Tag Archives: #raregeneticdiseases

Microarray Helps Detect Rare Disease (Joubert Syndrome)

© 2017            

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

Joubert Syndrome Type 2 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.

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] and/or Non Invasive Prenatal Screening [NIPS] 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 [NIPT], Non Invasive Prenatal Screening [NIPS] 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.

 

Duchenne Muscular Dystrophy (DMD)

Duchenne Muscular Dystrophy

© 2016            

By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Science 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

I had the pleasure to hear Pat Furlong, Founding President and CEO for the Parent Project Muscular Dystrophy http://www.parentprojectmd.org/site/PageServer?pagename=nws_index speak on August 26, 2016 at the Colorado Life Science Innovation Forum sponsored by the Colorado BioScience Association http://www.cobioscience.com/about-us as a panelist for “The Impact of Patient Input on R&D”.  

Pat has dedicated her life to helping end Muscular Dystrophy as well as finding treatment and cures for other rare genetic diseases: http://www.newyorker.com/magazine/2010/12/20/mother-courage-john-colapinto

Background: We saw a couple that wanted to have a Level II ultrasound and possible amniocentesis due to a family history Duchenne Muscular Dystrophy (DMD). The patient and maternal grandmother’s carrier X for Duchenne Muscular Dystrophy (DMD) had been identified.

Duchenne Muscular Dystrophy (DMD) is an X-linked disease (50% of males will be affected and 50% of females will be carriers).  Rarely carrier females may manifest symptoms of the disorder but symptoms are usually milder.

Level II ultrasound was performed and the probable sex of the baby on ultrasound was male. Since the couple was concerned about the 50% risk of having a male with Duchenne Muscular Dystrophy (DMD) amniocentesis was performed.

  • The amniocentesis returned as 46,XY normal male fetus and the Duchenne Muscular Dystrophy (DMD) gene testing for the Dystrophin gene was negative.

The couple’s second pregnancy was a probable female at time of Level II ultrasound. They were not concerned about the female carrier risk of for Duchenne Muscular Dystrophy (DMD). At the time of ultrasound three ultrasound markers for a chromosomal abnormality were identified. The couple elected to have an amniocentesis to rule-out a chromosomal abnormality.

  • The amniocentesis results returned as 47,XX,+18 – Trisomy 18 female. The couple was very disappointed to learn that their little girl was diagnosed with a probable fatal chromosomal abnormality.

Three years later the couple was pregnant again and wanted to have a Level II ultrasound to again determine sex. At time of Level II ultrasound the probable sex of the baby was male. Again since the couple was concerned about the 50% risk of having a male with Duchenne Muscular Dystrophy (DMD), amniocentesis was performed. 

  • The amniocentesis returned as 46,XY normal male fetus and the Duchenne Muscular Dystrophy (DMD) gene testing for the Dystrophin gene was negative.

The couple continues to speak with us annually still perplexed by the dilemma of statistical probability, since the wife was a known carrier of Duchenne Muscular Dystrophy (DMD) and each male had a 50% risk of being affected. They are still confused why both their males were normal and their one female turned out to have a chromosomal abnormality.

Analysis: The Dilemma of Statistical Probability is a problem that is constantly faced by healthcare providers regardless of the disease or defect the patient is concerned about.

We have pointed out to families for years that the statistical risk of having a miscarriage following an amniocentesis or having a child with Duchenne Muscular Dystrophy or some other disorder is either 0% or 100% for that patient.

*Recently a clinical trial on the effects of an investigational drug for boys ages 6-9 years with Duchenne Muscular Dystrophy was begun (DMD Myostatin Trial – call center 1-877-763-0415). We are all hoping for positive results. 

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