Aneuploidy is an abnormal copy number of one or more chromosomes and arises from aberrations in cell division. The most common anueploid conditions that can result in live birth are trisomies of the sex chromosomes; trisomies of chromosomes 13, 18, and 21; and monosomy X. Detection of aneuploidy is one of the major objectives of a prenatal screening program. Ultrasound is a helpful screening test to evaluate for aneuploid fetuses; however, invasive testing with chorionic villus sampling or amniocentesis is required for definitive diagnosis.
Keywordsaneuploidy, nondisjunction, meiosis, trisomy
Aneuploidy is a chromosomal anomaly in which the number of one or more chromosomes is abnormal. Normal human somatic cells (i.e., nonegg or sperm cells) carry 46 chromosomes: two copies of each of the 22 autosomal chromosomes and two sex chromosomes, either XX for female or XY for male. Monosomy and trisomy conditions result from the subtraction or addition of chromosomal material, respectively.
Aneuploid conditions are often suspected by prenatal ultrasound (US) when multiple, and sometimes severe, structural anomalies are seen. Different aneuploid conditions are typically associated with specific constellations of US findings. US on its own, however, is an insufficient screening tool for aneuploidy. Other methods, including serum biomarkers and noninvasive prenatal screening, should also be a part of a comprehensive prenatal screening program.
Aneuploidy refers to an abnormal copy number of one or more chromosomes. Aneuploid conditions have a subtraction (monosomy) or an addition (trisomy) of chromosomal material in one or more of the chromosome pairs.
Polyploidy refers to an abnormal copy number of all of the chromosomes. The normal human cell is diploid, meaning it contains two copies of genetic material, with one copy coming from each parent. A triploid cell has 69 chromosomes (69, XXX, 69 XXY, 69, XYY) and thus three copies of genetic material. Triploidy is most commonly the result of ovum fertilization by two spermatozoa. It is not compatible with life and usually ends in pregnancy loss in the first trimester. The rare fetuses born alive usually die shortly after birth.
Prevalence and Epidemiology
Aneuploidy is the most common genetic abnormality detected by prenatal diagnosis. Maternal age is directly related to the incidence of aneuploidy. For example, as maternal age increases, the combined risk of delivering a child affected by any of the three most common trisomies (trisomy 13, 18, or 21) increases from about 1 : 1065 at age 25 to 1 : 300 at age 35 and 1 : 28 at age 45.
Prenatal screening approaches use one or a combination of tests, including maternal serum biomarkers, cell-free fetal deoxyribonucleic acid, nuchal translucency, and detailed anatomic US. Each of these tests is associated with their own detection rates for the various aneuploid conditions, but none of them are considered diagnostic modalities. Chorionic villus sampling (CVS) and amniocentesis remain the mainstays for definitive prenatal diagnosis of aneuploidy. While percutaneous umbilical blood sampling can also be used, it is not commonly performed for aneuploidy detection in the absence of another indication for the procedure (e.g., planned fetal transfusion).
Fetal chromosomal abnormalities are more common in the first and second trimesters than in live births caused, in large part, by the high rate of spontaneous fetal loss in affected pregnancies. In one United Kingdom study, miscarriage or stillbirth occurred between 12 weeks and term in 49% of pregnancies diagnosed with trisomy 13, and in 72% of pregnancies diagnosed with trisomy 18. Similarly, for pregnancies affected by trisomy 21, the average fetal loss rate between the time of CVS and term was 32%, and between the time of amniocentesis and term was 25%. The midtrimester incidence of trisomies 13, 18, and 21 in a 35-year-old-woman is 1 : 2975, 1 : 1230 and 1 : 260, respectively.
The finding of a fetal structural anomaly on prenatal US increases the likelihood of an underlying chromosomal abnormality, and the magnitude of the increase depends on the specific anomaly. A finding, for example, of a shortened humerus is associated with a likelihood ratio for trisomy 21 of 4.8, whereas a thickening of the nuchal fold has a likelihood ratio of 23. The total number of anomalies detected as well as the specific combination of anomalies identified impacts the frequency of aneuploidy. While an isolated fetal anomaly is associated with fetal chromosomal abnormalities in 2%–18% of cases, aneuploidy was detected in up to 29% of fetuses with multiple anomalies.
Etiology and Pathophysiology
Aneuploidy results from aberrations in cell division, most commonly through nondisjunction of paired chromosomes in meiosis or of chromatids in mitosis. Aneuploidy can also occur as a result of anaphase lag during either meiosis or mitosis.
Meiosis is a specialized form of cell division that occurs in egg and sperm cells whereby the number of chromosomes is reduced in half. The cell first undergoes DNA replication, which results in two identical copies of each of the 46 chromosomes. The identical copies are called sister chromatids. Replication is followed by two rounds of cell division, ultimately producing four daughter cells, or gametes, each with half of the genetic information of the original parent cell. In the first division, called meiosis I , homologous chromosomes pair up along the equatorial line of the cell, where they engage in genetic recombination through a process called crossovers. The homologous chromosomes then separate from each other, producing two cells with only 23 chromosomes in each. Meiosis II, the second division, proceeds like a standard mitotic division. The 23 chromosomes line up in one line along the equatorial plate, and the sister chromatids of each chromosome separate and segregate to the opposite poles of the cell.
Disjunction is the term typically used to describe the normal separation of the homologous chromosomes or the sister chromatids to opposite poles during nuclear division. Nondisjunction is a failure of this segregation, where two chromosomes in meiosis I or two chromatids in meiosis II go together to one pole. The result is an increased number of chromosomes in one gamete and a decreased number of chromosomes in the other. Fertilization of the gamete with the missing chromosome results in a monosomic zygote, and fertilization of the gamete with the extra chromosome yields a trisomy.
Alternatively, aneuploidy may result from nondisjunction in postzygotic mitotic division. Like in meiosis II, failure of separation of the sister chromatids during mitosis results in excess genetic material in one daughter cell and decreased genetic material in the other.
In general, aneuploidy is predominantly the result of meiosis I errors. However, chromosome-specific patterns exist. Meiosis I errors predominate for the acrocentric chromosomes 15 and 21, while meiosis II errors predominate for trisomy 18. Trisomy 16 results almost exclusively from maternal meiosis I nondisjunction. Postzygotic mitotic nondisjunction accounts for up to 15% of trisomies 15, 18, and 21, and for the majority of trisomy 8.
The origin and mechanism of nondisjunction is not fully elucidated, but it appears to be the result of spindle microtubular dysfunction. Nondisjunction is also thought to be a spontaneous process, but some familial patterns have been found. The only well-documented and consistent risk factor for meiotic nondisjunction is advanced maternal age. The incidence, for example, of trisomy 21 in a 25-year-old woman is 1 : 1339 at term. In contrast, the incidence at term for a 40-year-old woman is 1 : 85.
Manifestations of Disease
Autosomal monosomies are not viable unless they occur in the setting of mosaicism, a condition in which there is a mixture of monosomic and karyotypically normal cell types. Pregnancies with an autosomal monosomy usually end in embryonic death. Monosomy of the X chromosome is the only nonlethal monosomy. Also known as Turner syndrome , monosomy X occurs in 4 : 10,000 female births and is associated with short stature, webbed neck, and gonadal dysfunction ( Chapter 152 ).
Unlike autosomal monosomies, not all autosomal trisomies are lethal in the prenatal period. The most common autosomal trisomies that can result in live births are trisomies of chromosomes 13, 18, or 21. Trisomy 13, also known as Patau syndrome , occurs in 0.5 : 10,000–2 : 10,000 births, while the incidence of trisomy 18, or Edwards syndrome, is 2 : 10,000 live births. Fetuses with either of these trisomies may survive to term, but most affected children do not live past 1 year, although substantially longer survival, especially with surgical intervention for correctable anomalies, has been reported. One study reported median survivals of 2.5 days and 6.0 days for trisomy 13 and trisomy 18, respectively.
Trisomy 21, or Down syndrome, occurs in 1.4 : 10,000 live births and is the most common chromosome abnormality in live born infants. Individuals with trisomy 21 can live into adulthood. Trisomy 21 is characterized by intellectual disability, dysmorphic features, and short stature and is often associated with cardiac, gastrointestinal, or renal malformations. Approximately 74% of cases of trisomy 21 are detected prenatally using traditional screening methods such as serum screening and US surveillance.
Several sex-linked trisomies are also associated with survival through adulthood. Klinefelter syndrome (47, XXY) occurs in approximately 10 : 10,000–20 : 10,000 male births. The syndrome is characterized by tall stature and hypogonadism that often results in infertility in the absence of specialized assisted reproductive technologies. Affected males may also have cognitive or behavioral problems. Triple X syndrome (47, XXX) and the presence of an extra Y chromosome (47, XYY) are both associated with increased growth velocity but otherwise have few defining clinical characteristics.
Imaging Technique and Findings
Antepartum detection of aneuploidy is one of the major objectives of prenatal screening programs. Aneuploid fetuses often have anatomic changes or abnormalities, many of which can be detected on detailed US examination of the fetus. US, however, remains a screening test. A CVS or amniocentesis are required for definitive diagnosis.
US findings vary for the different aneuploidy syndromes:
Sonographic findings in fetuses with trisomy 21 include thickening of the nuchal fold, cardiac abnormalities, duodenal atresia, shortened femur, shortened humerus, renal pyelectasis, absence of the nasal bone, echogenic bowel, choroid plexus cyst, and an echogenic intracardiac focus. None of these markers, however, are specific for the condition, and each of them are associated with significant false-positive rates. In the absence of serum screening, detection of trisomy 21 by US and age-related risk alone may be as low as 43% and as high as 69%.
Trisomy 18 is associated with abnormal hand positioning (a “clenched hand” appearance with the index finger overlapping the third finger and the fifth finger overlapping the fourth), micrognathia, horseshoe kidney, choroid plexus cysts, omphalocele, polyhydramnios, and intrauterine growth restriction. Congenital heart disease also occurs in over 50% of affected fetuses, with ventricular septal defects among the most common forms.
Although trisomy 13 is rarer than trisomies 18 or 21, trisomy 13 is sonographically detectable in over 90% of cases because of the multiple, and often severe, structural anomalies associated with the condition. An early defect in the development of the prechordal mesoderm, which is the origin of the midface, eye, and forebrain, causes many of the classic findings associated with trisomy 13, including alobar holoprosencephaly, cyclopia, midline facial clefts, or hypoplastic nose. Other common sonographic anomalies include posterior fossa anomalies, agenesis of the corpus callosum, ventriculomegaly, neural tube defects, cardiac malformations, horseshoe or polycystic kidneys, and omphalocele.
Turner syndrome is often characterized by an increased nuchal translucency, cystic hygroma, fetal hydrops, and cardiac defects. Among the cardiac defects, coarctation of the aorta is the most common (44% of all cardiac defects). Coarctation, however, is often very difficult to diagnose in early pregnancy.
Magnetic Resonance Imaging.
Magnetic resonance imaging (MRI) is not used routinely for the detection of aneuploidy. MRI would only be indicated when the suspected anomaly is one in which MRI has independently been shown to be useful. The mainstays for prenatal screening remain ultrasonography and serum testing, whether with measurements of serum analytes or assessment of cell-free DNA. For prenatal diagnosis, CVS and amniocentesis remain the diagnostic modalities of choice.