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Obstentrics_Williams. 47,XXX. 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). Afected 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,XXiis weakly associated with maternal age, and cell-free DNA screening has resulted in increased diagnoses (Table 14-5, p. 281). 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 deicit disorder, and overall cognitive scores are in the low-average range. No speciic pattern of malformations has been described, but genitourinary problems and seizure disorders are more common (Wigby, 2016). Pubertal development is unafected. Primary ovarian insuiciency has been reported (Holland, 2001).


Obstentrics_Williams

Obstentrics_Williams. has been described, but genitourinary problems and seizure disorders are more common (Wigby, 2016). Pubertal development is unafected. Primary ovarian insuiciency has been reported (Holland, 2001). Because of variable presentation and subtle abnormal indings, it is estimated that this diagnosis is ascertained clinically in only 10 percent of afected children.


Obstentrics_Williams

Obstentrics_Williams. Females with two or more extra X chromosomes-48,XXior 49,XXXX-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. 47,XXY-Klinefelter Syndrome. his is the most common sex chromosome abnormality and found in approximately 1 in 600 male infants. he additional X chromosome is maternally or paternally derived with equal propensity Qacobs, 1995; Lowe, 2001). The association with either advanced maternal or paternal age is weak (Milunsky, 2004).


Obstentrics_Williams

Obstentrics_Williams. Like 47,XX, newborns with 47,Y 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).


Obstentrics_Williams

Obstentrics_Williams. 47,XY. This aneuploidy occurs in approximately 1 in 1000 male newborns. As with 47,XXand Y individuals, afected 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 hal. Pubertal development is normal, and fertility is unimpaired. ffected children carry risks for oral and written language impairments, attention deicit 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-48Yor with both additional X and Y chromosomes-48,YYor 49,XYY-are more likely to have congenital abnormalities, medical problems, and intellectual disability (Tartaglia, 2011). • Abnormalities of Chromosome Structure


Obstentrics_Williams

Obstentrics_Williams. • Abnormalities of Chromosome Structure Structural chromosomal abnormalities include deletions, duplications, translocations, isochromosomes, inversions, ring chromosomes, and mosaicism (see Table 13-1). heir overall birth prevalence approximates 0.3 percent (Nussbaum, 2007). Identiication 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-speciically, are the parents at increased risk of carrying this abnormality? If so, what is their risk of having future afected ofspring?


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Obstentrics_Williams. 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. he 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 ofered, because if either parent carries a balanced translocation, the recurrence risk in subsequent pregnancies is signiicantly increased. Deletions involving DNA segments large enough to be seen with standard cytogenetic karyotyping are identiied in approximately 1 in 7000 births (Nussbaum, 2007). Common


Obstentrics_Williams

Obstentrics_Williams. FIGURE 13-6 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. deletions may be referred to by eponyms-for example, del 5p is called cri du chat syndrome.


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Obstentrics_Williams. 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 micro array analysis (CMA) , described later (p. 271), 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 micro duplication may involve the exact DNA region that causes a recognized microdeletion syndrome (Table 13-2). When a speciic microdeletion syndrome is suspected clinically, it is confirmed using either CMA or luorescence in situ hybridization.


Obstentrics_Williams

Obstentrics_Williams. 22qlel.2 Microdeletion Syndrome. his 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 diferent features, and thus poses some counseling challenges (Shprintzen, 2008). Features can vary widely, even among afected family members. Previously, diferent 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 afected individuals, associated abnormalities include conotruncal cardiac anomalies, Prevalence reflects live births. Data from National Library of Medicine, 2017; Johns Hopkins University, 2017.


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Obstentrics_Williams. Prevalence reflects live births. Data from National Library of Medicine, 2017; Johns Hopkins University, 2017. such as tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, and ventricular septal defects (McDonald-McGinn, 2015). Immune deiciency, such as T-cell lymphopenia, also develops in approximately 75 percent. More than 70 percent have velopharyngeal insuiciency 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 issures, bulbous nasal tip, micrognathia, short philtrum, and small or posteriorly rotated ears are characteristic facial features.


Obstentrics_Williams

Obstentrics_Williams. hese are DNA rearrangements in which a segment of DNA breas away from one chromosome and attaches to another. he rearranged chromosomes are called derivative (der) chromosomes. here are two types-reciprocal and robertsonian translocations.


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Obstentrics_Williams. Reciprocal Translocations. A double-segment or reciprocal translocation begins when breaks occur in two diferent chromosomes. The broken fragments are then exchanged, so that each afected chromosome contains a fragment of the other. If no chromosomal material is gained or lost in this process, the translocation is considered balanced. he 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. he risk of a major sttuctural 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,i2010).


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Obstentrics_Williams. Balanced translocation carriers are at risk to produce unbalanced gametes, resulting in abnormal ofspring. As shown in FIGURE 13-7 A carrier of a balanced translocation may produce offspring who are also carriers ofthe balanced rearrangement (8), ofspring with unbalanced translocations (C, D), or ofspring with normal chromosomal complements (A). n.N


Obstentrics_Williams

Obstentrics_Williams. n.N Figure 13-7, if an oocyte or sperm contains a translocated chromosome, fertilization results in an unbalanced translocation-monosomy for part of one afected chromosome and trisomy for part of the other. he 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 ofspring with an unbalanced translocation. Carriers identiied for other reasons, for example, during an infertility evaluation, have only a 5-percent risk. his is likely because the gametes are so abnormal that conceptions are nonviable.


Obstentrics_Williams

Obstentrics_Williams. Robertsonian Translocations. These involve only acrocentric chromosomes, which are chromosomes 13, 14, 15,i21, and 22. he 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. he 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 afect 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 ofspring will be trisomic for that chromosome.


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Obstentrics_Williams. Robertsonian translocations are found in 1 in 1000 individuals. The incidence of abnormal ofspring 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 ofered karyotype analysis. If neither parent is a carrier, the recurrence risk is extremely low.


Obstentrics_Williams

Obstentrics_Williams. Balanced robertsonian carriers have reproductive diiculties for a number of reasons. Ifthe 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. he most common robertsonian translocation is der(13; 14) (ql0;ql0), which accounts for up to 20 percent of cases of Patau s) ndrome (p. 257). These abnormal chromosomes are composed of either two q arms or two p arms of one chromosome fused together.


Obstentrics_Williams

Obstentrics_Williams. 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 non acrocentric 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


Obstentrics_Williams

Obstentrics_Williams. 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 T umer syndrome.


Obstentrics_Williams

Obstentrics_Williams. 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.


Obstentrics_Williams

Obstentrics_Williams. PericentricInversion. 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 signiicant risk for the carrier to produce abnormal gametes and abnormal ofspring. In general, the observed risk of abnormal ofspring in a peri centric 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. his is inv(9)(pllq12), which is a normal variant present in approximately 1 percent of the population.


Obstentrics_Williams

Obstentrics_Williams. Paracentric Inversion.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). he 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 ofspring is extremely low. If there are deletions at each end of the same chromosome, the ends may come together to form a ring chromosome. he 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 T umer syndrome.


Obstentrics_Williams

Obstentrics_Williams. centric inversion (one involving the centromere) or paracentric inversion (not involving the centromere). Individuals with pericen tric inversions are at increased risk for producing offspring with a duplication/deletion. Those with paracentric inversions are at increased risk for early pregnancy loss.


Obstentrics_Williams

Obstentrics_Williams. 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 luid 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 lask of amnionic luid, the inding 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 veriied in 60 to 70 percent of these fetuses (Hsu, 1984; Worton, 1984).


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Obstentrics_Williams. With chorionic villus sampling, studies demonstrate that up to 2 percent of placentas are mosaic, with the mosaicism conined to the in most of these cases (Bafero, 2012; Henderson, 1996). Amniocentesis should be ofered. In a series of more than 1000 pregnancies with mosaicism found from chorionic villus sampling, subsequent amniocentesis identiied true fetal mosaicism in 13 percent. Uniparental disomy, discussed later (p. 268), 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 15testing for uniparental disomy should be considered, as there may be fetal consequences (Grati, 2014a).


Obstentrics_Williams

Obstentrics_Williams. lthough outcomes with conined 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 (Bafero, 2012). Placental mosaicism for trisomy 16 confers a particularly poor prognosis.


Obstentrics_Williams

Obstentrics_Williams. 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 ofspring 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.


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Obstentrics_Williams. A monogenic or mendelian disorder is caused by a mutation or alteration in a single locus or gene in one or both members of a gene pair. Types of mendelian inheritance include autosomal dominant, autosomal recessive, X-linked, and Y-linked. Other monogenic inheritance patterns, described subsequently, include mitochondrial inheritance, uniparental disomy, imprinting, and trinucleotide repeat expansion-also termed anticipation. By age 25, approximately 0.4 percent of the population exhibits an abnormality attributed to a monogenic disorder, and 2 percent will have at least one such disorder during their lifetime (Table 13-3).


Obstentrics_Williams

Obstentrics_Williams. When considering inheritance, it is the phenotype that is dominant or recessive, not the genotype. With a dominant disease, the normal gene may direct the production of normal protein, but the phenotype is abnormal because it is determined by protein produced by the abnormal gene. With a recessive disease, a heterozygous carrier may produce detectable levels of an abnormal gene product but have no features of the condition because the phenotype is directed by the product of the normal co-gene. For example, erythrocytes from carriers of sickle-cell anemia contain approximately 30 percent hemoglobin S, but because the other 70 percent is hemoglobin A, these cells do not usually sickle in vitro. Genetic heterogeneiy explains how diferent genetic mechanisms can result in the same phenotype. Locus heterogeneiy indicates


Obstentrics_Williams

Obstentrics_Williams. Genetic heterogeneiy explains how diferent genetic mechanisms can result in the same phenotype. Locus heterogeneiy indicates TABLE 13-3. Selected Monogenic (Mendelian) Disorders that a speciic disease phenotype can be caused by mutations in diferent genetic loci. It also explains why some diseases appear to follow more than one type of inheritance. An example is retinitis pigmentosa, which may develop following mutations in at least 35 diferent genes or loci and may result in autosomal dominant, autosomal recessive, or X-linked forms. Alelic heterogeneiy describes how diferent mutations of the same gene may afect presentation of a particular disease. For example, although only one gene has been associated with cystic ibrosis-the cystic ibrosis conductance transmembrane regulator gene-more than 2000 mutations in this gene have been described and result in variable disease severity (Chaps. 14 and 51, pp. 289 and 997).


Obstentrics_Williams

Obstentrics_Williams. can arise from diferent mutations in the same gene. As an example, mutations in the ibroblast growth actor receptor 3 (FGF3) gene may result in several diferent skeletal disorders, including achondroplasia and thanatophoric dysplasia, both of which are discussed in Chapter 10 (p. 210). If only one copy of a gene pair determines the phenotype, that gene is considered to be dominant. Carriers have a 50-percent chance of passing on the afected gene with each conception. A gene with a dominant mutation generally speciies the phenotype in preference to the normal gene. That said, not all individuals will necessarily manifest an autosomal dominant condition the same way. Factors that afect the phenotype of an autosomal dominant condition include penetrance, expressivity, and occasionally, presence of codominant genes.


Obstentrics_Williams

Obstentrics_Williams. his characteristic describes whether or not a dominant gene is expressed at all. A gene with recognizable phenotypic expression in all individuals is 100-percent penetrant, whereas penetrance is incomplete if some carriers express the gene but some do not. his may be quantitatively expressed-for example, a gene that is expressed in some way in 80 percent of individuals who have that gene is 80-percent penetrant. Importantly, incomplete penetrance explains why some autosomal dominant diseases may appear to "skip" generations. Individuals with the same autosomal dominant trait may manifest the condition diferently, even within the same family. Genes with variable expressivity can produce disease manifestations that range from mild to severe. Examples include neuroibromatosis, tuberous sclerosis, and adult polycystic kidney disease.


Obstentrics_Williams

Obstentrics_Williams. If two diferent alleles in a gene pair are both expressed in the phenotype, they are considered to be codominant. Blood type, for example, is determined by expression of dominant A and B red-cell antigens that can be expressed simultaneously. Another example of codominance is the group of genes responsible for hemoglobin production. An individual with one gene directing production of hemoglobin S and the other directing production of hemoglobin C will produce both Siand C hemoglobin (Chap. 56, p. 1082).


Obstentrics_Williams

Obstentrics_Williams. Paternal age older than 40 is associated with increased risk for spontaneous genetic mutations, particularly single base substitutions. This may result in ofspring with new autosomal dominant disorders or X-linked carrier states. In particular, advanced paternal age has been associated with mutations in the ibroblast growth actor receptor 2 (FGF2) gene, which may cause craniosynostosis syndromes such as Apert, Crouzon, and Pfei fer syndromes; mutations in the FGF3 gene, which may result in the ET proto-oncogene, which may cause multiple endo crine neoplasia syndromes Qung, 2003; Toriello, 2008). Using whole genome sequencing, described later (p. 272), Kong and utes to a rise in the rate of single-nucleotide polymorphisms among ofspring. his rate is approximately two mutations for each year of paternal age. Because individual autosomal domi nant disorders are uncommon, the actual risk for any speciic condition is low, and no screening or testing is speciically rec ommended.


Obstentrics_Williams

Obstentrics_Williams. Advanced paternal age has also been associated with a structural abnormalities (Grewal, 2012; Toriello, 2008; Yang, 2007). It is not generally considered to pose an elevated risk for other aneuploidies, probably because the aneuploid sperm cannot fertilize an egg.


Obstentrics_Williams

Obstentrics_Williams. Recessive diseases develop only when both gene copies are abnormal. Many enzyme deficiency diseases display autosomal recessive inheritance, and enzyme activity in the carrier is usually about half of normal. Unless carriers are screened for a specific disease, such as cystic ibrosis, they usually are recognized only after the birth of an afected child or the diagnosis of an afected family member (Chap. 14, p. 289). If a couple has a child with an autosomal recessive disease, the recurrence risk is 25 percent for each subsequent pregnancy. hus, 1/4 of ofspring will be homozygous normal, 2/4 will be heterozygous carriers, and 114 will be homozygous abnormal. In other words, three of four children will be phenotypically normal, and 2/3 of phenotypically normal siblings are actually carriers.


Obstentrics_Williams

Obstentrics_Williams. A heterozygous carrier of a recessive condition is only at risk to have afected children if his or her partner is heterozygous or homozygous for the disease. Genes for rare autosomal recessive conditions have low prevalence in the general population. Thus, the likelihood that a partner will be a gene carrier is small, unless there is consanguinity or the partner is a member of an at-risk group. Heterozygous carriers are usually undetectable clinically but may have biochemical test abnormalities that can be used for carrier screening. Other recessive conditions can be identified only by molecular genetic testing (Chap. 14, p. 288). Inborn Errors of Metabolism Most of these autosomal recessive diseases result from absence of a crucial enzyme, leading to incomplete metabolism of proteins, lipids, or carbohydrates. The metabolic intermediates that build up are toxic to various tissues and may result in intellectual disability or other abnormalities.


Obstentrics_Williams

Obstentrics_Williams. Phenylketonuria. Also known as phenylalanine hydroxylase (PAH) deficiency, this autosomal recessive disease is caused by mutations in the PAH gene. PAH metabolizes phenylalanine to tyrosine, and homozygotes have diminished or absent enzyme activity. This leads to abnormally high levels of phenylalanine, resulting in progressive intellectual impairment, autism, seizures, motor deficits, and neuropsychological abnormalities (Blau, 2010). Because phenylalanine competitively inhibits tyrosine hydroxylase-which is essential for melanin production, afected individuals also have hair, eye, and skin hypopigmentation. More than 500 PAH gene mutations have been characterized, and the carrier frequency is 1 in 60, such that the disease afects approximately 1 in 15,000 newborns (American College of Obstetricians and Gynecologists, 2017 c). Prompt diagnosis and restriction of dietary phenylalanine beginning early in infancy are essential to prevent neurological damage, and all states mandate


Obstentrics_Williams

Obstentrics_Williams. of Obstetricians and Gynecologists, 2017 c). Prompt diagnosis and restriction of dietary phenylalanine beginning early in infancy are essential to prevent neurological damage, and all states mandate newborn screening for phenylketonuria (PKU).


Obstentrics_Williams

Obstentrics_Williams. Phenylalanine restriction alone would result in inadequate protein consumption, and phenylalanine-free amino acid-based supplementation is required. lso, in 2007, a synthetic form of the P AH cofactor tetrahydrobiopterin (sapropterin) was approved for PKU treatment. Approximately 25 to 50 percent of afected individuals are sapropterin-responsive and may experience a significant decline in phenylalanine levels and improvement in neuropsychiatric symptoms (Vockley, 2014). Lifelong maintenance of phenylalanine concentrations in the range of 2 to 6 mg/dL (120 to 360 �mol/L) is necessary to prevent worsening neurocognitive and psychiatric problems (American College of Obstetricians and Gynecologists, 2017 c). Fortunately, even those who have previously discontinued therapy may experience improved neuropsychological function with treatment.


Obstentrics_Williams

Obstentrics_Williams. During pregnancy, women with PKU whose phenylalanine levels remain above the recommended range are at risk to have otherwise normal (heterozygous) ofspring who sustain in utero damage as a result of being exposed to toxic phenylalanine concentrations. Phenylalanine is actively transported to the fetus. Hyperphenylalaninemia raises the risk for miscarriage and for PKU embryopathy, characterized by intellectual disability, microcephaly, seizures, growth impairment, and cardiac anomalies. Among women on unrestricted diets, the risk to have a child with intellectual disability exceeds 90 percent, microcephaly occurs in more than 70 percent, and as many as 1 in 6 children have cardiac defects (Lenke, 1980). he Maternal Phenylketonuria Collaborative Study, which included 572 pregnancies followed more than 18 years, reported that maintenance of serum phenylalanine levels in the recommended range between 2 and 6 mg/dL signiicantly reduced the fetal abnormality risk and resulted in childhood


Obstentrics_Williams

Obstentrics_Williams. more than 18 years, reported that maintenance of serum phenylalanine levels in the recommended range between 2 and 6 mg/dL signiicantly reduced the fetal abnormality risk and resulted in childhood IQ scores in the normal range (Koch, 2003; Platt, 2000). Preconceptional counseling and consultation with providers from experienced PKU centers is recommended.


Obstentrics_Williams

Obstentrics_Williams. Two individuals are considered consanguineous if they have at least one recent ancestor in common. Although uncommon in Western countries, more than 1 billion people are estimated to live in countries in which 20 to 50 percent of marriages are consanguineous (Romeo, 2014). In medical genetics, a union is consanguineous if between second cousins or closer relatives. First-degree relatives share half of their genes, second-degree relatives share a fourth, and third-degree relatives-first cousins-share one eighth. Because of the potential for shared deleterious genes, consanguinity confers an increased risk to have ofspring with otherwise rare autosomal recessive diseases or multifactorial disorders. In population-based series, first cousins are reported to have a twofold risk for congenital anomalies (Sheridan, 2013; Stoltenberg, 1997). Consang�inity also is associated with a greater rate of stillbirth (Kapurubandara, 2016). Because CMA performed using a single-nucleotide polymorphism


Obstentrics_Williams

Obstentrics_Williams. anomalies (Sheridan, 2013; Stoltenberg, 1997). Consang�inity also is associated with a greater rate of stillbirth (Kapurubandara, 2016). Because CMA performed using a single-nucleotide polymorphism platform may identiy consanguinity, it is important that preprocedural counseling include this possibility.


Obstentrics_Williams

Obstentrics_Williams. Incest is defined as a sexual relationship between first-degree relatives such as parent-child or brother-sister and is universally illegal. Progeny of such unions carry the highest risk of abnormal outcomes, and older studies reported that up to 40 percent of ofspring were abnormal as a result of recessive and multifactorial disorders (Baird, 1982; Freire-Maia, 1984). Most X-linked diseases are recessive. Common examples include color blindness, hemophilia A and B, and Duchenne and Becker muscular dystrophy. Males with an X-linked recessive gene are usually afected by the disease it causes, because they lack a second X chromosome to express the normal dominant gene. A male with an X-linked disease cannot have afected sons because they cannot receive his X chromosome. When a woman carries a gene causing an X-linked recessive condition, each of her sons has a 50-percent risk of being afected, and each daughter has a 50-percent chance of being a carrier.


Obstentrics_Williams

Obstentrics_Williams. Women with an X-linked recessive gene are generally unaffected by the disease it causes. In some cases, however, the random inactivation of one X chromosome in each cell-termed lyonization-is skewed, and female carriers may have features of the condition. For example, approximately 10 percent of female carriers of hemophilia A will have factor VIII levels less than 30 percent of normal, and a similar proportion of female hemophilia B carriers have factor IX levels less than 30 percent. Levels below these thresholds confer a greater risk for abnormal bleeding when afected women give birth (Plug, 2006). Indeed, even with higher levels, carriers are reported to be at increased risk for bleeding complications (Olsson, 2014). Similarly, female carriers of Duchenne or Becker muscular dystrophy carry an elevated risk for cardiomyopathy, and periodic evaluation for cardiac dysfunction and neuromuscular disorders is recommended (American Academy of Pediatrics, 2008).


Obstentrics_Williams

Obstentrics_Williams. X-linked dominant disorders mainly afect females, because they tend to be lethal in males. Two examples are vitamin D-resistant rickets and incontinentia pigmenti. One exception is fragile X syndrome, which is discussed subsequently. he prevalence of Y-linked chromosomal disorders is low. This chromosome carries genes important for sex determination and various cellular functions related to spermatogenesis and bone development. Deletion of genes on the long arm of Y results in severe spermatogenic defects, whereas genes at the tip of the short arm are critical for chromosomal pairing during meiosis and for fertility.


Obstentrics_Williams

Obstentrics_Williams. Human cells contain hundreds of mitochondria, each with its own genome and associated replication system. Oocytes contain approximately 100,000 mitochondria. Sperm hold only about 100, and these are destroyed after fertilization. Each mitochon drion has multiple copies of a 16.5-kb circular DNA molecule that contains 37 genes. Mitochondrial DNA encodes peptides and transfer RNAs. Mitochondria are inherited exclusively from the mother.


Obstentrics_Williams

Obstentrics_Williams. Mitochondria are inherited exclusively from the mother. hus, although males and females both can be afected by a mitochondrial disorder, transmission is only through the mother. When a cell replicates, mitochondrial DNA sorts randomly into each of the daughter cells, a process termed replicative segregation. A consequence of replicative segregation is that any mitochondrial mutation will be propagated randomly into the daughter cells. Because each cell holds multiple copies of mitochondrial DNA, the mitochondrion may contain only normal or only abnormal DNA, termed homoplasmy. Alternatively, it may contain both normal and mutated DNA, namely heteroplasmy. If a heteroplasmic oocyte is fertilized, the relative proportion ofmutated DNA may afect whether the individual manifests a given mitochondrial disease. It is not possible to predict the potential degree of heteroplasmy among ofspring, and this poses challenges for genetic counseling.


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Obstentrics_Williams. As of 2016, 33 mitochondrial diseases or conditions with known molecular basis were described in Online Mendelian Inheritance in Man Qohns Hopkins University, 2017). Examples include myoclonic epilepsy with ragged red fibers (MERRF), Leber optic atrophy, Kearns-Sayre syndrome, Leigh syndrome, several forms of mitochondrial myopathy and cardiomyopathy, and susceptibility to chloramphenicol toxicity. Mendel's irst law is that genes are passed unchanged from parent to progeny, and barring new mutations, this is true for many genes or traits. However, certain genes are unstable, and their size, and thus function, may be altered during parentto-child transmission. This is manifested clinically by anticipation-a phenomenon in which disease symptoms seem to be more severe and to appear at an earlier age in each successive generation. Examples of some DNA triplet (trinucleotide) repeat diseases are shown in Table 13-4.


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Obstentrics_Williams. his is the most common inherited form of intellectual disability and afects approximately 1 in 3600 males and 1 in 4000 to 6000 females (American College of Obstetricians and Gynecologists, 2017a). Fragile X syndrome is caused by expansion TABLE 13-4. Some Disorders Caused by DNA Triplet Repeat Expansion of a repeated trinucleotide DNA segment-cytosine-guanineguanine (CGG)-at chromosome Xq27.3. When the CGG repeat number reaches a critical size-the full mutation-the ragile X mental retardation 1 (FMR1) gene becomes methyl ated. Methylation inactivates the gene, which halts expression of FMR1 protein. his protein is most abundant in nerve cells and is essential for normal cognitive development.


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Obstentrics_Williams. Although transmission of the syndrome is X-linked, both the sex of the afected individual and the number of CGG repeats determine the degree of clinical normalcy or impair ment. Intellectual disability is generally more severe in males, in whom average IQ scores are 35 to 45 (Nelson, 1995). Afected tion-deicit/hyperactivity disorder. Fragile X syndrome is also the most common known cause of autism or "autistic like" behavior. Associated phenotypic abnormalities become more prominent with age and include a narrow face with large jaw, prominent ears, connective tissue abnormalities, and macroor chidism in postpubertal males. Clinically, four groups have been described (American College of Obstetricians and Gyne •cologists, 2017a): Premutation-55 to 200 repeats Intermediate-45 to 54 repeats


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Obstentrics_Williams. Premutation-55 to 200 repeats Intermediate-45 to 54 repeats Full mutations are expressed (penetrant) in all males and many females. When a full mutation is present, males typically have significant cognitive and behavioral abnormalities and phenotypic features. In females, random X-inactivation, however, results in variable expression, and the disability may be much less severe. With rare exception, the parent of origin of repeat expansion that leads to a full mutation is female (Monaghan, 2013).


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Obstentrics_Williams. For individuals with a premutation, evaluation and counseling are more complex. A female with the fragile X premutation is at risk to have ofspring with the full mutation, depending on the repeat number. The risk ofa full mutation in an ofspring is 5 percent or less if the CGG repeat number is <70 but exceeds 95 percent with 100 to 200 CGG repeats (Nolin, 2003). Expansion is extremely unlikely in a male premutation carrier, but all of his daughters will carry the premutation. Among women with no risk factors, approximately 1 in 250 carries a fragile X premutation, and the risk approximates 1 in 90 in those with a family history of intellectual disability (Cronister, 2008). Premutation carriers may themselves experience significant health consequences. Males with the premutation are at increased risk for the fragile X tremor ataxia syndrome (FXTAS). his syndrome is characterized by memory loss, executive function deficits, anxiety, and dementia (Monaghan, 2013). Females are at risk for


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Obstentrics_Williams. risk for the fragile X tremor ataxia syndrome (FXTAS). his syndrome is characterized by memory loss, executive function deficits, anxiety, and dementia (Monaghan, 2013). Females are at risk for FXTAS as well, although less so. hey also have a 20-percent risk for fragile X-associated primary ovarian insuficiency.


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Obstentrics_Williams. he American College of Obstetricians and Gynecologists (2016c, 2017a) recommends carrier screening for women with a family histof) of fragile X syndrome; individuals with unexplained intellectual disability, developmental delay, or autism; and women with primary ovarian insuiciency. Prenatal diagnosis can be accomplished by amniocentesis or chorionic villus sampling. Specimens obtained by either can define the CGG repeat number, although chorionic villus sampling may not accurately determine FMRl gene methylation status.


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Obstentrics_Williams. his term describes some genes that are inherited but not expressed, depending on whether they are inherited from the mother or father. hus, the resulting phenotype varies according to the parent of origin. Imprinting afects gene expression by epigenetic control, which modiies genetic structure using methods other than altering the underlying nucleotide sequence. For example, methyl group addition may alter gene expression and thereby afect the phenotype without changing the genotype. Importantly, the efect may be reversed in a subsequent generation, because a female who inherits an imprinted gene from her father will pass it in her oocytes with a maternal-rather than paternal-imprint, and vice versa. Selected diseases that can involve imprinting are shown in


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Obstentrics_Williams. Selected diseases that can involve imprinting are shown in Table 13-5. A useful example includes two very diferent dis eases that afect the same region of DNA. First, Prader-Willi syndrome is characterized by obesity and hyperphagia; short stature; small hands, feet, and external genitalia; and mild mental retardation. In more than 70 percent of cases, PraderWilli syndrome is caused by microdeletion or disruption for the paternal 15q 11.2-q 13. The remaining cases are due to maternal uniparental disomy or due to maternal gene imprinting with the paternal gene inactivated.


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Obstentrics_Williams. In contrast, Angelman syndrome includes severe intellectual disability; normal stature and weight; absent speech; seizure disorder; ataxia and jerky arm movements; and paroxysms of inappropriate laughter. In approximately 70 percent of cases, Angelman syndrome is caused by microdeletion for the maternal 15q 11.2-q 13. In 2 percent, the syndrome is caused by paternal uniparental disomy, and another 2 to 3 percent is due to paternal gene imprinting with the maternal genes inactivated. here are other examples of imprinting important to obstetrics. Complete hydatidiform mole, with a paternally derived diploid chromosomal complement, is characterized by abundant TABLE 13-5. Some Disorders That Can Involve Imprinting Angelman lSq11.2-q13 Maternal Beckwith-Wiedemann 11 p1S.5 Paternal Prader-Willi lSq11l.2-q13 Paternal Pseudohypoparathyroidism 20q13.2 Variable Russell-Silver syndrome 7p1l1.2 Maternal


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Obstentrics_Williams. Angelman lSq11.2-q13 Maternal Beckwith-Wiedemann 11 p1S.5 Paternal Prader-Willi lSq11l.2-q13 Paternal Pseudohypoparathyroidism 20q13.2 Variable Russell-Silver syndrome 7p1l1.2 Maternal Data from Online Mendelian Inheritance in Man (Johns Hopkins University, 201l7.) placental growth with no fetal structures (Chap. 20, p. 389). Conversely, an ovarian teratoma, with a maternally derived diploid chromosomal complement, is characterized by the growth of various fetal but no placental tissues (Porter, 1993).


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Obstentrics_Williams. his occurs when both members of a chromosome pair are inherited from the same parent. Often, uniparental disomy does not have clinical consequences. Although both copies are inherited from one parent, they are not identical. However, if chromosomes 6, 7, 11, 14, or 15 are involved, ofspring are at increased risk for an abnormality because of parent-of-origin diferences in gene expression (Shafer, 2001). Several genetic mechanisms may cause uniparental disomy, the most common of which is trisomic rescue, shown in Figure 13-9. After a nondisjunction event produces a trisomic conceptus, one of the three homologues may be lost. his will result in uniparental disomy for that chromosome in approximately one third of cases.


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Obstentrics_Williams. Isodisomy is the unique situation in which an individual receives two identical copies of one chromosome in a pair from one parent. his mechanism explains some cases of cystic ibrosis, in which only one parent is a carrier but the fetus inherits two copies of the same abnormal chromosome from that parent (Spence, 1988; Spotila, 1992). It also has been implicated in abnormal growth related to placental mosaicism. Traits or diseases are considered to have multifactorial inheritance if they are determined by the combination of multiple genes and environmental factors (Table 13-6). Polygenic traits are determined by the combined efects of more than one gene. Most congenital and acquired conditions, as well as common traits, display multifactorial inheritance. Examples include malformations such as clefts and neural-tube defects, diseases such as diabetes and heart disease, and features or traits such as head TABLE 13-6. Characteristics of Multifactorial Diseases


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Obstentrics_Williams. TABLE 13-6. Characteristics of Multifactorial Diseases There is a genetic contribution: No mendelian pattern of inheritance No evidence of single-gene disorder Nongenetic factors are also involved in disease causation: Lack of penetrance despite predisposing genotype Monozygotic twins may be discordant Familial aggregation may be present: Relatives are more likely to have disease-predisposing alleles Expression more common among close relatives: Adapted from Nussbaum, 2007. Genetics 269 FIGURE 13-9 Mechanism of uniparental disomy arising from trisomic "rescue." A. In normal meiosis, one member of each pair of homologous chromosomes is inherited from each parent. B. If nondisjunction results in a trisomic conceptus, one homologue is sometimes lost. In a third of cases, loss of one homologue leads to uniparental disomy.


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Obstentrics_Williams. size or height. Abnormalities that display multifactorial inheritance tend to recur in families, but not according to a mendelian pattern. If a couple has had a child with a multifactorial birth defect, their empirical risk to have another afected child is 3 to 5 percent. This risk declines exponentially with successively more distant relationships. Multifactorial traits that have a normal distribution in the population are termed continuously variable. A measurement that is more than two standard deviations above or below the population mean is considered abnormal. Continuously variable traits tend to be less extreme in the ofspring of afected individuals, because of the statistical principle of regression to the mean.


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Obstentrics_Williams. Some multifactorial traits do not appear until a threshold is exceeded. Genetic and environmental factors that create propensity or liability for the trait are themselves normally distributed, and only individuals at the extreme of the distribution exceed the threshold and exhibit the trait or defect. Phenotypic abnormality is thus an all-or-none phenomenon. Examples include cleft lip-palate and pyloric stenosis.


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Obstentrics_Williams. Certain threshold traits have a clear male or female predominance. If an individual of the less common gender has the characteristic or defect, the recurrence risk is greater in his or her ofspring (Fig. 13-10). An example is pyloric stenosis, which is approximately four times more common in males (Krogh, 2012). A female with pyloric stenosis has likely inherited more predisposing genetic factors than are necessary to produce the defect in a male, and the recurrence risk for her children or siblings is thus higher than the expected 3 to 5 percent. Her male siblings or male ofspring would have the highest liability because they not only will inherit more than the usual number of predisposing genes but also are the more susceptible gender.


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Obstentrics_Williams. he recurrence risk for threshold traits is also greater if the defect is severe. For example, the recurrence risk after the birth of a child with bilateral cleft lip and palate is approximately 8 percent, but it is only about 4 percent following a child with unilateral cleft lip alone. Structural cardiac anomalies are the most common birth defects, with a birth prevalence of 8 cases per 1000. More than o.�c 5. o..= FIGURE 13-10 Schematic example of a threshold trait, such as pyloric stenosis, which has a predilection for males. Each gender is normally distributed, but at the same threshold, more males than females will develop the condition. 100 genes believed to be involved in cardiovascular morphogenesis have been identiied, including those directing production of various proteins, protein receptors, and transcription factors (Olson, 2006; Weismann, 2007).


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Obstentrics_Williams. he risk of having a child with a cardiac anomaly is approximately 5 to 6 percent if the mother has the defect and 2 to 3 percent if the father has the defect (Burn, 1998). Selected left-sided lesions, including hypoplastic left heart syndrome, coarctation of the aorta, and bicuspid aortic valve, may have recurrence risks four-to sixfold higher (Lin, 1988; Lupton, 2002; Nora, 1988). Observed recurrence risks for specific cardiac malformations are listed in Table 49-4 (p. 953).


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Obstentrics_Williams. These disorders are also classic examples of multifactorial inheritance. Development of neural-tube defects (NTDs) may be influenced by hyperthermia, hyperglycemia, teratogen exposure, ethnicity, family history, fetal gender, and various genes. Selected risks are more strongly associated with the specific defect location. Hyperthermia has been linked with anencephaly risk; pregestational diabetes with cranial and cervicalthoracic defects; and valproic acid exposure with lumbosacral defects (Becerra, 1990; Hunter, 1984; Lindhout, 1992). Sonographic features ofNTDs are described in Chapter 10 (p. 192), their prevention with folic acid is discussed in Chapter 9 (p. 169), and fetal therapy for myelomeningocele is reviewed in Chapter 16 (p. 319).


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Obstentrics_Williams. More than 50 years ago, Hibbard and Smithells (1965) postulated that abnormal folate metabolism was responsible for many NTDs. For a woman with a prior afected child, the recurrence risk of 3 to 5 percent is decreased by at least 70 percent-and potentially by as much as 85 to 90 percent-with periconceptional oral folic acid supplementation at a dosage of 4 mg/d (Grosse, 2007; MRC Vitamin Study Research Group, 1991). However, most NTD cases do not occur in the setting of maternal folic acid deiciency, and it has become clear that the gene-nutrient interactions underlying folate-responsive NTDs are complex. he NTD risk may be afected by genetic variation in folate transport or accumulation, impaired folate utilization via secondary nutrient deficiencies such as vitamin BI2 or choline deficiency, and genetic variation in activity of folate-dependent metabolic enzymes (Beaudin, 2009).


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Obstentrics_Williams. All pregnant women should have the option of prenatal aneuploidy screening and prenatal genetic diagnosis (American College of Obstetricians and Gynecologists, 2016b). Aneuploidy screening may be performed with serum analyte-based screening or with a DNA-based screen, namely, cell-free DNA found in the maternal circulation. Prenatal genetic screening of the parents also aids carrier status determination in at-risk individuals (Chap. 14, p. 288).


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Obstentrics_Williams. For prenatal genetic diagnosis, the most commonly used tests are cytogenetic analysis (karyotyping), luorescence in situ hybridization (FISH), and chromosomal microarray analysis. Testing may be performed on amnionic fluid or chorionic villi. In selected circumstances, whole genome or whole exome sequencing may be considered, but these are not recommended for routine use. To diagnose a specific disease whose genetic basis is known, DNA-based tests are often employed, typically using polymerase chain reaction (PCR) for rapid ampliication of DNA sequences. Karyotype analysis is commonly performed to test for chromosomal abnormalities. Any tissue containing dividing cells or cells that can be stimulated to divide is suitable for cytogenetic analysis. Karyotyping detects numerical abnormalities, that is, aneuploidy. It also identiies balanced or unbalanced structural rearrangements of at least 5 to 10 megabases in size. Karyotyping has diagnostic accuracy exceeding 99 percent.


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Obstentrics_Williams. The dividing cells are arrested in metaphase, and their chromosomes are stained to reveal light and dark bands. The most commonly used technique is Giemsa staining, which yields the G-bands shown in Figure 13-3. Each chromosome has a unique banding pattern that permits its identiication and detection of deleted, duplicated, or rearranged segments. he accuracy of cytogenetic analysis rises with the number of bands produced. High-resolution metaphase banding routinely yields 450 to 550 visible bands per haploid chromosome set. Banding of prophase chromosomes generally yields 850 bands.


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Obstentrics_Williams. Because only dividing cells can be evaluated, the rapidity with which results are obtained correlates with the rapidity of cell growth in culture. Amnionic fluid, which contains epithelial cells, gastrointestinal mucosal cells, and amniocytes, usually yields results in 7 to 10 days. Fetal blood cells may provide results in 36 to 48 hours but are rarely needed (Chap. 14, p. 294). If fetal skin fibroblasts are evaluated postmortem, stimulation of cell growth can be more diicult, and cytogenetic analysis may take 2 to 3 weeks (Chap. 35, p. 647).


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Obstentrics_Williams. This technique may be used for rapid identiication of a speciic chromosome abnormality and for veriication of suspected microdeletion or duplication syndromes, such as the 22q 11.2 microdeletion described earlier (p. 260). Because of its 1-to 2-day turnaround time, FISH is often selected for cases in which indings may alter pregnancy management. To perform FISH, cells are ixed onto a glass slide, and fluorescent-labeled probes are hybridized to the ixed chromosomes (Figs. 13-11 and 13-12). Each probe is a DNA sequence that is complementary to a region of the chromosome or gene being investigated. If the DNA sequence is present, hybridization is detected as a bright signal visible by microscopy. The number of signals indicates the number of chromosomes or genes of that type in the cell being analyzed. Findings are probe-speciic. Namely, FISH does not provide information on the entire chromosomal complement but merely the chromosomal or gene region of interest.


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Obstentrics_Williams. he most common prenatal application of FISH involves testing interphase chromosomes with DNA sequences speciic to chromosomes 21, 18, 13, X, and Y. Figure 13-12 shows an example of interphase FISH using a-satellite probes for chromosomes 18, X, and Y to conirm trisomy 18. In a review of FIGURE 13-1 1 Steps in fluorescence in situ hybridization (FISH). more than 45,000 samples, the concordance between FISH analysis and standard cytogenetic karyotyping was 99.S percent (Tepperberg, 2001). he American College of Obstetricians and Gynecologists (20 16b) recommends that clinical decision-making based on FISH incorporate clinical information consistent with the suspected diagnosis, such as an abnormal aneuploidy screening test result or sonographic inding, or incorporate a conirmatory diagnostic test such as karyotyping or CMA. his test is 100 times more sensitive than standard karyotyping and detects microduplications and microdeletions as small as


Obstentrics_Williams

Obstentrics_Williams. his test is 100 times more sensitive than standard karyotyping and detects microduplications and microdeletions as small as FIGURE 13-12 Interphase fluorescence in situ hybridization (FISH) using a-satellite probes for chromosomes 18, X, and Y. In this case, the three light blue signals, two green signals, and absence of red signals indicate that this is a female fetus with trisomy 18. (Used with permission from Dr. Frederick Elder.)


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Obstentrics_Williams. Fluorescent probe illuminates chromosome region of interest 50 to 100 kilobases. Direct CMA can yield results in 3 to 5 days, whereas if cultured cells are required, results may take 10 to 14 days (American College of Obstetricians and Gynecologists, 2016b). Microarrays use either a comparative genomic hybridization (CGH) platform, a single-nucleotide polymorphism (SNP) platform, or a combination of the two. he CGH microarray platform compares test specimen DNA with a normal control sample. Shown in Figure 13-13, the CGH chip contains reference DNA fragments of known sequenceoligonucleotides. Fetal DNA from the amniocentesis or chorionic villus sampling specimen is labeled with a fluorescent dye and then hybridized to the DNA on the chip. Normal control DNA is labeled with a diferent probe and also hybridized to the chip. hen, the intensity of the luorescent signals from the two samples is compared. With an SNP array, the chip contains known DNA sequence variants-single-nucleotide


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Obstentrics_Williams. and also hybridized to the chip. hen, the intensity of the luorescent signals from the two samples is compared. With an SNP array, the chip contains known DNA sequence variants-single-nucleotide polymorphisms. When fetal DNA is labeled and hybridized to the chip, the luorescent signal intensity indicates copy number variation.


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Obstentrics_Williams. Both types of platforms detect aneuploidy, unbalanced translocations, and microdeletions and microduplications. Neither type of array platform currently detects balanced chromosomal rearrangements. For this reason, couples with recurrent pregnancy loss should be ofered karyotyping as the first-line test (Society for Maternal-Fetal Medicine, 2016). In addition, SNP arrays are able to identiY triploidy and can detect absence of heterozygosiy. he latter can occur with uniparental disomy when both copies of a chromosome are inherited from one parent. Further, absence of heterozygosity may occur when there is consanguinity, and counseling prior to performance of an SNP array should include this possibility.


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Obstentrics_Williams. Arrays may be genome-wide or may be targeted to known genetic syndromes. Genome-wide arrays are typically used in research settings, for example, to identiY novel microdeletion syndromes in individuals with intellectual disability (Slavotinek, 200S). Targeted arrays are generally preferred prenatally because the likelihood of detecting a copy number variant of uncertain clinical signiicance is lower. In a systematic 1.28 cm A Actual size of chip Nonhybridized Thousands of identical nucleotide DNA strands on one cell B 500,000 cells on each chip C One cell on chip Labeled fetal DNA is presented to the cells


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Obstentrics_Williams. FIGURE 13-13 Chromosomal microarray analysis. A. Actual microarray chip size. B. Each chip contains thousands of cells (squares). C & D. Each cell contains thousands of identical oligonucleotides on its surface, and each cell is unique in its nucleotide content. E. During genetic analysis, a mixture containing tagged fetal DNA is presented to the chip. Complementary DNA sequences bind. F. If a laser is shined on the chip, DNA sequences that have bound will glow. This identifies a matching sequence. (Modified with permission from Doody J: Treatment of the infertile couple. In Hofman BL, Schorge JO, Schaffer JI, et al (eds): Williams Gynecology, 2nd ed. New York, McGraw-Hili, 2012.) review, Hillman and colleagues (2013) identified copy number variants of uncertain significance in 1 to 2 percent of prenatal specimens. Not unexpectedly, this may be a source of signiicant distress to families, even with comprehensive pretest counseling.


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Obstentrics_Williams. In pregnancies at increased risk for autosomal trisomy based on aneuploidy screening, karyotyping or FISH plus karyotyping should be ofered, and CMA should be made available (American College of Obstetricians and Gynecologists, 2016b). When the karyotype is normal, CMA has identiied clinically relevant copy number variants in approximately 6.5 percent of pregnancies with fetal abnormalities and in 1 to 2 percent with no obvious fetal abnormality (Callaway, 2013). he American College of Obstetricians and Gynecologists (2016b) and the Society for Maternal-Fetal Medicine (2016) recommend that CMA be ofered as a irst-tier test when fetal structural abnormalities are identiied, replacing fetal karyotyping in these cases. If a particular anomaly that strongly suggests a speciic aneuploidy is identiied, such as an endocardial cushion defect (trisomy 21) or alobar holoprosencephaly (trisomy 13), karyotyping or FISH may be ofered as the initial test. It is recommended that genetic counseling


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Obstentrics_Williams. such as an endocardial cushion defect (trisomy 21) or alobar holoprosencephaly (trisomy 13), karyotyping or FISH may be ofered as the initial test. It is recommended that genetic counseling include information about the beneits and limitations of both CMA and karyotyping, and that each be made available to women who elect prenatal diagnosis (Society for Maternal-Fetal Medicine, 2016). CMA may identiy instances of autosomal dominant genetic disorders that have not yet manifested in an afected parent, and it may also identiy instances of nonpaternity.


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Obstentrics_Williams. For stillbirth evaluation, CMA is more likely than standard karyotyping to provide a genetic diagnosis, in part because it does not require dividing cells. he Stillbirth Collaborative Research Network found that when karyotyping was uninformative, approximately 6 percent of cases had either aneuploidy or a pathogenic copy number variant identiied with CMA (Reddy, 2012). Overall, CMA yields results nearly 25 percent more often than standard karyotyping alone.


Obstentrics_Williams

Obstentrics_Williams. Most fetuses with structural abnormalities have a normal karyotype and a normal CMA result. Whole genome sequencing (WGS) is a technique for analyzing the entire genome. Whole exome sequencing (WES) analyzes just the DNA coding regions, which account for approximately 1 percent of the genome. These next-generation sequencing tools are increasingly used in the postnatal setting to evaluate suspected genetic syndromes and intellectual disability. The American College of Medical Genetics Board of Directors (2012) states that WGS and WES may be considered for evaluation of the fetus with a likely genetic disorder in which CMA has failed to arrive at a diagnosis. The American College of 0bstetricians and Gynecologists (201i6a) suggests that this be in only selected circumstances, for example, with recurrent or lethal anomalies in which other approaches have been noninformative. Importantly, WGS and WES have signiicant limitations in their current form, including turnaround times that may


Obstentrics_Williams

Obstentrics_Williams. with recurrent or lethal anomalies in which other approaches have been noninformative. Importantly, WGS and WES have signiicant limitations in their current form, including turnaround times that may be prohibitively long and a high rate of variants of uncertain signiicance (American College of �1edical Genetics, 2012; Atwal, 2014). As a result, the clinical utility of this promising technology for prenatal cases is currently limited. • Fetal DNA in the Maternal Circulation Fetal cells are present in maternal blood at a very low concentration, only 2 to 6 cells per milliliter (Bianchi, 2006). Sometimes, intact fetal cells may persist in the maternal circulation for decades following delivery. Persistent fetal cells may engraft in the mother and result in microchimerism, which has been implicated in maternal autoimmune diseases such as scleroderma, systemic lupus erythematosus, and Hashimoto thyroiditis. For prenatal diagnosis, the use of intact fetal cells from maternal blood is


Obstentrics_Williams

Obstentrics_Williams. implicated in maternal autoimmune diseases such as scleroderma, systemic lupus erythematosus, and Hashimoto thyroiditis. For prenatal diagnosis, the use of intact fetal cells from maternal blood is limited by low cell concentration, cell persistence into successive pregnancies, and diiculties in distinguishing fetal from maternal cells. In these cases, however, cell-free DNA overcomes these limitations. Cell-Free DNA hese DNA fragments are derived from maternal cells and from apoptotic placental trophoblast cells-although DNA from the latter is often termed "fetal." Cell-free DNA can be reliably genotyping Maternal Real-time quantitative PCR Detection of single-gene disorders Genetics 273 detected in maternal blood after 9 to 10 weeks' gestation (American College of 0bstetricians and Gynecologists, 20 17b). he proportion of cell-free DNA that is placental is called the fetal fraction, and it composes approximately 10 percent of the total circulating cell-free DNA in maternal plasma.


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Obstentrics_Williams. 20 17b). he proportion of cell-free DNA that is placental is called the fetal fraction, and it composes approximately 10 percent of the total circulating cell-free DNA in maternal plasma. Unlike intact fetal cells, cell-free DNA is cleared within minutes from maternal blood. In research settings, cell-free DNA has been used to detect numerous single-gene disorders transmitted through paternally inherited alleles. These include myotonic dystrophy, achondroplasia, Huntington disease, congenital adrenal hyperplasia, cystic fibrosis, and a-thalassemia (Wright, 2009). Clinical applications of cell-free DNA are aneuploidy screening, fetal sex determination, and h D genotyping (Fig. 13-14). Aneuploidy Screening. Several diferent types of assays are used to screen for fetal autosomal trisomies and sex chromosomal aneuploidies. hese include whole-genome sequencing, which is also called massively parallel or shotgun sequencing; chromosome selective or targeted sequencing; and analysis of SNPs


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Obstentrics_Williams. sex chromosomal aneuploidies. hese include whole-genome sequencing, which is also called massively parallel or shotgun sequencing; chromosome selective or targeted sequencing; and analysis of SNPs (American College of Obstetricians and Gynecologists, 2016a,b). By simultaneously sequencing millions of DNA fragments, investigators can identiy whether the proportion or ratio of fragments from one chromosome is higher than expected. Sequences of fetal DNA are specific to individual chromosomes. hus, samples from women with a Down syndrome fetus have a larger proportion of DNA sequences from chromosome 21. The screening performance of cell-free DNA is excellent. In a metaanalysis of 37 studies of largely high-risk pregnancies, the pooled sensitivity to detect Down syndrome was 99 percent, and to identiy trisomies 18 and 13, 96 and 91 percent, respectively. For each, the speciicity was 99.9 percent (Gil, 2015). The false-positive rate is cumulative for each aneuploidy for which screening is


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Obstentrics_Williams. identiy trisomies 18 and 13, 96 and 91 percent, respectively. For each, the speciicity was 99.9 percent (Gil, 2015). The false-positive rate is cumulative for each aneuploidy for which screening is performed, but it is usually below 1 percent. As a result, cell-free DNA screening is recommended as !DNA isolation Cell-free fetal DNA determination Massively parallel genomic sequencing Trisomy 21, 18, and 13screening FIGURE 13-14 Cell-free DNA is actually derived from apoptotic trophoblast. The DNA is isolated from maternal plasma, and real-time quantitative polymerase chain reaction (PCR) may be used to target specific regions or sequences. This may be used for Rh D genotyping, detection of paternally inherited single-gene disorders, or fetal sex determination. Screening for autosomal trisomies and sex chromosomal aneuploidies is performed using whole-genome sequencing, chromosome selective or targeted sequencing, and analysis of single nucleotide polymorphisms.


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Obstentrics_Williams. a screening option in those at greater risk for fetal autosomal trisomy (American College of Obstetricians and Gynecologists, 2017b; Society for Maternal-Fetal Medicine, 2015). Unfortunately, cell-free DNA screens do not yield a result in 4 to 8 percent of cases. This may be due to assay failure, high assay variance, or low fetal fraction (Norton, 2012; Pergame nt, 2014; Quezada, 2015). Such pregnancies carry a greater risk for fetal aneuploidy. In addition, results may not relect the fetal DNA complement but rather may indicate conined placental mosaicism, early demise of an aneuploid cotwin, maternal mosaicism, or rarely occult maternal malignancy (Bianchi, 2015; Curnow, 2015; Grati, 2014b; Wang, 2014). Recommendations for counseling are discussed in Chapter 14 (p. 285).


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Obstentrics_Williams. Fetal Sex Determination. From the standpoint of genetic disease, fetal sex determination may be clinically useful if the fetus is at risk for an X-linked disorder. It may also be beneficial if the fetus is at risk for congenital adrenal hyperplasia because maternal corticosteroid therapy may be avoided if the fetus is male (Chap. 16, p. 317). In a metaanalysis of more than 6000 pregnancies by Devaney and associates (201i1), the sensitivity of cell-free DNA testing for fetal sex determination approximated 95 percent between 7 and 12 weeks' gestation and improved to 99 percent after 20 weeks. The test speciicity was 99 percent at both time periods, suggesting that cellfree fetal DNA is a reasonable alternative to invasive testing in selected cases.


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Obstentrics_Williams. Rh D Genotype In a predominantly white population, nearly 40 percent of fetuses of h D-negative women are themselves h D negative. Fetal h D genotype assessment from maternal blood can eliminate administration of anti-D immune globulin in these pregnancies, thereby reducing cost and potential risk. With h D alloimmunization, early identification of an h D-negative fetus might avoid unnecessary middle cerebral artery Doppler assessment or amniocentesis. Evaluation using cell-free DNA is done using real-time PCR to target several exons of the HD gene. These are typically exons 4,i5, and 7.


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Obstentrics_Williams. h D-genotyping is performed routinely with cell-free DNA in Denmark and the Netherlands (Clausen, 2012; de Haas, 2016). In a population-based study of more than 25,000 h D-negative women screened at 27 weeks, the false-negative rate-in which h D-negative status was missed-was only 0.03 percent. The false-positive rate-in which h immune globulin would be given unnecessarily-was less than 1 percent (de Haas, 2016). Similar results were reported from the United Kingdom, although the false-negative rate was higher in the irst trimester (Chitty, 2014). Investigators concluded that false-negative screening results might increase the alloimmunization risk, but by less than 1 case per million births (Chitty, 2014). h D alloimmunization is discussed in Chapter 15 (p. 301). Abele H, Babiy-Pachomow 0, Sonek J, et al: The cavum septum pellucidi in euploid and aneuploidy fetuses. Ultrasound Obstet Gynecol 2013; 42(2):156,o2013


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Obstentrics_Williams. Abele H, Babiy-Pachomow 0, Sonek J, et al: The cavum septum pellucidi in euploid and aneuploidy fetuses. Ultrasound Obstet Gynecol 2013; 42(2):156,o2013 American Academy of Pediatrics: Clinical report: cardiovascular health supervision for individuals afected by Duchenne or Becker muscular dystrophy. Pediatrics 116(6):1569,o2005, Reairmed December 2008 American College of Medical Genetics (ACMG) Board of Directors: Points to consider in the clinicl application of genomic sequencing. Genet Med 14(8):759,o2012 American College of Obstetricians and Gynecologists: Microarrays and nextgeneration sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynecology. Committee Opinion No. 682, December 20o16a American College of Obstetricians and Gynecologists: Prenatal diagnostic testing for genetic disorders. Practice Bulletin No. 162, May 2016b


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Obstentrics_Williams. American College of Obstetricians and Gynecologists: Prenatal diagnostic testing for genetic disorders. Practice Bulletin No. 162, May 2016b American College of Obstetricians and Gynecologists: Primary ovarian insuficiency. Committee Opinion No. 605, July 2014, Reairmed 2016c American College of Obstetricians and Gynecologists: Screening for fetal aneuploidy. Practice Bulletin No. 163, May 2016d American College of Obstetricians and Gynecologists: Carrier screening for genetic conditions. Committee Opinion No. 69o1, March 20 17a American College of Obstetricians and Gynecologists: Cell free DNA screening for fetal aneuploidy. Committee Opinion No. 640, September 2015, Reafirmed 2017b American College of Obstetricians and Gynecologists: Management of women with phenylketonuria. Committee Opinion No. 636, June 20o15, Reairmed 20ol7c


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