© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director, 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. Neurofibromatosis) 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.

Case Study: We received a phone call from a new mother who found out she has one affected newborn twin with Neurofibromatosis and the other twin is unaffected. Since there was no known history of Neurofibromatosis on either mother or father’s side of the family the family was unprepared for the diagnosis.

Neurofibromatosis Type 1 (NF1) is characterized by small or large usually benign tumors of the nerves and connective tissue in the skin and/or other organs. Patients usually have freckling on the armpits and groin and multiple brownish (café-au-lait) spots on the skin. The gene is found on chromosome #17q11.2

Neurofibromatosis Type 1 (NF2) is characterized by benign tumors which develop on the 8th nerve causing dizziness, balance problems, ringing in the ears and deafness. The gene is found on chromosome #22q12.2.

Inheritance: Risk may approach 50% if inherited in an autosomal dominant manner. Autosomal dominant diseases caused by a mutation in a single gene characteristically are variable in onset and severity. Neurofibromatosis can be caused by a new mutation in that individual and subsequently that individual will have a 50% chance of passing the new mutation to a child causing the disease.

Incidence of a new mutation as a cause for this disease is approximately 50%. 50% of cases are transmitted from a carrier parent who may or may not be aware of the presence of the disease.

  • NF1 (17q11.2) – Occurrence 1 in 3000 births – Approximate number of gene mutations, more than 1000
  • NF2 (22q12.2) – Occurrence 1 in 25,000 births – Approximate number of gene mutations, at least 200


Approximate Risks to a Child if the Affected Individual is:

  • Grandparent/Second Degree Relative: Risk should be less than 12.5% that a child will be affected
  • Parent/First Degree Relative: Risk should be less than 25% that a child will be affected
  • Mother/Father/Sibling: Risk may approach 50% that a child will be affected

**Patient should be made aware that no DNA screening is 100% reliable. The risk for being a carrier of the disease is reduced by testing, but no DNA laboratory will declare an individual to be a “non-carrier” due to unknown mutations.

Analysis: Due to the large number of mutations, DNA testing by gene sequencing is NOT performed routinely for Neurofibromatosis unless a known mutation has been identified in an affected relative.