Tag Archives: #reproductivemedicine

ACOG Guidelines

ACOG Access To Genetic Testing

ACOG Fetal Aneuploidy Guidelines

ACOG Microarray Analysis

ACOG Microarrays & Next Gen Sequencing

ACOG Planned Home Birth

ACOG Ultrasound in Pregnancy

Reproductive Medicine – 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

© 2018, GENASSIST, Inc.           

By Keith S. Wexler, MBA, CFO, Business Development Director Life Sciences, 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:  We saw a 36 year old female with one healthy child at approximately 10 weeks gestation who tested “High Risk”(1 in 20) for a having a child with 22q11.2 Deletion Syndrome.

Prior to Maternal Fetal DNA screening tests or microarray in pregnancy, the only way that a patient would know if they had child with a microdeletion was at delivery with an “affected” child.

DiGeorge Syndrome (22q11.2 Deletion Syndrome): Is characterized by heart problems, kidney problems, and/or immune system problems, movement problems and seizures. This syndrome is caused by a loss or rearrangement of a small portion of the long arm of chromosome #22 [22q11.2].

  • Approximate Incidence – 1 in 2,000 births.

The 22q11.2 Deletion Syndrome has several names attributed to it because of the variability of the presentation. The syndrome has also been called Velocardiofacial Syndrome describing involvement of the palate, heart and face, Shprintzen Syndrome or DiGeorge Syndrome.

http://www.22q.org/

Findings can include:

  • cleft palate
  • hearing, speech and learning problems
  • facial changes including small chin
  • low set ears and wide set eyes
  • delayed growth and feeding difficulties
  • poor muscle tone,
  • heart defects such as interrupted aortic arch, common outlet for aorta and pulmonary arteries, ventricular septal defect or Tetralogy of Fallot
  • frequent infections due to hypoplasia of the thymus
  • low calcium due to hypoparathyroidism
  • decreased kidney function.

Approximately 10% of 22q11.2 deletion syndrome cases are familial being inherited from a parent who might have mild symptoms or be unaware of the 22q11.2 deletion in one of their #22 chromosomes.

Approximately 90% of cases are due to a new deletion in that individual and will place each of their children at a 50% (1:2) risk of inheriting the deleted chromosome #22.

“Routine” screening for Microdeletions on all patients is controversial because of the low prevalence of these disorders and the possibility of “false positive” and “false negative” results.

However, when a patient is identified as a candidate for invasive testing i.e. Chorionic Villus Sampling (CVS) and/or amniocentesis, the addition of Microdeletions may be indicated, particularly if family history or ultrasound findings suggest an increased possibility for detection of one of these rare disorders.

Reproductive Medicine – Y Chromosome Genetic Diseases

© 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

There are many disorders that have been linked to the X chromosome (e.g. hemophilia, some types of muscular dystrophy and male developmental delay.

The Y chromosome is quite small and contains relatively few genes which nonetheless are still very important. Several of the genes are linked to male infertility and spermatogenesis and have been identified on the long arm (q-arm) of the Y chromosome (Yq11.2-11.22) including USP9Y, CDY1, DAZ1, DAZ2, DDX3Y, HSFY1 and RBMY1A1.

The SHOX gene identified on the short arm of both the X chromosome (Xp22.33) and the Y chromosome (Yp11.3) has a role in bone growth and maturation.

Mutations in the SHOX gene have been implicated in shortening of the arms and legs including Langer Mesomelic Dysplasia, Leri-Weil Dyschondrosteosis and Turner Syndrome.

  • The SRY gene (Sex Determining Region on the Y chromosome) is also located on Yp11.3
  • The SOX9 gene on chromosome 17q24.3 is related to the SRY gene and plays a role in bone growth

Swyer Syndrome – a disorder reported in approximately 1:86,000 newborn females also called 46,XY Complete Gonadal Dysgenesis presents with female genitalia and a nonfunctional SRY gene. Mutations in the SRY gene n have been identified in up to 15% of these children who may also present with neuropathy and skeletal abnormalities, usually Campomelic Dysplasia.

Other disorders linked to the Y chromosome include:

  • Retinitis Pigmentosa linked to the RPY gene
  • Jacobs Syndrome (XYY)
  • Hypertrichosis Pinnae (excessive ear hair)

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

© 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?  

Reproductive Medicine – Statistical Probability Dilemmas

© 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: 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. Although the family was aware of the possibility of having Preimplantation Genetic Diagnosis (PGD) of the embryos, they chose to achieve pregnancy naturally.

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 chose to have a second pregnancy and again achieved pregnancy naturally. 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 had a family that both the mother and father were carriers of Sickle Cell Anemia and had 4 sons affected with Sickle Cell Anemia. The father was confused why with Mendelian genetics statistical probability of autosomal recessive disease (25% if both parents are gene carriers) 4 sons should have yielded:

  • 1 son – unaffected (25%)
  • 2 sons – carriers (50%)
  • 1 son – affected (25%)

He and his wife truly did not understand that statistical probability could be any variation on the theme including 4 affected sons.

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% in each pregnancy regardless of the statistical risk. 

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