Chromosomal abnormalities figure prominently in genetic disease. Aneuploidy accounts for more than 50 percent of first-trimester miscarriages, approximately 20 percent of second-trimester losses, and 6 to 8 percent of stillbirths and early-childhood deaths (Reddy, 2012; Stevenson, 2004; Wou, 2016). In the European Surveillance of Congenital Anomalies (EUROCAT) network of population-based registries, chromosomal abnormalities were identified in 0.4 percent of births (Wellesley, 2012). Of recognized pregnancies with aneuploidy, trisomy 21 composes just more than half of all cases. Trisomy 18 accounts for almost 15 percent, and trisomy 13 for 5 percent (Fig. 13-1).
Prevalence and relative proportion of selected chromosomal abnormalities from EUROCAT (European Surveillance of Congenital Anomalies) population-based registries that included >10,000 aneuploid live births, fetal deaths, and pregnancy terminations, 2000–2006. (Data from Wellesley, 2012.)
Karyotypes are described using the International System for Human Cytogenomic Nomenclature (McGowan-Jordan, 2016). Abnormalities fall into two broad categories—those of chromosome number, such as trisomy, and those of chromosome structure, such as a deletion or translocation. Each chromosome has a short arm, termed the “p” or petit arm, and a long arm, known as the “q” arm, selected because it is the next letter in the alphabet. The two arms are separated by the centromere.
When reporting a karyotype, the total number of chromosomes is listed first, corresponding to the number of centromeres. This is followed by the sex chromosomes, XX or XY, and then by a description of any structural variation. Specific abnormalities are indicated by standard abbreviations, such as del (deletion) and inv (inversion). The affected region or bands of the p or q arms are then designated, so that the reader will know the exact abnormality location and type. Examples are shown in Table 13-1.
TABLE 13-1Examples of Karyotype Designations Using the 2016 International System for Human Cytogenetic Nomenclature ||Download (.pdf) TABLE 13-1 Examples of Karyotype Designations Using the 2016 International System for Human Cytogenetic Nomenclature
|Karyotype ||Description |
|46,XX ||Normal female chromosome constitution |
|47,XY,+21 ||Male with trisomy 21 |
|47,XX,+21/46,XX ||Female who is a mosaic of trisomy 21 cells and cells with normal constitution |
|46,XY,del(4)(p14) ||Male with terminal deletion (del) of the short arm of chromosome 4 at band p14 |
|46,XX,dup(5)(p14p15.3) ||Female with duplication (dup) of the short arm of chromosome 5 from band p14 to band p15.3 |
|45,XY,der(13;14)(q10;q10) ||Male with balanced robertsonian translocation (der) of the long arms of chromosomes 13 and 14—the karyotype now has one normal 13, one normal 14, and the translocation chromosome, reducing the normal 46 chromosome complement to 45 |
|46,XX,t(11;22)(q23;q11.2) ||Female with a balanced reciprocal translocation (t) between chromosomes 11 and 22, with breakpoints at 11q23 and 22q11.2 |
|46,XY,inv(3)(p21q13) ||Male with inversion (inv) of chromosome 3 that extends from p21 to q13—a pericentric inversion because it includes the centromere |
|46,X,r(X)(p22.1q27) ||Female with one normal X and one ring (r) X chromosome, with the regions distal to p22.1 and q27 deleted from the ring |
|46,X,i(X)(q10) ||Female with one normal X chromosome and an isochromosome (i) of the long arm of the other X |
|ish 22q11.2(HIRAx2) ||FISH of metaphase cells using a probe for the HIRA locus of the 22q11.2 region, with 2 signals identified (no evidence of microdeletion) |
|ish del(22)(q11.2q11.2) (HIRA-) ||FISH of metaphase cells using a probe for the HIRA locus of the 22q11.2 region, with only one signal identified, consistent with the microdeletion |
|arr[GRCh38] 18p11.32q23 (102328_79093443)x3 ||Microarray analysis (arr), genome build GRCh38, showing a single copy gain on chromosome 18 from band p11.32 to band q23 (essentially the entire chromosome), consistent with trisomy 18 |
|arr[GRCh38] 4q32.2q35.1 (163146681_183022312)x1 ||Microarray analysis (arr), genome build GRCh38, showing a copy loss on the long arm of chromosome 4 at bands q32.2 through q35.1 (19.9 Mb) |
|arr[GRCh38] 15q11.2q26 (23123715_101888908)x2 hmz ||SNP microarray analysis (arr), genome build GRCh 38, showing homozygosity for the entire long arm of chromosome 15 |
Terminology is similar for fluorescence in situ hybridization. Described in Genetic Tests, this technique is used to rapidly identify of a specific chromosome abnormality and verify suspected microdeletion or microduplication syndromes. The report begins with the designation ish for in situ hybridization performed on metaphase cells and nuc ish for hybridization performed on interphase nuclei. If no abnormality is identified, this is followed by the probe’s specific chromosomal region, such as 22q11.2, and then the name of the probe and the number of signals visualized—for example, HIRAx2. If a deletion is identified, del is included before the chromosomal region, and the name of the probe is followed by a minus sign (HIRA-), as shown in Table 13-1. The 22q11.2 microdeletion syndrome is discussed in Abnormalities of Chromosome Structure.
A recent addition to the standard nomenclature is terminology to represent copy number variants identified by chromosomal microarray analysis, which is discussed in Chromosomal Microarray Analysis. Copy number variant is another term for a microdeletion or microduplication of DNA too small to be visualized with a standard karyotype. The array designation begins with the abbreviation arr and the version of the genome build to which the nucleotide designations are aligned, such as GRCh38 for Genome Reference Consortium human build 38. This is followed by the number of the chromosome on which the abnormality is identified, by the p or q arm, and by the specific bands in question. Array reports next include the affected base pair coordinates, thus conveying the exact size and location within the genome for every abnormality identified—including copy number variants of uncertain significance.
Abnormalities of Chromosome Number
The most easily recognized chromosomal abnormalities are numerical. Aneuploidy is inheritance of either an extra chromosome—resulting in trisomy, or loss of a chromosome—monosomy. These differ from polyploidy, which is an abnormal number of haploid chromosome sets, such as triploidy. The estimated incidence of various numerical chromosomal abnormalities is shown in Figure 13-1.
These account for approximately half of all chromosomal abnormalities. In most cases, trisomy results from nondisjunction, which is failure of normal chromosomal pairing and separation during meiosis. Nondisjunction may occur if the chromosomes: (1) fail to pair up, (2) pair up properly but separate prematurely, or (3) fail to separate.
The risk of any autosomal trisomy rises steeply with maternal age, particularly after age 35 (Fig. 13-2). Oocytes are suspended in midprophase of meiosis I from birth until ovulation, in some cases for 50 years. Following completion of meiosis at ovulation, nondisjunction results in one gamete having two copies of the affected chromosome, leading to trisomy if fertilized. The other gamete, receiving no copy of the affected chromosome, will be monosomic if fertilized. It is estimated that 10 to 20 percent of oocytes are aneuploid secondary to meiotic errors, compared with 3 to 4 percent of sperm. Although each chromosome pair is equally likely to have a segregation error, it is rare for trisomies other than 21, 18, or 13 to result in a term pregnancy, and most fetuses with trisomies 18 and 13 die before term.
Prevalence of autosomal trisomies according to maternal age found in population-based birth defects surveillance programs in the United States, 2006–2010, which included live births, stillbirths, and pregnancy terminations. (Data from Mai, 2013. Redrawn with permission from Dashe JS: Aneuploidy screening. Obstet Gynecol 128(1):181, 2016.)
After a pregnancy with an autosomal trisomy, the risk for any autosomal trisomy in a future pregnancy approximates 1 percent until the woman’s age-related risk exceeds this. Accordingly, prenatal diagnosis with chorionic villus sampling or amniocentesis is offered in these subsequent pregnancies (Chap. 14, Technique). Parental chromosomal studies are not indicated unless the affected pregnancy was caused by an unbalanced translocation or other structural rearrangement.
In 1866, J. L. H. Down described a group of intellectually disabled children with distinctive physical features. Nearly 100 years later, Lejeune (1959) demonstrated that Down syndrome is caused by an autosomal trisomy (Fig. 13-3). Trisomy 21 causes 95 percent of Down syndrome cases, whereas 3 to 4 percent of cases are due to a robertsonian translocation, described later (Isochromosomes). The remaining 1 to 2 percent results from an isochromosome or from mosaicism. The nondisjunction that yields trisomy 21 occurs during meiosis I in approximately 75 percent of cases, and the remaining events are during meiosis II.
Abnormal male karyotype with trisomy 21, consistent with Down syndrome (47,XY,+21). (Used with permission from Dr. Frederick Elder.)
Down syndrome is the most common nonlethal trisomy. Its approximate prevalence is 1 in 500 recognized pregnancies. However, fetal losses and pregnancy terminations yield an estimated prevalence of 13.5 in 10,000 births in the United States—1 per 740 (Mai, 2013; Parker, 2010). The fetal death rate beyond 20 weeks’ gestation approximates 5 percent (Loane, 2013). Coinciding with the older maternal age distribution during the past four decades, the prevalence of Down syndrome has risen approximately 33 percent (Loane, 2013; Parker, 2010; Shin, 2009).
Notably, adult women with Down syndrome are fertile, and a third of their offspring will have Down syndrome (Scharrer, 1975). Males with Down syndrome are almost always sterile because of markedly reduced spermatogenesis.
Approximately 30 percent of second-trimester fetuses with Down syndrome have a major malformation that can be identified sonographically (Hussamy, 2017; Vintzileos, 1995). As discussed in Chapter 14 (Sonographic Screening), when both major anomalies and minor aneuploidy markers are considered, an estimated 50 to 60 percent of Down syndrome pregnancies can be detected sonographically (American College of Obstetricians and Gynecologists, 2016d). Approximately half of liveborn neonates with Down syndrome are found to have cardiac defects, particularly ventricular septal defects and endocardial cushion defects (Figs. 10-29 and 10-30) (Bergstrom, 2016; Freeman, 2008). Gastrointestinal abnormalities are identified in 12 percent and include esophageal atresia, Hirschsprung disease, and duodenal atresia (Fig. 10-38) (Bull, 2011).
Characteristic features of Down syndrome are shown in Figure 13-4. Typical findings include brachycephaly; epicanthal folds and up-slanting palpebral fissures; Brushfield spots, which are grayish spots on the periphery of the iris; a flat nasal bridge; and hypotonia. Infants often have loose skin at the nape of the neck, short fingers, a single palmar crease, hypoplasia of the middle phalanx of the fifth finger, and a prominent space or “sandal-toe gap” between the first and second toes. Some of these findings are prenatal sonographic markers for Down syndrome, reviewed in Chapter 14 (Sonographic Screening).
Trisomy 21—Down syndrome. A. Characteristic facial appearance. B. Redundant nuchal tissue. C. Single transverse palmar crease. (Used with permission from Dr. Charles P. Read and Dr. Lewis Waber.)
Health problems common in children with Down syndrome include hearing loss in 75 percent, severe optical refractive errors in 50 percent, cataracts in 15 percent, obstructive sleep apnea in 60 percent, thyroid disease in 15 percent, and a higher incidence of leukemia (Bull, 2011). The degree of mental impairment is usually mild to moderate, with an average intelligence quotient (IQ) score of 35 to 70. Social skills in affected children are often higher than predicted by their IQ scores.
Data suggest that approximately 95 percent of liveborn infants with Down syndrome survive the first year. The 10-year survival rate is at least 90 percent overall and is 99 percent if major malformations are absent (Rankin, 2012; Vendola, 2010). Several organizations offer education and support for prospective parents faced with prenatal diagnosis of Down syndrome. These include the March of Dimes, National Down Syndrome Congress (www.ndsccenter.org), and National Down Syndrome Society (www.ndss.org).
Trisomy 18—Edwards Syndrome
The association between this constellation of abnormalities and an autosomal trisomy was first described by Edwards (1960). In population-based series, prevalence of trisomy 18 approximates 1 in 2000 recognized pregnancies—including abortuses, stillbirths, and live births, and approximately 1 in 6600 liveborn neonates (Loane, 2013; Parker, 2010). The difference in prevalence is explained by the high in-utero lethality of the condition and the termination of many affected pregnancies. Perhaps not surprisingly, survival of liveborn neonates is likewise bleak. More than half die within the first week, and the 1-year survival rate approximates only 2 percent (Tennant, 2010; Vendola, 2010). The syndrome is three- to fourfold more common in females (Lin, 2006; Rosa, 2011). Unlike Down and Patau syndromes, which involve acrocentric chromosomes and thus may stem from a robertsonian translocation, Edwards syndrome uncommonly results from a chromosomal rearrangement.
Virtually every organ system can be affected by trisomy 18. Common major anomalies include heart defects in more than 90 percent—particularly ventricular septal defects, as well as cerebellar vermian agenesis, myelomeningocele, diaphragmatic hernia, omphalocele, imperforate anus, and renal anomalies such as horseshoe kidney (Lin, 2006; Rosa, 2011; Yeo, 2003). Sonographic images of several of these are shown in Chapter 10.
Cranial and extremity abnormalities are also frequent and include a prominent occiput, posteriorly rotated and malformed ears, micrognathia, clenched hands with overlapping digits, radial aplasia with hyperflexion of the wrists, and rockerbottom or clubbed feet (Fig. 13-5). A “strawberry-shaped” cranium is noted in approximately 40 percent of cases, abnormally wide cavum septum pellucidum in more than 90 percent, and choroid plexus cysts in up to 50 percent (Abele, 2013; Yeo, 2003). Importantly, isolated choroid plexus cysts are not associated with trisomy 18. These cysts only raise the risk for trisomy 18 if fetal structural abnormalities or an abnormal aneuploidy screening test result is also present (Reddy, 2014).
Trisomy 18—Edwards Syndrome. A. This transventricular sonographic view shows fetal choroid plexus cysts and an angulated “strawberry-shaped” skull. B. Radial clubhand is manifested as a single forearm bone (radius), with the hands in a fixed, hyperflexed position at right angles to the forearms. C. This three-dimensional (3-D) sonographic image shows the characteristic hand position of clenched fists with overlapping digits. D. 3-D sonographic image displays a rockerbottom foot.
Pregnancies with trisomy 18 that reach the third trimester often develop fetal-growth restriction, and the mean birthweight is <2500 g (Lin, 2006; Rosa, 2011). Because abnormal fetal heart rate tracings are common during labor, mode of delivery and management of heart rate abnormalities should be discussed in advance. In older reports, more than half of undiagnosed fetuses underwent cesarean delivery for “fetal distress” (Schneider, 1981).
Trisomy 13—Patau Syndrome
This constellation of fetal abnormalities and their association with an autosomal trisomy was first described by Patau and colleagues (1960). The prevalence of trisomy 13 approximates 1 in 12,000 live births and 1 in 5000 recognized pregnancies, which includes abortuses and stillbirths (Loane, 2013; Parker, 2010). As with trisomy 18, trisomy 13 is highly lethal, and most affected fetuses are lost or terminated.
Approximately 80 percent of pregnancies with Patau syndrome result from trisomy 13. The remainder is caused by a robertsonian translocation involving chromosome 13. The most frequent structural chromosomal rearrangement is a translocation between chromosomes 13 and 14, der(13;14)(q10;q10). This translocation is carried by approximately 1 in 1300 individuals, although the risk of an affected liveborn neonate is less than 2 percent (Nussbaum, 2007).
Trisomy 13 is associated with abnormalities of virtually every organ system. One characteristic finding is holoprosencephaly (Fig. 10-15). This is present in approximately two thirds of cases and may be accompanied by microcephaly, hypotelorism, and nasal abnormalities that range from a single nostril to a proboscis. Cardiac defects are found in up to 90 percent of fetuses with trisomy 13 (Shipp, 2002). Other abnormalities that suggest trisomy 13 include neural-tube defects—particularly cephalocele, microphthalmia, cleft lip-palate, omphalocele, cystic renal dysplasia, polydactyly, rockerbottom feet, and areas of skin aplasia (Lin, 2007). For the fetus or newborn with a cephalocele, cystic kidneys, and polydactyly, the differential diagnosis includes trisomy 13 and the autosomal-recessive Meckel-Gruber syndrome. Sonographic images of several of these are shown in Chapter 10 (Neural-Tube Defects).
Few fetuses with trisomy 13 survive until birth. Of those that do, the 1-week survival rate approximates 40 percent, and 1-year survival rate is only about 3 percent (Tennant, 2010; Vendola, 2010). Counseling regarding prenatal diagnosis and management options is similar to that described for trisomy 18.
Unlike other aneuploidies, fetal trisomy 13 confers risk to the pregnant woman. Hyperplacentosis and preeclampsia develop in up to half of pregnancies with trisomy 13 carried beyond the second trimester (Tuohy, 1992). Chromosome 13 contains the gene for soluble fms-like tyrosine kinase-1 (sFlt-1), which is an antiangiogenic protein associated with preeclampsia (Chap. 40, Endothelial Cell Injury). Investigators have documented overexpression of the sflt-1 protein by trisomic 13 placentas and in serum of women with preeclampsia (Bdolah, 2006; Silasi, 2011).
In the absence of mosaicism, discussed later (Chromosomal Mosaicism), other autosomal trisomies rarely yield a liveborn neonate. Case of live births with trisomy 9 and with trisomy 22 have been noted (Kannan, 2009; Tinkle, 2003). Trisomy 16 is the most common trisomy found with first-trimester losses and accounts for 16 percent of these losses. However, it is not identified later in gestation. Trisomy 1 has never been reported.
Nondisjunction creates an equal number of nullisomic and disomic gametes. As a rule, missing chromosomal material is more devastating than extra chromosomal material, and almost all monosomic conceptuses are lost before implantation. The one exception is monosomy for the X chromosome (45,X), Turner syndrome, which is discussed subsequently. Despite the strong association between maternal age and trisomy, maternal age and monosomy are not linked.
This is an abnormal number of complete haploid chromosomal sets. Polyploidy accounts for approximately 20 percent of spontaneous abortions but is rare in later gestations.
Triploid pregnancies have three haploid sets—69 chromosomes. One parent must contribute two sets, and the phenotypic presentation differs according to the parent of origin. With diandric triploidy, also known as type I triploidy, the extra chromosomal set is paternal, resulting from fertilization of one egg by two sperm or by a single diploid—and thus abnormal—sperm. Diandric triploidy produces a partial molar pregnancy, discussed in Chapter 20 (Epidemiology and Risk Factors). Diandric triploidy accounts for most triploid conceptions, but their first-trimester loss rate is extremely high. As a result, two thirds of triploid pregnancies identified beyond the first trimester are caused instead by digynic triploidy (Jauniaux, 1999). With a digynic triploid pregnancy, also known as type II triploidy, the extra chromosomal set is maternal, and the egg fails to undergo the first or second meiotic division before fertilization. Digynic triploid placentas do not develop molar changes. However, the fetus usually displays asymmetrical growth restriction.
The prevalence of recognized triploid pregnancies approximates 1 in 5000 pregnancies (Zalel, 2016). Triploidy is a lethal aneuploidy, and more than 90 percent of fetuses with either the diandric or digynic form have multiple structural anomalies. These include central nervous system defects—particularly involving the posterior fossa, as well as cardiac, renal, and extremity anomalies (Jauniaux, 1999; Zalel, 2016). Counseling, prenatal diagnosis, and delivery options are similar to those for trisomies 18 and 13. The recurrence risk for a woman whose triploid fetus survived past the first trimester is 1 to 1.5 percent, and thus prenatal diagnosis is offered in future pregnancies (Gardner, 1996).
Tetraploid pregnancies have four haploid sets of chromosomes, resulting in either 92,XXXX or 92,XXYY. This suggests a postzygotic failure to complete an early cleavage division. The conceptus invariably succumbs, and the recurrence risk is minimal.
Sex Chromosome Abnormalities
First described by Turner (1938), this syndrome later was found to be caused by monosomy X (Ford, 1959). The prevalence of Turner syndrome is approximately 1 in 2500 liveborn girls (Cragan, 2009; Dolk, 2010). The missing X chromosome is paternally derived in 80 percent of cases (Cockwell, 1991; Hassold, 1990). Screening for Turner syndrome with cell-free DNA is discussed in Chapter 14 (Cell-Free DNA Screening).
Turner syndrome is the only monosomy compatible with life, but it is also the most common aneuploidy in first-trimester losses, accounting for 20 percent. This is explained by the wide range in phenotype. Approximately 98 percent of affected conceptuses are so abnormal that they abort early in the first trimester. Of the remainder, many manifest large, septated cystic hygromas in the late first or early second trimester (Fig. 10-22). When cystic hygromas are accompanied by hydrops fetalis, fetuses nearly always die in utero (Chap 15, Hydrops Fetalis). Less than 1 percent of pregnancies with Turner syndrome yield a liveborn neonate. And, only half of these actually have monosomy X. Approximately a fourth have mosaicism, such as 45,X/46,XX or 45,X/46,XY, and another 15 percent have isochromosome X, that is, 46,X,i(Xq)(Milunsky, 2004; Nussbaum, 2007).
Abnormalities associated with Turner syndrome include left-sided cardiac defects—such as coarctation of the aorta, hypoplastic left heart syndrome, or bicuspid aortic valve—in 30 to 50 percent; renal anomalies, particularly horseshoe kidney; and hypothyroidism. Other features are short stature, broad chest with widely spaced nipples, congenital lymphedema—puffiness over the dorsum of hands and feet, and a “webbed” posterior neck resulting from cystic hygromas. Intelligence scores are generally in the normal range, but affected individuals are at risk for difficulties with visual-spatial organization, nonverbal problem solving, and interpretation of social cues (Jones, 2006). Growth hormone is typically administered in childhood to ameliorate short stature (Kappelgaard, 2011). More than 90 percent have ovarian dysgenesis and require estrogen repletion starting just before adolescence. An exception is mosaicism involving the Y chromosome, as this confers risk for germ cell neoplasm—regardless of whether the child is phenotypically male or female. Accordingly, eventual prophylactic bilateral gonadectomy is indicated (Cools, 2011; Schorge, 2016).
Approximately 1 in 1000 female newborns has an additional X chromosome—47,XXX. The extra X is maternally derived in more than 90 percent of cases (Milunsky, 2004). Affected infants do not have a characteristic appearance, and in the past most children did not come to attention until school age. However, the incidence of 47,XXX is weakly associated with maternal age, and cell-free DNA screening has resulted in increased diagnoses (Table 14-5). Frequent features include tall stature, hypertelorism, epicanthal folds, kyphoscoliosis, clinodactyly, and hypotonia (Tartaglia, 2010; Wigby, 2016). More than a third are diagnosed with a learning disability, half have attention deficit disorder, and overall cognitive scores are in the low-average range. No specific pattern of malformations has been described, but genitourinary problems and seizure disorders are more common (Wigby, 2016). Pubertal development is unaffected. Primary ovarian insufficiency has been reported (Holland, 2001). Because of variable presentation and subtle abnormal findings, it is estimated that this diagnosis is ascertained clinically in only 10 percent of affected children.
Females with two or more extra X chromosomes—48,XXXX or 49,XXXXX—are likely to have physical abnormalities apparent at birth. These abnormal X complements are associated with intellectual disability. For both males and females, the IQ score is lower with each additional X chromosome.
This is the most common sex chromosome abnormality and found in approximately 1 in 600 male infants. The additional X chromosome is maternally or paternally derived with equal propensity (Jacobs, 1995; Lowe, 2001). The association with either advanced maternal or paternal age is weak (Milunsky, 2004).
Like 47,XXX, newborns with 47,XXY usually appear phenotypically normal and do not have a higher incidence of anomalies. As children, boys are typically taller than average and have normal prepubertal development. However, they have gonadal dysgenesis, do not undergo normal virilization, and require testosterone supplementation beginning in adolescence. They may develop gynecomastia. IQ scores usually lie in the average to low-average range, and many have delays in language development and reading (Boada, 2009; Girardin, 2011).
This aneuploidy occurs in approximately 1 in 1000 male newborns. As with 47,XXX and XXY individuals, affected boys tend to be tall. A third have macrocephaly, nearly two thirds demonstrate hypotonia, and tremors are also common (Bardsley, 2013). Rates of major anomalies are not elevated, although hypertelorism and clinodactyly may be identified in more than half. Pubertal development is normal, and fertility is unimpaired. Affected children carry risks for oral and written language impairments, attention deficit disorder is diagnosed in more than half, and the rate of autism spectrum disorder is also increased (Bardsley, 2013; Ross, 2009). Intelligence scores generally lie in the normal range.
Males with more than two Y chromosomes—48,XYYY—or with both additional X and Y chromosomes—48,XXYY or 49,XXXYY—are more likely to have congenital abnormalities, medical problems, and intellectual disability (Tartaglia, 2011).
Abnormalities of Chromosome Structure
Structural chromosomal abnormalities include deletions, duplications, translocations, isochromosomes, inversions, ring chromosomes, and mosaicism (see Table 13-1). Their overall birth prevalence approximates 0.3 percent (Nussbaum, 2007). Identification of a structural chromosomal abnormality raises two primary questions. First, what phenotypic abnormalities or later developmental abnormalities are associated with this finding? Second, is evaluation of parental karyotype indicated—specifically, are the parents at increased risk of carrying this abnormality? If so, what is their risk of having future affected offspring?
Deletions and Duplications
A chromosomal deletion indicates that a portion of a chromosome is missing, whereas a duplication means that a portion has been included twice. Most deletions and duplications occur during meiosis and result from malalignment or mismatching during the pairing of homologous chromosomes. The misaligned segment may then be deleted, or if the mismatch remains when the two chromosomes recombine, it may result in a deletion in one chromosome and duplication in the other (Fig. 13-6). When a deletion or duplication is identified in a fetus or infant, parental karyotyping should be offered, because if either parent carries a balanced translocation, the recurrence risk in subsequent pregnancies is significantly increased. Deletions involving DNA segments large enough to be seen with standard cytogenetic karyotyping are identified in approximately 1 in 7000 births (Nussbaum, 2007). Common deletions may be referred to by eponyms—for example, del 5p is called cri du chat syndrome.
A mismatch during pairing of homologous chromosomes may lead to a deletion in one chromosome and a duplication in the other. Del = deletion; Dupl = duplication.
Microdeletions and Microduplications
These chromosomal deletions or duplications—smaller than 3 to 5 million base pairs—are too small to be detected with standard karyotyping. However, prenatal chromosomal microarray analysis (CMA), described later (Chromosomal Microarray Analysis), permits identification of syndromes associated with these microdeletion or duplications. When CMA is used, the region of DNA that is missing or duplicated is termed a genomic copy number variant. Despite the relatively small size, a microdeletion or duplication may involve a stretch of DNA that contains multiple genes—causing a contiguous gene syndrome, which can encompass serious but unrelated phenotypic abnormalities (Schmickel, 1986). In some cases, a microduplication may involve the exact DNA region that causes a recognized microdeletion syndrome (Table 13-2). When a specific microdeletion syndrome is suspected clinically, it is confirmed using either CMA or fluorescence in situ hybridization.
TABLE 13-2Selected Microdeletion Syndromes ||Download (.pdf) TABLE 13-2 Selected Microdeletion Syndromes
|Syndrome ||Prevalence ||Location ||Features |
|Alagille ||1:70,000 ||20p12.2 ||Cholestasis (paucity of intrahepatic bile ducts), cardiac disease, skeletal disease, ocular abnormalities, dysmorphic facies |
|Angelman ||1:12,000 to 1:20,000 ||15q11.2–q13 (maternal genes) ||Dysmorphic facies—”happy puppet” appearance, mental retardation, ataxia, hypotonia, seizures |
|Cri-du-chat ||1:20,000 to 1:50,000 ||5p15.2–15.3 ||Abnormal laryngeal development with “cat-like” cry, hypotonia, mental retardation |
|Kallmann syndrome ||1:10,000 to 1:86,000 ||Xp22.3 ||Hypogonadotropic hypogonadism, anosmia |
|Langer-Giedion ||Rare ||8q23.3 ||Trichorhinophalangeal syndrome, dysmorphic facies, sparse hair, redundant skin, mental retardation |
|Miller-Dieker ||Rare ||17p13.3 ||Neuronal migration abnormalities with lissencephaly, microcephaly, dysmorphic facies |
|Prader-Willi ||1:10,000 to 1:30,000 ||15q11.2–q13 (paternal genes) ||Obesity, hypotonia, mental retardation, hypogonadotropic hypogonadism, small hands and feet |
|Retinoblastoma ||1:280,000 ||13q14.2 ||Retinoblastoma, retinoma (benign neoplasm), non-retinal (second primary) tumors |
|Rubenstein-Taybi ||1:100,000 to 1:125,000 ||16p13.3 ||Dysmorphic facies, broad thumbs/toes, mental retardation, increased tumor risk |
|Smith-Magenis ||1:15,000 to 1:25,000 ||17p11.2 ||Dysmorphic facies, speech delay, hearing loss, sleep disturbances, self-destructive behaviors |
|Velocardiofacial/DiGeorge/Shprintzen ||1:4,000 ||22q11.2 ||Conotruncal cardiac defects, cleft palate, velopharyngeal incompetence, thymic and parathyroid abnormalities, developmental delay |
|WAGR ||1:500,000 ||11p13 ||Wilms tumor, aniridia, genitourinary anomalies (including ambiguous genitalia), mental retardation |
|Williams-Beuren ||1:7500 to 1:10,000 ||7q11.23 ||Dysmorphic facies, dental malformation, mental retardation, aortic and peripheral pulmonary artery stenosis |
|Wolf-Hirschhorn ||1:20,000 to 1:50,000 ||4p16.3 ||Dysmorphic facies, delayed growth and development, cleft lip/palate, coloboma, cardiac septal defects |
|X-linked ichthyosis ||1:6,000 ||Xp22.3 ||Steroid sulfatase deficiency, corneal opacities |
22q11.2 Microdeletion Syndrome
This syndrome is also known as DiGeorge syndrome, Shprintzen syndrome, and velocardiofacial syndrome. It is the most common microdeletion, with a prevalence of 1 in 3000 to 6000 births. Although inherited in an autosomal dominant fashion, more than 90 percent of cases arise from de novo mutations. The full deletion includes 3 million base pairs, encompasses 40 genes, may include 180 different features, and thus poses some counseling challenges (Shprintzen, 2008). Features can vary widely, even among affected family members. Previously, different constellations of features were thought to characterize the DiGeorge and Shprintzen phenotypes, but it is now accepted that they represent the same microdeletion (McDonald-McGinn, 2015).
In approximately 75 percent of affected individuals, associated abnormalities include conotruncal cardiac anomalies, such as tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, and ventricular septal defects (McDonald-McGinn, 2015). Immune deficiency, such as T-cell lymphopenia, also develops in approximately 75 percent. More than 70 percent have velopharyngeal insufficiency or cleft palate. Learning disabilities, autism spectrum disorder, and intellectual disability are also common. Other manifestations include hypocalcemia, renal anomalies, esophageal dysmotility, hearing loss, behavioral disorders, and psychiatric illness—particularly schizophrenia. Short palpebral fissures, bulbous nasal tip, micrognathia, short philtrum, and small or posteriorly rotated ears are characteristic facial features.
These are DNA rearrangements in which a segment of DNA breaks away from one chromosome and attaches to another. The rearranged chromosomes are called derivative (der) chromosomes. There are two types—reciprocal and robertsonian translocations.
A double-segment or reciprocal translocation begins when breaks occur in two different chromosomes. The broken fragments are then exchanged, so that each affected chromosome contains a fragment of the other. If no chromosomal material is gained or lost in this process, the translocation is considered balanced. The prevalence of reciprocal translocations approximates 1 in 600 births (Nussbaum, 2007). Although the balanced translocation carrier is usually normal phenotypically, repositioning of specific genes within chromosomal segments can cause abnormalities. The risk of a major structural or developmental abnormality in an apparent balanced translocation carrier is approximately 6 percent. Interestingly, using CMA technology, up to 20 percent of individuals who appear to have a balanced translocation are found instead to have missing or redundant DNA segments (Manning, 2010).
Balanced translocation carriers are at risk to produce unbalanced gametes, resulting in abnormal offspring. As shown in Figure 13-7, if an oocyte or sperm contains a translocated chromosome, fertilization results in an unbalanced translocation—monosomy for part of one affected chromosome and trisomy for part of the other. The observed risk of a specific translocation can often be estimated by a genetic counselor. In general, translocation carriers identified after the birth of an abnormal child have a 5- to 30-percent risk of producing liveborn offspring with an unbalanced translocation. Carriers identified for other reasons, for example, during an infertility evaluation, have only a 5-percent risk. This is likely because the gametes are so abnormal that conceptions are nonviable.
A carrier of a balanced translocation may produce offspring who are also carriers of the balanced rearrangement (B), offspring with unbalanced translocations (C, D), or offspring with normal chromosomal complements (A).
These involve only acrocentric chromosomes, which are chromosomes 13, 14, 15, 21, and 22. The acrocentric chromosomes have extremely short p arms. In a robertsonian translocation, the q arms of two acrocentric chromosomes fuse at one centromere to form a derivative chromosome. The other centromere and both sets of p arms are lost. Because the number of centromeres determines the chromosome count, a robertsonian translocation carrier has only 45 chromosomes. Fortunately, the p arms of the acrocentric chromosomes—the satellite regions—contain redundant copies of genes that code for ribosomal RNA. As these are present in multiple copies on other acrocentric chromosomes, their loss does not affect the translocation carrier, who is usually phenotypically normal. However, when the derivative chromosome is paired during fertilization with a haploid chromosome from the partner, resulting offspring will be trisomic for that chromosome.
Robertsonian translocations are found in 1 in 1000 individuals. The incidence of abnormal offspring approximates 15 percent if a robertsonian translocation is carried by the mother and 2 percent if carried by the father. Robertsonian translocations are not a major cause of miscarriage and are found in fewer than 5 percent of couples with recurrent pregnancy loss. When a fetus or child is found to have a translocation trisomy, both parents should be offered karyotype analysis. If neither parent is a carrier, the recurrence risk is extremely low.
Balanced robertsonian carriers have reproductive difficulties for a number of reasons. If the fused chromosomes are homologous, that is, from the same chromosome pair, the carrier can produce only unbalanced gametes. Each egg or sperm contains either both copies of the translocated chromosome, which would result in trisomy if fertilized, or no copy, which would result in monosomy. If the fused chromosomes are nonhomologous, four of the six possible gametes would be abnormal. The most common robertsonian translocation is der(13;14)(q10;q10), which accounts for up to 20 percent of cases of Patau syndrome (Trisomy 18—Edwards Syndrome).
These abnormal chromosomes are composed of either two q arms or two p arms of one chromosome fused together. Isochromosomes are thought to arise when the centromere breaks transversely instead of longitudinally during meiosis II or mitosis. They can also result from a meiotic error in a chromosome with a robertsonian translocation. An isochromosome containing the q arms of an acrocentric chromosome behaves like a homologous robertsonian translocation, and such a carrier can produce only abnormal unbalanced gametes. When an isochromosome involves nonacrocentric chromosomes, with p arms containing important genetic material, the fusion and abnormal centromere break results in two isochromosomes. One is composed of both p arms, and one is composed of both q arms. It is likely that one of these isochromosomes would be lost during cell division, resulting in the deletion of all the genes located on the lost arm. Thus, a carrier is usually phenotypically abnormal and produces abnormal gametes. The most common isochromosome involves the long arm of the X chromosome, i(Xq), which is the etiology of 15 percent of cases of Turner syndrome.
When there are two breaks in the same chromosome, and the intervening genetic material is inverted before the breaks are repaired, the result is a chromosomal inversion. Although no genetic material is lost or duplicated, the rearrangement may alter gene function. There are two types—pericentric and paracentric inversions.
This results from breaks in both the p and q arms of a chromosome, such that the inverted material includes the centromere (Fig. 13-8). A pericentric inversion causes problems in chromosomal alignment during meiosis and confers significant risk for the carrier to produce abnormal gametes and abnormal offspring. In general, the observed risk of abnormal offspring in a pericentric inversion carrier is 5 to 10 percent if ascertainment was made after the birth of an abnormal child. But the risk is only 1 to 3 percent if prompted by another indication. An important exception is a pericentric inversion on chromosome 9. This is inv(9)(p11q12), which is a normal variant present in approximately 1 percent of the population.
Mechanism of meiosis in the setting of either pericentric inversion (one involving the centromere) or paracentric inversion (not involving the centromere). Individuals with pericentric inversions are at increased risk for producing offspring with a duplication/deletion. Those with paracentric inversions are at increased risk for early pregnancy loss.
If there are two breaks within one arm of a chromosome—either p or q—the inverted material does not include the centromere, and the inversion is paracentric (see Fig. 13-8). The carrier makes either normal balanced gametes or gametes that are so abnormal as to preclude fertilization. Thus, although infertility may be a problem, the risk of having an abnormal offspring is extremely low.
If there are deletions at each end of the same chromosome, the ends may come together to form a ring chromosome. The telomere regions, which are the ends of a chromosome, contain specialized nucleoprotein complexes that stabilize the chromosome. If just the telomeres are lost, all necessary genetic material is retained, and the carrier is essentially balanced. If a deletion extends more proximally than the telomere, the carrier is likely to be phenotypically abnormal. An example of this is a ring X chromosome, which may result in Turner syndrome.
A mosaic individual has two or more cytogenetically distinct cell lines that are derived from a single zygote. Phenotypic expression of mosaicism depends on several factors, including whether the cytogenetically abnormal cells involve the fetus, part of the fetus, just the placenta, or some combination. Of amnionic fluid cultures, mosaicism is found in approximately 0.3 percent but may not reflect the fetal chromosomal complement (Carey, 2014). When the abnormal cells are present in only a single flask of amnionic fluid, the finding is likely pseudomosaicism, caused by cell-culture artifact (Bui, 1984; Hsu, 1984). When abnormal cells involve multiple cultures, however, true mosaicism is more likely, and further testing may be warranted. A second cell line is verified in 60 to 70 percent of these fetuses (Hsu, 1984; Worton, 1984).
Confined Placental Mosaicism
With chorionic villus sampling, studies demonstrate that up to 2 percent of placentas are mosaic, with the mosaicism confined to the placenta in most of these cases (Baffero, 2012; Henderson, 1996). Amniocentesis should be offered. In a series of more than 1000 pregnancies with mosaicism found from chorionic villus sampling, subsequent amniocentesis identified true fetal mosaicism in 13 percent. Uniparental disomy, discussed later (Imprinting), was found in 2 percent, and the remainder resulted from confined placental mosaicism (Malvestiti, 2015). If mosaicism is detected for a chromosome known to contain imprinted genes—such as chromosomes 6, 7, 11, 14, or 15—testing for uniparental disomy should be considered, as there may be fetal consequences (Grati, 2014a).
Although outcomes with confined placental mosaicism are generally good, fetal-growth restriction is more common, and the stillbirth risk is also higher (Reddy, 2009). Fetal-growth restriction may stem from impaired functioning of the aneuploid placental cells (Baffero, 2012). Placental mosaicism for trisomy 16 confers a particularly poor prognosis.
Mosaicism confined to the gonads likely arises from a mitotic error in cells destined to become the gonad, resulting in a population of abnormal germ cells. Because spermatogonia and oogonia divide throughout fetal life, and spermatogonia continue to divide throughout adulthood, gonadal mosaicism may also follow a meiotic error in previously normal germ cells. Gonadal mosaicism can account for de novo diseases in the offspring of normal parents. Autosomal dominant examples are achondroplasia and osteogenesis imperfecta, and X-linked ones include Duchenne muscular dystrophy. Gonadal mosaicism also explains the 6-percent recurrence risk after the birth of a child with a disease caused by a “new” mutation.