Diseases Detectable by Prenatal Diagnosis

Why do chromosomal abnormalities occur?

Chromosomes are large molecules mainly composed of DNA that convey genetic information contained in the cell nucleus.

Human cells contain 22 pairs of autosomes and one pair (XX or XY) of sex chromosomes, making a total of 46 chromosomes. These 22 pairs (autosomes) are numbered from 1 to 22.

Autosomes pair up to form 46 chromosomes, along with the X and Y sex chromosomes.

Normally, during cell division, autosomes number 46, or sex chromosomes are XX or XY, but sometimes there are excesses or deficiencies, resulting in numerical abnormalities in the chromosomes.

Additionally, structural abnormalities can occur when chromosomes are broken and re-synthesized between chromosomes.

Numerical abnormalities

Abnormalities caused by the deficiency or excess of chromosomes, where usually paired chromosomes become abnormal.

When the normal "disomy" becomes one chromosome, it's called "monosomy", three chromosomes are "trisomy", and four chromosomes are "tetrasomy".

Structural abnormalities

Occur when a chromosome is broken and re-synthesized between chromosomes.

It refers to single abnormalities where part of a chromosome is cut and attaches to another chromosome, or inverts within a single chromosome, changing the structure itself.

Types of Chromosomal Abnormalities (22 pairs of autosomes and trisomy)

The types of autosomal trisomy reported are summarized in the table below.

Many trisomy cases result in miscarriage, but rare cases of live births do occur.

Chromosomal Diseases Detectable by NIPT

Among trisomies, the diseases targeted by NIPT are "Trisomy 21 (Down Syndrome)", "Trisomy 13 (Patau Syndrome)", and "Trisomy 18 (Edwards Syndrome)".

Trisomy 21 (Down Syndrome)

It is a chromosomal disorder where the 21st chromosome is present in triplicate.

It occurs in about 1 in 600 live births and is the most common chromosomal abnormality.

Main symptoms include hypotonia, characteristic facial features, intellectual disability, and developmental delays.

Trisomy 13 (Patau Syndrome)

It is a chromosomal disorder where the 13th chromosome is present in triplicate.

It occurs in about 1 in 10,000 live births.

Main symptoms include microcephaly, eye abnormalities, cleft lip/palate, inguinal hernia, and single transverse palmar crease.

Trisomy 18 (Edwards Syndrome)

It is a chromosomal disorder where the 18th chromosome is present in triplicate.

It occurs in about 1 in 6,000 live births and is more common in females (male: female ratio is 1:3).

Main symptoms include growth retardation, congenital heart defects, complications in the respiratory, digestive, and musculoskeletal systems, and hearing loss.

*Mosaic trisomy

Mosaic trisomy occurs when normal and trisomy cells coexist due to nondisjunction during post-fertilization cell division, often resulting in milder symptoms due to the presence of many normal cells.

The Most Common "Down Syndrome"

Down Syndrome, caused by trisomy of the 21st chromosome, was discovered in 1959.

It is known for moderate intellectual disability, characteristic facial features, congenital heart defects, hypotonia, and gastrointestinal issues.

Most cases result from nondisjunction during the formation of the egg, leading to an extra 21st chromosome.

This condition is not inherited as the parents' chromosomes are normal.

However, the frequency of nondisjunction increases with the mother's age.

It is also thought to occur in about 10% of paternal meiotic divisions.

Causes of Down Syndrome

*Translocation type Down Syndrome, often called Robertsonian translocation, occurs when one of the 21st chromosomes attaches to another chromosome.

This type of Down Syndrome is not related to the mother's age but is more common when one parent, especially the mother, is a carrier of the translocation.

*Translocation type

This condition occurs when one of the 21st chromosomes attaches to another chromosome, making part of the chromosome trisomic. In this case, one parent is a carrier of the translocated chromosome.

There are two possibilities:

1. Both parents have normal chromosomes.

2. One parent is a carrier of the translocation.

In the second case, the translocation is hereditary.

Translocation carriers have no symptoms despite the structural changes in their chromosomes.

The probability of de novo mutation versus inherited translocation is about 3:1.

Robertsonian translocation, which involves chromosomes 13, 14, 15, 21, and 22, occurs when the long arms of these chromosomes join together and the short arms are lost.

The centromere is the part where the long and short arms of a chromosome intersect.

As a result, individuals with Robertsonian translocation have 45 chromosomes instead of the normal 46.

This is the most common type of translocation.

Among these, translocation between chromosomes 14 and 21 is most frequent, and children with this chromosome may have a normal karyotype, be translocation carriers, or have trisomy 21.

Children with trisomy 21 from translocation are called translocation type Down Syndrome.

If the mother is a carrier of the translocation, the birth rate of Down Syndrome children is 10%, and it is even lower if the father is the carrier.

The next most common case is when 21 trisomy children are born due to Robertsonian translocation between chromosomes 13 and 21.

Translocation carriers have one less chromosome.

However, because important genes are not lost from the centromere or the short arm, they are healthy and have no phenotype abnormalities.

*Phenotype

Phenotype refers to the physical expression of an organism's genotype, including morphology, structure, behavior, and physiological traits.

Sex Chromosome Diseases Detectable by Definitive Diagnosis

Among chromosomal diseases, there are those related to sex chromosomes.

Normally, males have XY and females have XX sex chromosomes, but numerical abnormalities are common in sex chromosomes.

They are often discovered during amniocentesis in cases where the mother's age is high, or may not be diagnosed until adolescence.

Trisomy (three sex chromosomes) or tetrasomy (four sex chromosomes) often have milder symptoms compared to autosomal trisomy and may never be detected throughout life.

However, since they affect sex chromosomes, they can cause infertility or genital malformations.

Klinefelter Syndrome (XXY)

Occurs in about 1 in 500 male births.

It is characterized by an extra X chromosome in addition to the normal XY.

Main symptoms include gynecomastia, long limbs, scant body hair, skeletal abnormalities or osteoporosis, heart disease, reduced motor ability, and infertility.

The more X chromosomes, the more severe the symptoms, and there is a higher incidence of heart disease.

Many cases have no symptoms and may never be noticed throughout life.

Triple X Syndrome (XXX)

Occurs in about 1 in 1,000 female births.

It is characterized by an extra X chromosome in addition to the normal XX.

Main symptoms include tall stature, learning disabilities, speech delay, language development delay, delayed motor skill development, behavioral and emotional disorders.

Reproductive capacity is normal.

XYY Syndrome (XYY)

Occurs in about 1 in 840 male births.

It is characterized by an extra Y chromosome in addition to the normal XY.

Symptoms reported include tall stature, hyperactivity, and intellectual impairment, but there are also reports of high intelligence.

There are reports of genital and kidney abnormalities, but no proven association with XYY syndrome.

The more Y chromosomes, the more severe the symptoms. Reproductive capacity is normal.

It is now generally considered within the range of normal individual variation, and may never be detected throughout life.

Mosaic Chromosomes

Occurs in both males and females.

There are various forms, and the incidence is said to be 1 in 10-100 billion.

XX, XY, XO, XXY, and Y can coexist in mosaic cases, which may or may not be associated with disabilities.

Mosaic chromosomes are not detected in blood tests; body cell tests are required.

Sex Chromosome Monosomy

Sex chromosome monosomy is viable for X chromosome (XO, Turner Syndrome) but lethal for Y chromosome (YO), leading to death shortly after fertilization. Similarly, YY and OO are also lethal.

XO is seen in about 1 in 500-600 live births, while it is rarer at about 1 in 3,000 live births due to high fetal loss.

Turner Syndrome

Occurs only in females.

It is characterized by the complete or partial absence of one of the X chromosomes (X, XO).

Symptoms include short stature, webbed neck, congenital heart defects, infertility, etc.

There is no intellectual disability, but 10% have coarctation of the aorta.

Numerical Abnormalities of Sex Chromosomes

Sex chromosome syndrome is said to be caused by numerical abnormalities in chromosomes.

This is caused by nondisjunction of chromosomes.

About half of Klinefelter syndrome cases are due to nondisjunction in the father’s chromosomes (X and Y chromosomes).

Turner syndrome is not related to maternal age, but about 80% of the X chromosomes present as monosomy are derived from the mother.

Thus, most cases involve the loss of the father's sex chromosome.

XO monosomy is seen in about 10% of spontaneous miscarriages.

Miscarriage occurs in about 15% of all pregnancies.

The probability of a live birth with Turner syndrome from XO monosomy is 1/200.

The reason for the difference between XO monosomy cases that lead to miscarriage and those that lead to live birth is still unknown.

Klinefelter syndrome and Turner syndrome have symptoms such as poor development of secondary sexual characteristics and infertility, but there is almost no intellectual impairment or survival issues.

Men with XYY and women with XXX have normal fertility.

Y chromosome contains few genes and does not have physiological functions for protein or DNA blueprints, so men with an extra Y chromosome (XYY) have no significant disabilities.

What about the X chromosome?

The X chromosome has many genes apart from determining sex.

Even with changes in the X chromosome, like in women with XXX, only one X is active, and the other two Xs are inactivated, so there are no major disabilities.

It has been found that X chromosome inactivation is not complete, and some gene regions remain active, which could potentially have some effects.

Importance of Genetic Counseling

Genetic counselors provide information and psychological support to pregnant women and their families who need genetic medicine, such as NIPT.

They offer counseling on what to do next if a positive result is obtained.

What Genetic Counselors Can Do

For example, if you have a child with Down Syndrome, they provide information on future support systems.
They clarify the problems faced by pregnant women and their families, and provide the necessary information and psychological support for the final decision to give birth or not.

You can ask genetic counselors about specialized areas related to genetics.
Just taking a test can increase anxiety depending on the results.
However, the presence of a genetic counselor can significantly reduce this anxiety.