By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.
Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.
Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center
Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital
Mode of Inheritance Definitions:
- Autosomal Dominant Inheritance: Risk is 50% (1 in 2) that a child will be affected if there is an affected parent.
- Autosomal Recessive Inheritance: Risk is 25% (1 in 4) if both parents are gene carriers.
- *Contiguous Gene Syndrome(s) – usually refer to multiple syndromes caused by gain (duplications) or loss (deletions) of small pieces of a specific chromosome which are only detected by special testing using fluorescent probes or microarray methods. Symptoms may vary between affected individuals depending on the genes duplicated or lost.
- Microdeletion(s) Inheritance: Most microdeletions are sporadic which means that they usually occur spontaneously and are not inherited from a parent. If however a parent is a carrier of a microdeletion on one chromosome the risk to each child may approach 50% (1 in 2) if the child inherits the parent’s abnormal chromosome.
Case 1: A patient contacted our office stating that she lost her last child to DiGeorge Syndrome. Her healthcare provider wanted her to see us for a genetic consultation to discuss the risk of recurrence for DiGeorge Syndrome.
- The patient stated that she did not want to have a genetic consultation since she was with a new partner and therefore could not have another child with DiGeorge Syndrome.
Case 2: A healthcare provider ordered a Maternal Fetal DNA panel and the patient’s result returned with an increased risk of 1 in 20 for a baby affected with DiGeorge Syndrome.
- The patient contacted us on her own to schedule a genetic consult to discuss prenatal diagnostic testing. She was confused about the inheritance pattern for DiGeorge Syndrome since her healthcare provider told her that if her husband tested negative for DiGeorge that her baby would not be affected.
Both these cases help illustrate a confusion or misunderstanding of the inheritance pattern on the part of the patient and the healthcare provider both believing that microdeletions occur in an Autosomal Recessive manner like Cystic Fibrosis or Sickle Cell Anemia.
Fetal DNA from the trophoblasts circulating in the maternal circulation makes it possible for laboratories to screen for Fetal DNA in pregnancy.
Fetal DNA represents approximately 10-14% of Cell Free DNA in the maternal Circulation.
Prior to Maternal Fetal DNA screening tests in pregnancy, with a negative family history, the only way that a patient would know if they were “carriers” of a microdeletion was at delivery with an “affected” child. Most microdeletions are sporadic which means that they usually occur spontaneously and are not inherited from a parent.
In addition to DiGeorge Syndrome (22q11.2) other examples of Contiguous Gene Syndromes include:
- Alagille Syndrome (20p12)
- Angelman Syndrome (15q11)
- Langer-Giedion Syndrome (8q24.1)
- Miller-Dieker (17p13.3)
- Prader-Willi Syndrome (15q11)
- Rubenstein-Taybi (16p13)
- Williams Syndrome (7q11.23)
* The incidence of spontaneous gene mutations for Autosomal Dominant disorders is approximately 1500 per 1,000,000.
MICRODELETION TEST ADDITIONS (varies by laboratory):
Angelman Syndrome (15q11): Is a specific type of severe developmental delay where a patient may have balance and/or walking problems. This type of developmental delay is caused by a loss of a small portion of the long arm of chromosome #15.
- Incidence – (1 in 12,000 births).
Cri Du Chat Syndrome(5p- Syndrome): Is a specific type of developmental delay where a patient may have a cry resembling a cat or kitten. This type of developmental delay is caused by a loss of a small portion of the short arm of chromosome #5.
- Incidence – (1 in 20,000 births).
DiGeorge Syndrome (22q11.2 Deletion Syndrome): Is characterized by heart problems, kidney problems, and/or immune system problems, movement problems and seizures. This syndrome is caused by a loss or rearrangement of a small portion of the long arm of chromosome #22 [22q11.2].
- Incidence – (1 in 2,000 births).
Jacobsen Syndrome (11q23 Deletion Syndrome): Is variable but most individuals affected are characterized by developmental delay involving motor skills and speech, behavioral problems. Part of the syndrome includes Paris-Trousseau Syndrome due to a platelet abnormality with bleeding and bruising.
- Incidence – (1 in 100,000 births).
Langer-Giedion Syndrome (8q24.1 – Trichorhinophalangeal Syndrome Type 2): Is characterized by sparse hair (tricho), prominent nose (rhino), shortening and deformities of fingers and occasionally toes (phalangeal). Outgrowth of bone from the surface of bone (exostoses) and developmental delay may also occur.
- Incidence – (1 in 25,000 births).
1p36 Syndrome: Is characterized by developmental delay and weak muscle tone. This syndrome is caused by a deletion of genes at the end of the short arm of chromosome #1.
- Incidence – (1 in 5,000 births).
Prader-Willi Syndrome (15q11): Is characterized by developmental delay and weak muscle tone. A compulsive eating disorder which can lead to obesity can develop later. This syndrome is caused by a deletion of a small portion of the long arm of chromosome #15.
- Incidence – (1 in 10,000 births).
Wolf-Hirschhorn Syndrome: Is characterized by low birth weight, low muscle tone, growth and developmental delay. This syndrome is caused by a deletion of a small portion of the short arm of chromosome #4 [4p-].
- Incidence – (1 in 50,000 births).
At the current time the value of “routine” screening for Microdeletions on all patients is controversial because of the low prevalence of these disorders and the possibility of “false positive” and “false negative” results. Yet, as more patients have Non Invasive Prenatal Testing [NIPT] using Maternal Fetal DNA in pregnancy great care must be taken that the patient is counseled about the mode of inheritance an appropriate prenatal diagnostic testing if desired.