Diagnostic Tests

Diagnostic Tests

Chromosome analysis (karyotype)

The most common diagnostic test (and historically has been around the longest) is a chromosome analysis (also known as a karyotype).  This test is commonly performed on women who are advanced maternal age, and until recently, was the first line test for a structural abnormality found on ultrasound. Cells from a CVS or amniocentesis are cultured, then treated with several chemicals that arrest the chromosomes in the metaphase stage of cellular division, lyse (break) the nucleus and stain the chromosomes (so they are visible to count).  It takes specialized training (cytogeneticists and cytogentic technologists) to recognize each chromosome, make sure they are numerically correct and structurally intact.  In the case of Down syndrome, there is an extra copy of the 21st smallest chromosome (hence the name trisomy 21).  In the case of a de novo (not inherited) translocation (chromosome rearrangement), the cytogeneticist would identify which chromosomes were rearranged and whether any large portions of the rearrangement were missing or duplicated.


The newest (and rapidly becoming the most common) diagnostic test is the microarray.

Think of chromosomes as a set of encyclopedias.  In a chromosome analysis, all the books are counted, but the analysis does not identify whether all the pages are present.  Yes, a chromosome analysis can detect a large deletion (the size of a large chapter perhaps), but smaller pathogenic (disease causing) deletion is just too small to be seen, even with a high-resolution chromosome analysis.  With a microarray, sophisticated molecular techniques are used to identify and count the individual pages of the book.  Why is this important?  Until very recently, chromosomes were the gold standard.  If the chromosomes were normal – there was the assumption the developing fetus was normal.  Pretty simple thought process that turns out to be completely wrong.

When gametocytes (sperm and egg) undergo meiosis (the process that halves the amount of genetic material in the egg and sperm so that when fertilization occurs – the fetus has a normal amount of genetic material) small amounts of genetic material are oftentimes omitted or duplicated.  It is not surprising that small deletion or duplication of genetic material occur given the complexity of cellular division and duplication.  These errors in the genetic code, depending on their location and size can range from mild effects to profound deleterious consequences in a fetus or offspring.  But make no mistake – pathogenic deletions/duplications have an adverse affect.

While the fact that molecular deletions/duplication happen is not surprising, the frequency at which they do is shocking!  Recent studies put the frequency of this phenomena at approximately 1.5-2% of all pregnancies independent of maternal age.   You read that correctly – 1 in 50 to 1 in 75 pregnancies will have a pathogenic genetic abnormality not identifiable by any means other than a microarray.  These genetic abnormalities will not be detected by NIPT, not by the California Prenatal Screening Program and not even detected by a chromosome analysis.  Perhaps even more shocking than the frequency of a microarray abnormality is the fact that it occurs independent of maternal age.

Most people are aware that chromosome abnormalities are found more frequently in women who are advanced maternal age.  That is – as a woman ages, her risk of having a child with a chromosome abnormality increase with each passing year.  For example, at age 18 the risk of having a child with Down syndrome is approximately 1 in 1,500 while at age 42 the risk is about 1 in 40.  Unlike chromosome abnormalities, microarray abnormalities happen in women who are 26 as frequently as they happen to women who are 36.

Does this mean all women should be offered a diagnostic test and microarray?  Yes.  The simple statistical fact is that a 26 year old is more likely to have a fetus affected with a pathogenic microarray abnormality than a 37 year old woman is to have a child affected with Down syndrome.  If the standard of care is to offer the second patient a diagnostic procedure it is obvious the first one should be offered one as well.  In fact, it is now the standard that anyone undergoing genetic counseling at our office will be offered an invasive procedure and diagnostic microarray analysis.

Substantiating the stated risk of a microarray abnormality is the corroboration in the pediatric literature.  Microarray abnormalities are so common it is the first test ordered by pediatricians for a child with developmental delay, autism, intellectual deficits and motor delay.  Not surprising, approximately 20% of those children will have an identifiable microarray abnormality.


Specific Genetic Disorders                                                            

When a patient is at risk for a specific genetic disorder, molecular techniques can be used to identify the presence of a pathogenic mutation in a specific gene.  Usually, this type of testing is performed when a patient has a family history that puts the fetus at risk for a specific genetic disorder or findings on an ultrasound are suggestive enough to warrant testing for a particular genetic disorder.

An example of a common inherited genetic disorde tested for in pregnancy is cystic fibrosis.  All women undergo cystic fibrosis screening as part of their initial prenatal panel.  If they are found to be a carrier and their partner is similarly found to be a carrier, molecular testing on the fetus can be undertaken to determine whether the fetus is affected, unaffected and a carrier or unaffected and not a carrier.

An example of an ultrasound finding that would lead to a specific molecular diagnostic test would be the identification of thin, deformed bones throughout the fetal skeleton.  This finding is classic for osteogenesis imperfecta (brittle bone disease).  This is a condition that would not be verified by a screening test nor any other diagnostic test other than a targeted molecular test looking for a specific mutation in a specific gene.






Why is an ultrasound exam so important in pregnancy?

— During the first trimester, a fetal ultrasound determines the health of an early pregnancy with the measurement of the nuchal translucency.

— During the second trimester, a fetal ultrasound rules out most birth defects with a comprehensive evaluation of the fetal anatomy.

— During the third trimester, a fetal ultrasound evaluates the size of the developing baby and identifies pregnancies with abnormal growth.