Basics

Our DNA carries our hereditary information. Duplication of DNA is the first step of cell division. The large DNA strands are then assembled into large structures, called chromosomes, to ensure both daughter cells receive the identical content as the cell they originated from. Humans have 46 chromosomes, comprised of 23 pairs: 22 so-called autosomes, which are named by increasing numbers from one to 22. One pair is comprised of chromosomes X and Y, called sex chromosomes. Women have two X-chromosomes and men have one X and one Y chromosome. The complete set of chromosomes of any cell is called its karyotype. In order to describe the karyotype in short, the total number of chromosomes per cell are listed/called followed by the type of sex chromosomes. So, men have the karyotype 46, XY and women have the karyotype 46, XX. The genetic information stored in the DNA of the chromosomes makes up nearly 100% of all the genetic information of a cell, which is called the genotype. The total of all physiological and psychological traits is called the phenotype. The phenotype is derived from the genotype (plus possible environmental factors).

Karyogram of the human chromosomes. Preparation from a white blood cell.

The distribution of chromosomes, during the formation of germ cells (egg cells and sperms), can be defective. If the resulting germ cells form with another germ cell the developing fetus can have either more or less chromosomes than usual.

If an individual has only one chromosome instead of a pair, this is called a monosomy, and if three chromosomes are present, it called a trisomy.

Incorrect Distribution of Autosomes

Maldistributions of autosomes lead to autosomal aneuploidies. If an embryo has an autosomal aneuploidy (no matter if a monosomy or a trisomy), in most cases he will not be viable. His mother in most cases will not even realize that she was pregnant for a short time. Exceptions are trisomies of chromosomes 13, 18 and 21. In many cases fetuses with a trisomy 13 or 18 survive the whole duration of pregnancy but most of them die after days or weeks, due to their enormous disabilities. The syndromes caused by these trisomies are called Patau syndrome (trisomy 13) and Edwards syndrome (trisomy 18). Only individuals with a Down syndrome (caused by a trisomy 21) are viable. Individuals with a Down syndrome typically reach an age of more than 60 years on average. Because of their mental disabilities, people with a Down syndrome are often in need of long-term care. When a physician detects a trisomy 21 prenatally, most parents decide to have an abortion. Today many options for support are available for parents of children with special needs.

Maldistribution of sex chromosomes

Children who are born with a sex chromosome aneuploidy (SCA) are generally much less affected than children with an aneuploidy of the autosomes. They typically have no mental disability. The best-known SCAs are Turner syndrome (women with monosomy X, 45,X) and Klinefelter Syndrome (men with the karyotype 47,XXY). Less known because phenotypically even less noticeable are Jacobs syndrome (men with the karyotype 47,XYY) and Triple X syndrome (women with karyotype 47,XXX). Most people with an SCA remain undiagnosed throughout their lives because they have no striking phenotype. If they are diagnosed at all, then typically at an older age. 75% of all men with a Klinefelter Syndrome are never diagnosed. That leads to the misconception that these syndromes are rare diseases, while in reality they are not rare at all – even in comparison to the Down syndrome:

SCA Sex chromosomal aneulpoidies

Table:  Frequencies of the different SCAs (syndromes based on the  incorrect distribution of the sex chromosomes).

Patients with an SCA often have learning impairments in their childhood age. They may have behavioral problems like a low frustration tolerance or a low self-esteem. In addition, they may be at risk for additional diseases. Women with a Turner Syndrome and men with a Klinefelter syndrome typically suffer from infertility. In any case it is important to diagnose these syndromes as early as possible to be able to treat them and to considerably improve the quality of life of those affected.

Microdeletions

In the process of germ cell formation, not only whole chromosomes can be distributed erroneously, but sometimes also fragments of a chromosome can be lost. This is called a deletion. When the lost fragment is so small that the deletion cannot be seen microscopically, it is called a microdeletion. Most microdeletions are very rare, and the affected person can have a very varying phenotype. The most frequent microdeletion affects a part of chromosome 22. The associated syndrome is called 22q11.2 microdeletion syndrome. Before the genetic basis of the syndrome was known, it was called DiGeorge syndrome. One in 1,000 to one in 2,500 people are affected by a DiGeorge Syndrome. As with SCAs, underdiagnosis and late diagnosis are also very frequent with DiGeorge Syndrome, thus depriving the patients of their required therapy. ProviaTest allows doctors/neonatologists to screen newborns early on for this and many other microdeletions which otherwise may never be diagnosed.

Prenatal Screening

The trisomies of chromosomes 21, 18 and 13 and also other genetic conditions can be detected precisely already during pregnancy by an amniocentesis. This invasive procedure comprises taking a small amount of amniotic fluid, which surrounds the fetus, by a hollow needle. The DNA from the fetal cells floating in the amniotic fluid is prepared and analyzed. Given its high accuracy, amniocentesis is still the gold standard of prenatal analysis. It can be performed between weeks 15 and 18 of gestation. The procedure is quite unpleasant for the pregnant women, but the main issue with this method is the rate of 0.5% to 2% of pregnancies that undergo a spontaneous abortion as side effect of the procedure. To avoid this risk, other less invasive methods were sought.

By analyzing the appearance of the fetal neck fold (nuchal translucency) between 11 and 14 weeks of gestation, it is possible to ascertain the risk that the fetus has a trisomy 21. The accuracy of the calculation can be improved by measuring the concentration of two hormones, “PAPP-A” and “ß-HCG” in mothers’ blood. If the result is “low risk”, then a trisomy 21 can almost be excluded. However, in the adverse case of “high risk for a trisomy 21” many results are false positive. This is why every “high risk” result has to be verified by an amniocentesis. The method of measuring the nuchal translucency and the hormonal concentration, however, has reduced the number of invasive procedures. This is why it is referred to as a screening test. It is not as accurate as the diagnostic amniocentesis but is not invasive and has helped to reduce the number of amniocenteses.

A much more accurate screening method for trisomies 21, 18 and 13 was introduced only a few years ago: non-invasive prenatal screening testing (NIPTs). With a simple blood draw from the pregnant women the risk for the three trisomies can be ascertained with 99% accuracy. The worldwide triumph of the NIPTs can be attributed particularly to the less than 1% false positive rate, which led to a strong decline in the number of invasive procedures. However, even for the NIPTs a confirmation of a positive result is strongly recommended.

Because of their accuracy for testing trisomies 21, 18 and 13 NPTs are recommended in several medical guidelines and paid for by public health insurances in various countries. 

Newborn-Screening

In most countries, newborns are generally screened for rare but dangerous metabolic and hormonal diseases. For this purpose, a few days after birth some drops of blood are taken from the newborn’s heel and analyzed in specialized laboratories. Phenylketonuria may be the disease that is most well-known by its name. An enzymatic defect prevents a certain amino acid from decomposing and therefore it enriches in the body. To prevent this harmful enrichment the patients must maintain a strict diet, low in this amino acid. The newborn screening programs differ by country in number and nature of the screened syndromes.

ProviaTest offers a panel of 39 metabolic and hormonal diseases plus Cystic Fibrosis in collaboration with Heidelberg University Hospital screening center. ProviaTest additionally provides for an extension of newborn screening to SCAs and microdeletions which otherwise would not be diagnosed in many cases.

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