Cytogenetics Laboratory – Faculty of Medicine in Rijeka

Location:

Faculty of Medicine in Rijeka
Department of Medical Biology and Genetics (main building, second floor)

Braće Branchetta 20, 51 000 Rijeka

Contact:

Phone: +385 (0)51 651 131
Fax: +385 (0)51 678 89
E-mail: medgen@medri.uniri.hr

Service description

1. NONINVASIVE PRENATAL TESTING – PANORAMA

PANORAMA is a noninvasive prenatal screening test used to assess the risk of trisomy 13, 18, 21, sex chromosome aneuploidy and triploidy in the fetus during the current pregnancy. The test analyses fetal DNA from a pregnant woman’s blood sample containing cell-free fetal and maternal DNA. The analysed fetal DNA originates from the placenta; in 98% of all pregnancies, this DNA is identical to the DNA found in the fetal cells. Before doing the test, it is recommended to consult a physician. The test results can be shown as follows:

LOW RISK indicates a reduced probability that the fetus has one of the tested syndromes, but there is no guarantee that there are no chromosomal abnormalities, i.e. a healthy child

HIGH RISK indicates a high probability that the fetus has one of the tested chromosomal abnormalities but cannot confirm it. It is recommended to confirm the results by a diagnostic method such as fetal blood sampling, chorionic villus sampling (from 11^th to 13^th week of pregnancy) or amniocentesis (from 15^th to 18^th week of pregnancy).

SAMPLE REQUIRED FOR THE TEST: pregnant woman’s blood (8–10 ml, two test tubes) from the 9^th week of pregnancy
PATIENT ADMISSION: MONDAY AND TUESDAY FROM 9 AM TO 1 PM (you must first schedule an appointment by phone)
- DURATION OF THE TEST: 10–15 DAYS
SERVICE COST: HRK 3,200.00
- Payment at the Department or to the Faculty’s transfer account
- Account name: University of Rijeka, Faculty of Medicine, B. Branchetta 20, 51000 Rijeka, Croatia
- Bank: Zagrebačka banka d.d.
- IBAN: HR9323600001101410222
- SWIFT: ZABAHR2X
- Reference number: HR00-payer’s OIB-03
- Payment description: NIPT Panorama and patient’s name and surname

2. CYTOGENETIC ANALYSIS OF AMNIOTIC FLUID

CYTOGENETIC ANALYSIS OF AMNIOTIC FLUID detects the fetal karyotype. This test requires 20 ml of amniotic fluid obtained by amniocentesis and performed at the Clinic for Gynecology and Obstetrics (CHC Rijeka). Cytogenetic analysis is performed using the GTG banding method. The test results are ready after 2–3 weeks.

SAMPLE REQUIRED FOR THE TEST: 20 mL of amniotic fluid
PATIENT ADMISSION: WEDNESDAY (amniocentesis is performed at the CHC Rijeka, Clinic for Gynecology and Obstetrics)
- DURATION OF THE TEST: 2–3 WEEKS
SERVICE COST: HRK 2,500.00 or internal referral of the CHC Rijeka

ABOUT AMNIOCENTESIS:

Amniocentesis is a procedure in which amniotic fluid is aspirated under ultrasound. It is performed between the 16^th and 20^th week of pregnancy. The ultrasound enables monitoring of the needle passing through the front abdominal wall into the amniotic cavity, which makes this procedure relatively safe. However, it should be kept in mind that amniocentesis is an invasive test and that in 0.5% of cases, complications such as fetal loss or sepsis may occur.

INDICATIONS FOR AMNIOCENTESIS:

Positive screening test (various first- and second-trimester prenatal screening tests)
Ultrasound findings (fetal anomalies)
Down syndrome in a previous pregnancy and/or family – structural chromosomal aberrations present in a previous pregnancy and/or in the parents
Maternal age (the frequency of chromosomal aberrations, especially trisomy 21 (Down syndrome), increases with advanced maternal age. For example, a 20-year-old woman has a 1:1,600 probability of giving birth to a child with Down syndrome, while at the age of 35, that probability is 1:350 and at 41, the chance is 1:80)

*ADDITIONAL TESTS: CYTOGENETIC ANALYSIS OF PARENTS’ PERIPHERAL BLOOD LYMPHOCYTES in cases of detected FETAL STRUCTURAL ABERRATIONS (balanced and unbalanced aberrations, deletions, additions, marker chromosome, etc.). The duration of the test is up to 3 weeks.

3. CYTOGENETIC ANALYSIS OF PERIPHERAL BLOOD LYMPHOCYTES

CYTOGENETIC ANALYSIS OF PERIPHERAL BLOOD LYMPHOCYTES detects the human karyotype, which represents a person’s chromosome complement. The term karyotype differs from the term karyogram, which describes the chromosomal image of a single cell, i.e. a cell line. The karyogram does not always have to match the karyotype, as is the case with mosaic karyotypes (two or more karyograms make up a karyotype). Each human somatic cell has 46 chromosomes, i.e. 22 homologous pairs of autosomes and one pair of gonosomes (pair of sex chromosomes). The pair of sex chromosomes is different in women and men. The shape of both sex chromosomes is the same in women (XX) and different in men (XY).

SAMPLE REQUIRED FOR THE TEST: blood
PATIENT ADMISSION: MONDAY AND TUESDAY FROM 9 AM TO 1 PM (you must first schedule an appointment by phone)
- DURATION OF THE TEST: 3 WEEKS
SERVICE COST: HRK 2,400.00 or internal referral of the CHC Rijeka

INDICATIONS FOR CYTOGENETIC ANALYSIS OF PERIPHERAL BLOOD LYMPHOCYTES:

primary or secondary amenorrhea or premature menopause
abnormal semen analysis results – azoospermia or severe oligospermia
unexplained infertility
clinically abnormal fetal growth
ambiguous genitalia
phenotypic abnormality or dysmorphism
multiple congenital anomalies
intellectual disability or developmental delay
suspected chromosomal disorder
tissue of a malformed or stillborn fetus of unknown etiology
chromosomal abnormality detected in prenatal diagnosis
structural chromosomal changes in the family
familial intellectual disability of chromosomal origin.

4. CYTOGENETIC ANALYSIS OF ABORTED FETAL CELLS

CYTOGENETIC ANALYSIS OF ABORTED FETAL CELLS detects the karyotype. The sample for analysis is obtained by evacuating the fetus after detection of fetal death by ultrasound. The karyotype can be detected either in the fetal skin cells or in the embryonic membrane cells (trophoblast). Cytogenetic analysis of aborted fetal cells enables better genetic counselling and monitoring of the subsequent pregnancy.

It should be emphasised that 15% of clinical pregnancies end in spontaneous abortion, of which 50–60% are caused by a particular chromosomal aberration. These are often numerical aberrations such as trisomy, triploidy and X chromosome monosomy.

SAMPLE REQUIRED FOR THE TEST: aborted fetal tissue
PATIENT ADMISSION: CHC Rijeka, Clinic for Gynecology and Obstetrics
- DURATION OF THE TEST: 2–3 WEEKS

5. MOLECULAR CYTOGENETIC ANALYSIS – RAPID DETECTION OF MOST COMMON ANEUPLOIDIES

MOLECULAR CYTOGENETIC ANALYSIS is performed using the fluorescent in situ hybridisation (FISH) method. The analysis can be performed on amniotic fluid cells (uncultivated and/or cultured amniotic fluid cells), peripheral blood lymphocytes and aborted fetal cells. These test results must be accompanied by a karyotype.

Rapid test for most common aneuploidies

Molecular cytogenetic analysis of uncultivated amniotic fluid cells

This method quickly detects the most common aneuploidies (trisomy 21, 13 and 18 and sex chromosome aneuploidies) and provides information only about the number of tested chromosomes. This method does not provide information about the number of other chromosomes or structural chromosomal changes. Appropriate commercial tests are used for this analysis.

SAMPLE REQUIRED FOR THE TEST: 6–10 mL of amniotic fluid
PRIJEM PACIJENATA: WEDNESDAY (CHC Rijeka, Clinic for Gynecology and Obstetrics)
- DURATION OF THE TEST: 3 DAYS
SERVICE COST: HRK 2,900.00 or internal referral of the CHC Rijeka

INDICATIONS:

Positive screening test (various first- and second-trimester prenatal screening tests)
Ultrasound findings (fetal anomalies)
Maternal age

6. MOLECULAR KARYOTYPING

MOLECULAR KARYOTYPING uses comparative genomic hybridisation to analyse unbalanced changes in the number of copies in the genome (deletions or duplications) with a resolution of up to 100kb. This test requires the patient’s DNA, which can be isolated from different cells (amniotic fluid, peripheral blood lymphocytes). The test results are ready in 2–3 weeks. This test is carried out in collaboration with the Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana.

SAMPLE REQUIRED FOR THE TEST: DNA
PATIENT ADMISSION: as agreed
- DURATION OF THE TEST: 3–4 WEEKS
SERVICE COST: HRK 7,672.50 (+ HRK 220.78kn for DNA isolation) or internal referral of the CHC Rijeka

What is cytogenetics?

Cytogenetics is a science that studies the morphology and behaviour of chromosomes during mitosis and meiosis and tries to connect chromosomal findings with the principles of general genetics. Although the observation of chromosomes had already begun at the end of the 19th century, it was not until 1956 that Tjio and Levan discovered that human cells contain a total of 46 chromosomes. Shortly after this discovery, Ford and Hamerton identified 23 chromosomes in human spermatocytes. The increasing interest in cytogenetics has led to the need to standardise terminology in this field.

The first guidelines were established at the conference held in Denver in 1960. The same year, the term human karyotype was systematised and introduced, representing a person’s chromosome complement. The term karyotype differs from the term karyogram, which describes the chromosomal image of a single cell, i.e. a cell line. The karyogram does not always have to match the karyotype, as is the case with mosaic karyotypes (two or more karyograms make up a karyotype). Each human somatic cell has 46 chromosomes, i.e. 22 homologous pairs of autosomes and one pair of gonosomes (pair of sex chromosomes). The pair of sex chromosomes is different in women and men. The shape of both sex chromosomes is the same in women (XX) and different in men (XY).

Chromosomal aberrations

1.1. NUMERICAL CHROMOSOMAL ABERRATIONS

Any deviation from the normal number of chromosomes (euploidy) for a specific species represents a numerical chromosomal aberration. The normal number of chromosomes is 46 in human somatic cells (diploid number – 2n) and 23 (haploid number – n) in sex cells (gametes).

Polyploidy is a numerical chromosomal aberration characterised by an increased haploid set of chromosomes (3n, 4n, 5n, etc.). Types of polyploidy are triploidy (3n = 69), tetraploidy (4n = 92), pentaploidy (5n = 115), etc.

Aneuploidy is a numerical chromosomal aberration characterised by a change in the number of chromosomes within a pair of chromosomes. We distinguish between polysomy and monosomy. The presence of 3, 4 or 5 homologous chromosomes represents trisomy, tetrasomy or pentasomy as a type of polysomy. Monosomy is a type of aneuploidy in which there is only one instead of two homologous chromosomes. Each aneuploidy also changes the total number of chromosomes – monosomy is characterised by 45, trisomy by 47 and tetrasomy by 48 chromosomes in the karyotype.

A change in the number of chromosomes always results in a change in the carrier’s phenotype. Most discovered and described chromosomopathies have certain characteristics that distinguish them from one another. However, almost all chromosomopathies have the following phenotypic changes that are more or less present: intellectual and/or somatic disability, malformations, i.e. dysmorphia of the face, hands and feet, malformations of internal organs, especially the heart, kidneys, brain and intestines, abnormalities of the external genitalia and pathological adermatoglyphia. The most common aneuploidies and polypoloidies are characterised by associated specific symptoms called syndromes.

1. Down syndrome – trisomy 21 (47,XX,+21 or 47,XY,+21)

The clinical presentation of Down’s syndrome (DS) was described by Langdon Down in 1866, while in 1957, Lejeune discovered trisomy 21 as a genetic cause. It is the most common aneuploidy and occurs with a frequency of 1:770 newborns, slightly more often in boys than in girls (3:2). It is characterised by intellectual disability, the level of which can vary. A significant intrauterine and postnatal delay in physical development and growth is present. The head is reduced in size, and the back of the head is flat. The eyes are slanted, “mongoloid” and widely spaced (hypertelorism), the medial canthus contains a skin fold (epicanthus) and there are white Brushfield spots along the limbal ring. The nose is small, and the nasal root is wide. The mouth is small, so a normally large tongue often protrudes from the oral cavity. At the age of 5 to 6 years, the tongue becomes pronouncedly fissured (lingua scrotalis). The ears are almost always abnormally shaped, small and low. The teeth are irregular in shape and number and erupt late. The hands are wide and short with short fingers, and clinodactyly (radial inclination of the fifth finger) is common. The palms may have a four-finger furrow (monkey furrow) with altered dermatoglyphic patterns. The muscles are conspicuously hypotonic, and the joints are hyperflexible. Approximately 40% of children with Down syndrome have a congenital heart defect, most commonly septal defects. They often have intestinal stenosis and atresia, as well as low resistance to infections. On average, life expectancy is reduced to half compared with the healthy population, and it depends to a large extent on the malformations of vital organs and living conditions. In the pre-penicillin era, the life span of people with Down syndrome was significantly shorter due to their susceptibility to infections. Children never reach the mental abilities of healthy children (their IQ at the age of 15 is only 40–50), and they especially lack abstract reasoning. Most children are incapable of schooling and remain socially dependent throughout their lives.

2. Patau syndrome – trisomy 13 (47,XX,+13 or 47,XY,+13)

After Down’s syndrome, Patau’s syndrome (Patau et al., 1960) is one of the more common autosomal trisomies (1:5,000 newborns). It is clinically characterised by very severe malformations of the brain (arhinencephaly), eyes (microphthalmia or anophthalmia), cleft lip, jaw and palate (cheilognathopalatoschisis), polydactyly and heart defects (septal defects), kidneys (cystic kidneys, horseshoe kidneys) and digestive tract (intestinal malrotation). Life expectancy is poor, and most children die in the first months of life.

3. Edwards syndrome – trisomy 18 (47,XX,+18 or 47,XY,+18)

The first patient with trisomy 18 was described by Edwards in 1960. The frequency of Edwards syndrome is 1:5,000 newborns. This syndrome is more common in girls than in boys (4:1). The main features are intrauterine dystrophy (hydramnios, small placenta, low birth weight), craniofacial dysmorphia (microcephaly or hydrocephaly, pronounced dolichocephaly, microphthalmia, abnormally shaped ears, small and narrow nose, small mandible, high palate), short sternum, cardiac, renal and gastrointestinal anomalies. The syndrome is also characterised by typical finger flexion contractures (second finger over the third and fifth over the fourth), which is very pronounced in the first weeks of life. Life expectancy is also poor, and most children die within the first year of life. Children who live longer usually have less pronounced organ anomalies and pronounced intellectual disabilities.

4. Klinefelter syndrome (47,XXY or 48,XXXY)

Klinefelter’s syndrome was clinically detected even before the discovery of its genetic cause (Klinefelter et al., 1942). The main symptoms are relatively high growth, testicular atrophy with scarce or absent spermatogenesis with preserved Leydig cells, sterility, gynecomastia and sometimes intellectual disability. Since it is usually not clinically recognisable before puberty, the syndrome is most often detected in men who are treated for infertility and, in most cases, lead a normal life. The frequency of Klinefelter’s syndrome is 1:1000 male newborns.

5. XYY syndrome (47,XYY)

XYY syndrome is not phenotypically clearly defined, so it is mainly a cytogenetic term. It appears in 1:1000 male newborns who are mostly indistinguishable from children with a normal male karyotype. In addition to increased growth velocity during puberty, the syndrome is also characterised by mental disorders in social adjustment, aggressive tendencies and possible infertility. It is still unclear whether such persons have a genetic predisposition to criminal behaviour. The answer to this sensitive question can have significant social, moral and ethical consequences.

6. Triple X syndrome (47,XXX)

Women with triple X syndrome do not differ phenotypically from women with a normal karyotype. They are clinically healthy and usually fertile. A smaller number of such women have primary or secondary amenorrhea, while some have emotional difficulties in social adjustment and milder intellectual disabilities. Their children usually have a normal karyotype. This syndrome is most often discovered accidentally, with a frequency of 0.8–1:1,000 female newborns.

7. Tetra X syndrome (48,XXXX)

Tetra X syndrome is a polysomy characterised by severe intellectual disability, with an IQ below 50% of the standard for the corresponding age. Life expectancy is not reduced. Some features of this syndrome are microcephaly, oval face, hypertelorism, epicanthus, strabismus and short fingers with clinodactyly of the fifth finger. Menarche in puberty does not differ from that in normal persons.

8. Turner syndrome – monosomy X (45,X)

Turner syndrome was also clinically detected much earlier than the discovery of its genetic cause (Turner, 1932). It represents almost the only example of monosomy compatible with an almost normal life expectancy. The frequency is 1:2,500 female newborns, and it is assumed that only 1:40 children with Turner syndrome are born, while the rest are spontaneously aborted in the first months of pregnancy. Recognisable symptoms are low birth weight and length, micrognathia, epicanthus, ptosis of one or both upper eyelids and abnormally shaped and low-set ears. The neck is short, with lateral skin folds that extend from the ear to the shoulder (pterygium). The hair ends low on the neck with a straight line, and the skin is often filled with pigmented nevi. Newborns’ hands and feet have pseudolymphatic edemas, the joints are hyperelastic, and cubitus valgus is pronounced. There may be cardiac anomalies (20%) and renal anomalies (40–60%). Adults reach a height of approximately 150 cm, with primary amenorrhea, sterility and the absence of secondary sexual characteristics. Instead of ovaries, there are only fibrous strands and no germinal epithelial cells. Mental development is normal in most children, and intellectual disability occurs in less than 20%. Life expectancy of a child with Turner syndrome depends on the presence and severity of cardiac and renal anomalies, whereas growth and fertility cannot be improved. On the other hand, cyclical estrogen and progesterone replacement therapy at the expected puberty can induce secondary sexual characteristics and avoid mental disorders and early osteoporosis.

9. Triploidy (69,XXX ili 69,XXY ili 69,XYY)

Triploidy is mainly encountered in human genetics during the cytogenetic analysis of spontaneously aborted fetuses. In 80% of triploidies, the additional haploid set of chromosomes is of paternal origin, which leads to the development of partial hydatidiform mole, i.e. a type of pathological pregnancy with hydatidiform placental abnormalities. Interestingly, in the case of an excess maternal haploid set of chromosomes, such a placental abnormality does not occur. Given their parental origin, this phenomenon of gene or chromosome expression differences is called genomic imprinting. It is extremely rare for children to be born with a triploid karyotype. However, since the symptoms of the cases described so far are quite characteristic, we can talk about triploidy as a syndrome. The distinctive facial appearance is associated with arhinencephaly, cheilognathopalatoschisis, colobomas, syndactyly of the third and fourth fingers, numerous internal organ anomalies and placental abnormalities. Vitality is very poor, so infants with triploidy usually die during childbirth or after several days.

10. Tetraploidy (92,XXYY)

Tetraploidy among live-born infants has been described in only a few cases, of which all children died immediately after birth. It is characterised by microcephaly, facial dysmorphia, limb malformations and anomalies of the urinary tract and brain.

11. Uniparental disomy

Uniparental disomy is a special type of mutation characterised by homologous chromosomes of the same parental origin in a diploid karyotype. This aberration may or may not cause phenotypic alterations, which depends on the already mentioned genomic imprinting. Uniparental disomy can occur as a result of the fertilisation of two aneuploid gametes (one disomic and the other nullisomic given the same chromosome) or, which is more often the case, as a result of the chromosome loss (anaphase lag) very early in the embryonic period in the case of a trisomic zygote. Chromosomal nondisjunction in meiosis I leads to heterodisomy, while chromosomal nondisjunction in meiosis II leads to isodisomy.

Causes of numerical chromosomal aberrations

Changes in chromosome number result from chromosomal nondisjunction that can occur during meiosis or mitosis. Chromosomal nondisjunction during meiosis is called primary if the germ cell is euploid. Secondary nondisjunction occurs if the germ cell is already aneuploid. Chromosomal nondisjunction can occur in meiosis I or II during oogenesis or spermatogenesis, thereby producing aneuploid gametes. Mitotic nondisjunction occurs in the early postzygotic stage but can also occur in the first zygote division. Such nondisjunction results in multiple cell lines with different numbers of chromosomes. These cell lines can be all aneuploid or represent a combination of euploid and aneuploid lines, depending on whether the nondisjunction occurred during the first zygote division or subsequent germ cell divisions. Newly formed aneuploid cells will continue to divide further, creating tissues with an altered number of chromosomes. The appearance of cells in the body/organism with different numbers of chromosomes is called mosaicism or mixoploidy. This type of mixoploidy is called developmental mixoploidy. Proliferative mixoploidy occurs later in life and is related to ageing and neoplastic formations. Mixoploidy is more often associated with gonosomes.

One of the mechanisms of aneuploidy is anaphase lag, where a single chromosome lags during anaphase and does not reach the spindle pole with the other chromosomes. Thus, it is not included in the new nucleus, which also results in a numerical chromosomal aberration. There are various mechanisms for polyploidy in humans: the possibility of unreduced female or male gamete formation, polyspermy, suppression of the first or second polar body in oogenesis or suppression of a zygote in which cytokinesis did not occur after karyokinesis. Based on experiments on animals, all the mentioned mechanisms seem acceptable.

1.2. STRUCTURAL CHROMOSOMAL ABERRATIONS

Structural chromosomal aberrations are mutations caused by breakage and abnormal reunion of broken ends. The broken parts can change position on the chromosome, move to another chromosome, turn inside the chromosome or be lost during cell division. This type of aberration can be balanced or unbalanced, depending on whether there is an excess or deficiency of genetic material. Balanced structural aberrations usually do not cause phenotypic changes. They can arise de novo (fresh mutation) or by parental inheritance. They are classified into intrachromosomal, in which chromosomal segments are relocated within one chromosome, and interchromosomal, in which segments shift between two or more chromosomes.

1.2.3. INTRACHROMOSOMAL STRUCTURAL ABERRATIONS

Deletions (del) represent the loss of a chromosomal segment. The terminal or central part of the chromosomal arm can be lost (terminal and interstitial deletion). They cause partial monosomy of deleted loci. In the case of terminal deletion of both arms, the broken ends are joined, forming a ring (r) chromosome, which has a centromere. Various terminal deletions have been described in humans and represent clinically recognisable syndromes. Example of karyotype: 46,XY,del(4)(p15) – Wolf syndrome.

Inversions (inv) are balanced structural aberrations caused by double-strand breaks. The fragment between the breaks is turned 180° and reinserted into the chromosome. Inversion is usually not accompanied by phenotypic changes, but if the mutation is de novo, it may result in a phenotypic change. Inversion carriers are most often detected by karyotyping due to reproductive disorders: spontaneous abortions or birth defects. If the inverted part of the chromosome includes the centromere, the inversion is pericentric. If it affects part of only one chromosomal arm, the inversion is paracentric. Chromosome shape changes in pericentric inversion but remains unchanged in paracentric inversion. Inversion interferes with the normal conjugation of homologous chromosomes during gametogenesis and causes the formation of an inversion loop.

Isochromosome (i) is a type of structural aberration resulting from the transverse division of the centromere. This creates a metacentric chromosome with the genetic material of two p arms or, more often, two q arms. The result of isochromosomes is partial monosomy and partial trisomy of one chromosomal arm. The isochromosome is often detected on the X chromosome, and a person with isochromosome i(Xq) usually has recognisable Turner syndrome. Karyotype example: 46,X,i(Xq).

1.2.4. INTERCHROMOSOMAL STRUCTURAL ABERRATIONS

The most common type of interchromosomal aberrations are translocations, which result from the transfer of genetic material from one homologous chromosome to another or the exchange of chromosomal fragments between two or more heterologous chromosomes. Translocations can be reciprocal and Robertsonian. Robertsonian translocation or centric fusion occurs only between acrocentric chromosomes, i.e. between homologous or heterologous. After the breaks occur in or near the centromere, the q arms of acrocentric chromosomes merge, while the p arms are lost. The loss of p arms is compensated by genes from other p arms of acrocentric chromosomes. Therefore this type of translocation is a balanced aberration and generally has no phenotypic consequences for the carrier. If this aberration occurs fresh, a major congenital change may occur in 3% of cases.

Karyotype example: 45,XX,rob(13;21)(q10;q10) – silent carrier of Robertsonian translocation

Reciprocal translocations represent the transfer of broken chromosome fragments between two or more chromosomes. This type of translocation can be interstitial or terminal.

Karyotype example: 46,XX,t(2;5)(q21;q31) – silent carrier of reciprocal translocation

Carriers of Robertsonian or reciprocal translocations can produce balanced gametes in addition to unbalanced gametes and thus have healthy children. Therefore, these people are recommended to undergo prenatal diagnosis (e.g. amniocentesis). Unfortunately, translocation carriers are discovered only after several spontaneous abortions or birth defects.