunction with three Molecular Diagnostic Reference Laboratories: Mount Sinai Medical Center in New York under the direction of Dr. Robert Desnick; New York University Medical Center under the direction of Dr. Harry Ostrer; and at Hadassah-Mt. Scopus in Jerusalem, Israel. Testing is performed only after the interested person has received genetic counseling to clarify the benefits and limitations.