Tag Archives: #microarraypanels

Canavan Disease

© 2018, 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

Definition:

  • Microarray: Computerized analytic system for looking for specific DNA fragments associated with specific diseases (e.g. Spinal Muscular Atrophy or Tay Sachs).

Canavan Disease is a common Ashkenazi Jewish inherited disease with a carrier frequency of (1 in 40) and affects (1 in 6400) pregnancies.

Canavan Disease: Autosomal recessive inheritance (25% if both parents are gene carriers) has been described.

Canavan Disease is a fatal metabolic blood disease usually detected by age 18 months and is characterized by brain deterioration.

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.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in the lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases established 1983 by Abbey Meyers and others got Orphan Drug Act passed 1983.

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. Canavan 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), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

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.

Panels, Panels Everywhere But…

© 2018, 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: As a clinician who has been actively involved in the fields of OB/GYN, Clinical Genetics and Laboratory Cytogenetics (we had our own cytogenetics laboratory for over 30 years), I continue to reflect on the role of genetics in the clinical practice of medicine.

Multiplex panels have opened the possibility of identifying individuals who may be asymptomatic carriers of serious disorders which may manifest in their children or identify genetic changes (mutations) or chromosomal variations which may place a patient and other family members at immediate or future risk.

I have been approached over the past year by companies with Microarray Panels asking whether the American College of OB/GYN (ACOG) will hand down recommendations with the accepted number of disease that should be tested for so that they can design a panel to follow ACOG guidelines (like Cystic Fibrosis, Maternal Fetal DNA etc.)

I remind them that a standard of care is only established when 51% of all OB/GYN’s in the country agree and perform testing on their patients as a routine part of their clinical practice.

These risks are illustrated by:

  • Autosomal dominant deleterious mutations (50% inheritance pattern) – tumor suppressor genes etc.
  • Autosomal recessive diseases (25% inheritance pattern if both parents are gene carriers) – glycogen storage diseases or hemoglobinopathies etc.
  • Chromosomal changes which may cause future serious illness or premature demise.

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 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 the disease is a Microdeletion
  • 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.

Analysis: In the August 2017 publication of Obstetrics and Gynecology (Vol 130, No. 2, pp279-84), Stevens, B. et al “propose specific criteria for the development of expanded carrier screening panels…to help…maximize clinical testing and minimize patient stress, unnecessary cost of follow-up testing and clinician time spent facilitating and performing follow up counseling and testing”.

The article points out that 73% of conditions on current panels Do Not meet their proposed criteria.

Their analysis, suggestions and reasons for inclusion or exclusion are not only carefully researched but well founded and need to be applauded for attempting to provide a sound basis for Carrier Screening. They selected 7 commercial laboratories for their analysis.

The researchers used guidelines from The American College of Medical Genetics and Genomics, The American College of OB/GYN, The National Society of Genetic Counselors and the Society for Maternal-Fetal Medicine. The diseases in their study were primarily:

  • Autosomal recessive conditions with few exceptions
  • With a carrier detection rates of 70% or greater
  • With a carrier prevalence of at least 1 in 100 or higher in at least one well studied population

The study excluded:

  • Adult onset conditions
  • Incomplete penetrance
  • Poorly studied populations
  • Mild phenotype

Conclusion:

The goals of the researchers extreme efforts are clear. They also suggest the clinicians could create their own customized panels, an option which is currently available with several laboratories.

As clinicians we have to deal with the absolute cutoff for various laboratory results such as I in 100 or 1 in 250 or greater than the risk for a 35 year old pregnant patient. This criteria is no different than we had to evaluate in the past.

However, by using these well thought out and reasonable criteria several problems are raised for the clinician:

  • What do we do with serious disorders that are uncommon with unknown carrier frequencies?
  • How do we address serious disorders with carrier frequencies of 1 in 110 or 1 in 125 or even 1 in 101 or 1 in 102?  
  • What is the responsibility of the clinician to his or her patient and family?

Perhaps, as discussed in the excellent editorial in the same journal by Mary E. Norton “…the path of least resistance may be test for everything and deal with the fallout”…and fallout there will most certainly be! “Initial reports estimate that 25% or more of individuals will be identified as carriers; identifying a carrier will next lead to screening for the reproductive partner…”

It is too early to restrict the development of various panels. Certainly the testing will continue to expand and identify additional disorders that will meet (or beat) the criteria we attempt to develop at this point in time.

 

 

 

 

 

 

Ashkenazi Jewish Genetic Diseases – Thrombocytopenia Amegakaryocytic (Congenital)

© 2016

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

With the wonderful advancements with Microarray Screening Panels, a patient can be screened prior to a pregnancy, for a single disease up to a “general panel” that can help screen for hundreds of diseases.

If the patient were found to be a carrier of a disease and/or diseases then the patient’s partner can be tested to help rule out his/her carrier state for those diseases.

Thrombocytopenia Amegakaryocytic (Congenital) is an Ashkenazi Jewish inherited disease with a carrier frequency of (1 in 75) and affects (1 in 7,401) pregnancies.

Thrombocytopenia Amegakaryocytic (Congenital): Autosomal recessive inheritance (25% if both parents are gene carriers) has been described.

Thrombocytopenia Amegakaryocytic (Congenital) is characterized by low blood platelets in infancy which progresses to low red and white blood cells in later childhood. Thrombopoitin (TPO) which regulates platelet production is increased but there is little to no platelet production response to the increased TPO. Mutations in the C-Mpl gene – a TPO surface receptor located on the short arm of chromosome #1 (1p34) has been described in many of these cases.

Symptoms include bruising and bleeding. There is an increased risk for the development of acute myelogenous leukemia and myelodysplastic syndrome (where the body makes abnormal cells in blood or bone marrow).

Platelet transfusions and ultimately bone marrow transplantation is usually required in severe cases.

*The Preconception Ashkenazi Jewish Screen is available in a variety of Panels:

  • Basic Panel – 3 Diseases
  • Expanded Panel – 8 Diseases
  • *Full Panel – 18 Diseases – (One company is running a 3 part Ashkenazi panel that has up to 39 diseases)

*The Full Panel is now also part of many Microarray Panels that can test for over 100 diseases.

The Jewish population is the United States as of 2012 was 6,543,820 making up 2.1% of the entire U.S. population (1).

The Ashkenazi Jewish Inherited Disease Panel was created to help screen for specific ethnic inherited diseases. Preconception testing is suggested to help identify or rule-out the parents as being carriers.

(1) US Census Bureau, Statistical Abstract of the United States, 2012. 

Thrombocytopenia Amegakaryocytic (Congenital)

date count down© 2016

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

With the wonderful advancements with Microarray Screening Panels, a patient can be screened prior to a pregnancy, for a single disease up to a “general panel” that can help screen for hundreds of diseases.

If the patient were found to be a carrier of a disease and/or diseases then the patient’s partner can be tested to help rule out his/her carrier state for those diseases.

Thrombocytopenia Amegakaryocytic (Congenital) is an Ashkenazi Jewish inherited disease with a carrier frequency of (1 in 75) and affects (1 in 7,401) pregnancies.

Thrombocytopenia Amegakaryocytic (Congenital): Autosomal recessive inheritance (25% if both parents are gene carriers) has been described.

Thrombocytopenia Amegakaryocytic (Congenital) is characterized by low blood platelets in infancy which progresses to low red and white blood cells in later childhood. Thrombopoitin (TPO) which regulates platelet production is increased but there is little to no platelet production response to the increased TPO.

Mutations in the C-Mpl gene – a TPO surface receptor located on the short arm of chromosome #1 (1p34) has been described in many of these cases.

Symptoms include bruising and bleeding. There is an increased risk for the development of acute myelogenous leukemia and myelodysplastic syndrome (where the body makes abnormal cells in blood or bone marrow). Platelet transfusions and ultimately bone marrow transplantation is usually required in severe cases.

*The Preconception Ashkenazi Jewish Screen is available in a variety of Panels:

  • Basic Panel – 3 Diseases
  • Expanded Panel – 8 Diseases
  • *Full Panel – 18 Diseases – (One company is running a 3 part Ashkenazi panel that has up to 39 diseases)

*The Full Panel is now also part of many Microarray Panels that can test for over 100 diseases.

The Jewish population is the United States as of 2012 was 6,543,820 making up 2.1% of the entire U.S. population (1).

The Ashkenazi Jewish Inherited Disease Panel was created to help screen for specific ethnic inherited diseases. Preconception testing is suggested to help identify or rule-out the parents as being carriers.

(1) US Census Bureau, Statistical Abstract of the United States, 2012. 

Ashkenazi Jewish Genetic Diseases – Niemann Pick Disease Types A & B

ashkenazi-niemann-pick

© 2016  

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

Niemann-Pick Disease Types A & B are Ashkenazi Jewish inherited diseases with a carrier frequency of (1 in 90) and affects (1 in 32,000) pregnancies.

Niemann-Pick Disease Types A & B: Autosomal recessive inheritance (25% if both parents are gene carriers) has been described.

Niemann-Pick Disease Type A is due to little or no production of the enzyme (acid sphingomyelinase) and is more severe than Type B.

  • Type A usually presents early in childhood and is often fatal by age 2-4 years.
  • Type A is characterized by early enlargement of the liver and spleen, swollen lymph nodes, difficulty feeding, decreased muscle tone, frequent lung infections and brain damage. 

Niemann-Pick Disease Type B is more variable in the production of the enzyme (acid sphingomyelinase).

  • Type B usually appears later in childhood, varies in severity and is characterized by enlarged liver and spleen, respiratory infections, slow growth and developmental delay.

http://www.nnpdf.org/

*The Ashkenazi Jewish Screen is available in a variety of Panels:

  • Basic Panel – 3 Diseases
  • Expanded Panel – 8 Diseases
  • *Full Panel – 18 Diseases – (One company is running a 3 part Ashkenazi panel that has up to 39 diseases)

*The Full Panel is now also part of many Microarray Panels that can test for over 100 diseases.

The Jewish population is the United States as of 2012 was 6,543,820 making up 2.1% of the entire U.S. population (1).

The Ashkenazi Jewish Inherited Disease Panel was created to help screen for specific ethnic inherited diseases. Preconceptional testing is suggested to help identify or rule-out the parents as being carriers.

(1) US Census Bureau, Statistical Abstract of the United States, 2012 

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