Tag Archives: #autosomalrecessivediseases

Reproductive Medicine – Patient Confusion Over Who Should Be Screened Before Pregnancy?

Friday, 05 October 2018 15:45
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© 2018, GENASSIST, Inc.     

By Keith S. Wexler, MBA, CFO, Business Development Director, Consultant

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:

We received the following cold-email and it helps illustrate the excitement and confusion that all of the wonderful genetic tests that are available to consumers are creating and the misunderstanding of the pros and cons of seeking such testing:  

  • “I am interested in more information regarding genetic screening for Fanconi Anemia. My daughter is contemplating getting pregnant and my wife and I would like to rule out the potential of our daughter being a carrier by screening me for the gene.”             

Our email response to the father was:

  • Who in the family has Fanconi Anemia?
  • What led you and your wife to request Fanconi Anemia testing?
  • Are you of Ashkenazi ancestry? If yes, are you aware that there are Ashkenazi Jewish Inherited Disease panels that can help identify or rule-out over 40 diseases often for the same cost as trying to rule out a single disease?
  • Even if you are not a “carrier” do you understand that does Not rule out your daughter being a carrier, since your daughter’s mother can be a carrier?

To date, we have not received a response to our questions.Fanconi Anemia is has a carrier frequency of (1 in 89) and affects up to (1 in 31,000) pregnancies. It is more common in individuals of Ashkenazi Jewish heritage.

  • Very rarely, Fanconi Anemia can be inherited in a Sex (X-Linked) manner.
  • 50% of male or female children from a carrier female (mother) can inherit the gene.
  • Mutations in up to 15 genes have been described as involved in the disease.

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

Fanconi Anemia is characterized by abnormal skin pigmentation, abnormal forearms, abnormal or absent thumbs and urinary tract abnormalities.

Heart, intestinal and other skeletal abnormalities may be present. Bone marrow failure usually occurs in early childhood and patients with this disease are at an increased risk for malignancies.

Analysis:The dilemma for healthcare providers, especially genetic counselors, that are being called upon to help patients navigate the myriad of genetic test(s), microdeletion, microarray panels is addressing the when and why the patient is requesting the specific test(s) he/she is requesting.

Although on the surface, the above email inquiry seems simple, “I want to be tested for Fanconi Anemia…to rule out the potential of our daughter being a carrier by screening me for the gene” really does not make medical sense.

Even if the mother and father are Fanconi Anemia negative, that does not mean that the daughter does not have Fanconi Anemia.

If the father wants to rule out whether or not his daughter is a carrier or not of a specific gene, then logic would dictate that he should test the daughter.

This raises a huge ethical dilemma for the parents depending upon which state or country the family lives in. In the United States, there are many states that will not allow a parent to test their “unaffected” child to see if he or she is a carrier of a disease until the child becomes an adult.

If the disease that the parent is concerned about (i.e. Alzheimer’s, Parkinson’s etc.) will not affect the child until he or she is an adult, many states believe that since the test result may affect that child’s “quality of life”, and it should be the child’s decision and not the parents decision to get tested.

How does a parent weight the benefits of “protecting” his or her child from harm (i.e. Fanconi Anemia) versus the possible damage of finding out information that might or might not affect their child in his or her lifetime?  

Ethnicity Unknown – Universal Carrier Screening

Friday, 24 November 2017 08:00
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© 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

Overview: The United States prides itself as a multicultural multiethnic society. The medical community attempts to classify certain disorders by ethnic origin. The racial, religious and cultural diversity among the population makes the concept of screening on the basis of “ethnicity” alone a naïve concept.

In the last several months GENASSISTTM has been contacted by a carrier parent(s) or patients with a first degree family member who is found to be a carrier for a disease that is more common in a specific ethnic group using DNA/Microarray screening that can screen patients for over 100 diseases.

Single ethnic screening tests for Sickle Cell Anemia, Alpha or Beta Thalassemia, Tay Sachs Disease, Cystic Fibrosis, Canavan Disease are being replaced by more comprehensive panels. With traditional “ethnicity” screening:

  • Black/African Americans are screened for Sickle Cell Anemia
  • Ashkenazi Jews for Tay Sachs or Canavan Disease
  • Caucasians for Cystic Fibrosis
  • Greeks/Italians for Beta Thalassemia

Yet we know that French Canadians and Cajuns have a high incidence of Tay Sachs, Saudi Arabians have a high incidence of Sickle Cell Disease and Asians and Pacific Islanders have a high incidence of Alpha Thalassemia. Also, many couples when questioned are either unsure or have no knowledge of their ethnic background or define themselves as multiracial and/or multiethnic.

http://ecs.counsyl.com/

Over the past 10-20 years the prohibitive costs of screening for carriers of various autosomal recessive diseases made consideration of more expanded screening untenable.

With single disease screening varying in cost from $250 to $350 per disease, patients and healthcare providers appropriately limited the number of disorders screened for or decided against the type of screening altogether.

Likewise, insurance companies have either been unwilling or reluctant to cover “ethnic screening” except for the most basic, due to the cost.

The Ashkenazi Screen that screens for 18 diseases that are the most common in the Ashkenazi Jewish population previously cost almost $6000 for the entire panel.  

Insurance companies would only pay for a limited panel of Tay Sachs, Canavan Disease and Cystic Fibrosis.

Patients could have the expanded panel but insurance might not pay for the additional diseases unless an affected family member with a specific disease or a known carrier was identified. Therefore, the cost of screening possible “carrier” patients was financially prohibitive for most patients.

Following the trend toward safer and more accurate Non Invasive Prenatal Testing, [NIPT] more healthcare professionals are working with Microarray companies to make “Universal” carrier screening available to their patients.

Microarray is defined as a DNA platform that uses probes to identify critical sites along the genome associated with specific diseases. These Microarray technological breakthroughs now allow patients to screen for many diseases from A (Alpha-1 Antitrypsin Deficiency) to Z (Zellweger Spectrum Disorders) for a fraction of the cost.

Analysis: Universal Microarray “ethnic” screening panels are reliable, available and cost effective.

Although we cannot screen for “everything”, the panels allow increased screening for more of the disorders that can seriously impact the health of the child.

Also, the cost of screening is now within reach of most families.  With carrier frequencies as high a 1:25, now is an appropriate time to review our approach.

Pre Pregnancy Genetic Screening – Dihydrolipoamide Dehydrogenase Deficiency (DLD)

Monday, 14 August 2017 08:00
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© 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: On February 23, 2017 the American College of OB/GYN (ACOG) issued a guideline recommending that all healthcare providers should – “Offer All Women Pre Pregnancy Genetic Screening – Testing Partners May Be Considered As Well”.

There are between 4,000 and 20,000 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.

This is a follow-up to September 25, 2015 release: ACOG Release First Ever Guidance on Pregnancy in Women With Genetic Conditions.

Analysis: The healthcare provider is faced with the responsibility of recommending testing which may detect patients who are carriers of 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 even which diseases should be tested for except for those already with recommended (e.g Cystic Fibrosis, Fragile X, SMA 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 be expected as the number of diseases tested for in a panel increases the greater percentage of “variants of uncertain clinical significance” will increase.

Dihydrolipoamide Dehydrogenase Deficiency (DLD) is a rare Ashkenazi Jewish inherited disease with a carrier frequency of (1 in 107) and affects (1 in 45,796) pregnancies.

Dihydrolipoamide Dehydrogenase Deficiency (DLD): Autosomal recessive inheritance (25% if both parents are gene carriers) has been described.

Dihydrolipoamide Dehydrogenase Deficiency (DLD) is variable in onset and severity and may be characterized by:

  • Abdominal pain
  • Enlarged liver
  • Vomiting
  • Brain dysfunction due to the abnormal accumulation of amino acids

 

 

 

Lipoamide Dehydrogenase Deficiency E3

Monday, 28 November 2016 08:00
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http://genassistabcs.com/black-singles-over-40/

© 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

Lipoamide Dehydrogenase Deficiency E3 is an Ashkenazi Jewish inherited disease with a carrier frequency of (1 in 71) and affects (1 in 20,000) pregnancies.

Lipoamide Dehydrogenase Deficiency E3: Autosomal recessive inheritance (25% if both parents are gene carriers) has been described.

Lipoamide Dehydrogenase DeficiencyE3 is characterized by variable onset and severity from fatigue to severe lactic acidosis causing hyperventilation, abdominal pain and possible vomiting. If untreated, may be fatal.

http://genassistabcs.com/dating-sites-worldwide/

*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 

Ashkenazi Jewish Genetic Diseases – Joubert Syndrome Type 2

Friday, 25 November 2016 08:00
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ashkenazi-joubert-syndrome

© 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

Case Study:

A 32 year old patient who had told her OB/GYN on her medical intake form that she was of Caucasian ancestry was found to be a carrier of Joubert Syndrome Type 2 on a Microarray screening test. The OB/GYN is using Microarray screening on many of his patients as a way to help identify rare autosomal recessive diseases early in pregnancy so that there is time to also screen the partner.

The patient’s partner also described himself as being of Caucasian ancestry. When the Joubert testing on the partner was performed, he was also found to be a carrier of Joubert Syndrome Type 2.

After the patient and her partner were found to be carriers of Joubert Syndrome Type 2, they both contacted their families. After further research, both the patient and her partner discovered that they were of Ashkenazi Jewish ancestry.

Joubert Syndrome Type 2 (Cerebelloculorenal Syndrome) is an Ashkenazi Jewish inherited disease with a carrier frequency of (1 in 110) and affects (1 in 48,000) pregnancies.

Joubert Syndrome Type 2 (Cerebelloculorenal Syndrome) : Autosomal recessive inheritance (25% if both parents are gene carriers) has been described.

Joubert Syndrome Type 2 (Cerebelloculorenal Syndrome) is characterized by decreased muscle tone and coordination, abnormal eye movements and breathing patterns, possible developmental delay and/or seizures, kidney and liver problems.

The patient and her partner were referred to our office for an amniocentesis to confirm or rule out a baby with Joubert Syndrome Type 2.

Amniocentesis was performed and the baby was found to be unaffected with the disease, but was found to be a carrier of a single mutation for Joubert Syndrome Type 2.

http://www.jsrdf.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

Analysis:  Prior to the Microarray screening panels, many of which are screening for over 100 autosomal recessive diseases, this patient and her partner would not have known that they were “silent” carriers of the Joubert Syndrome Type 2 until they delivered a child that was affected with the disease.

It is unlikely that a 33 year old patient would have chosen to have an amniocentesis if all of her Non Invasive Prenatal Testing [NIPT] results came back as “Low Risk”.

The dilemma for healthcare providers is that even if the patient had chosen to have an amniocentesis due to a high risk result on a screening test, testing for Joubert Syndrome Type 2 would not have been included since there was no family history of Joubert Syndrome Type 2 nor did the patient nor her partner know that they were carriers.

Microarray helped unlock a risk for an “ethnic disease” that would not have been detected only a few years ago.

As we head forward in the brave new world of Non Invasive Prenatal Testing and Microarray, we will be performing more chromosome, microdeletion and/or microarray problem focused amniocentesis, rather than amniocentesis traditionally based upon a mother’s maternal age related risk.

However, as with any screening test, that means that women of all ages who are detected as being carriers for rare diseases will have the weigh the risks, benefits and limitations of invasive testing. 

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