© 2017, GENASSIST, Inc.     

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

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Smith Lemli Opitz Syndrome) and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers)
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family
  • Whether there is testing for the disease and/or syndrome

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background.

With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required.

[*A recent study, that is ongoing, has suggested a possible relationship between maternal age (35 years or older) and/or paternal age (greater than 40 years) and autism and/or autism spectrum disorder(s) in a child. Reference: Israel & Mt. Sinai, NY.  *Some recent studies have suggested risk may be as high as 1:50 to 1:80.       

Smith-Lemli-Opitz Syndrome is a disorder of variable severity inherited in an autosomal recessive manner (25% if both parents are gene carriers).

Smith-Lemli-Opitz Syndrome is caused by a deficiency in the 7 Dehydrocholesterol Reductase (DHCR-7) enzyme that affects cholesterol metabolism.

Smith-Lemli-Opitz Syndrome affects multiple systems resulting in possible:

Cleft palate

Characteristic facial features

Heart defects

Extra fingers and/or extra toes

Fusion of 2nd and 3rd toes

Underdeveloped male genitalia

Variable developmental delay

Gastrointestinal problems (occasional)

Smith-Lemli-Opitz Syndrome is reported to affect 1 in 20,000 to 1 in 60,000 births.

Smith-Lemli-Opitz Syndrome gene carriers are more frequent than the incidence of live born suggesting that many Smith-Lemli-Opitz Syndrome infants are miscarried or stillborn.

The diagnosis can be made by serum determination of elevated cholesterol and 7 Dehydrocholesterol/cholesterol ratios.

*Prenatal diagnosis is available.

Treatment is directed at specific findings in the affected individual and cholesterol supplementation with bile acid may alleviate some of the symptoms.

Statin drugs may reduce cholesterol levels.