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Chromosome Disorders


Key Points

  • Early identification of an underlying genetic condition in a patient can aid in defining a treatment plan and help to identify resources for better care for patients and their families.

  • In counseling the family of a newborn with a newly diagnosed chromosomal disorder, it is important to include the organ systems affected in the baby and the severity of each malformation when discussing prognosis. The variability of most phenotypes should be emphasized, with a care plan tailored to the needs of the individual patient.

  • Although the prognosis in trisomy 13 and trisomy 18 is extremely poor, there is emerging evidence that in some cases, interventions can improve the survival and quality of life for the child and the family, and they should be discussed with the parents during a prenatal or postnatal visit.

  • The use of chromosomal microarray testing allows the identification of smaller genomic deletions and duplications that are largely undetectable by standard karyotyping techniques, and it is recommended as a first-tier test in the genetic evaluation of a newborn with multiple congenital anomalies (excluding cases with high clinical suspicion for well-recognized whole chromosome disorders such as trisomies 13, 18, and 21 and Turner syndrome).

  • Noninvasive prenatal screening (NIPS) is a relatively new technology that analyzes the cell-free fetal DNA fraction circulating in maternal peripheral blood. The fetal DNA is derived from cells forming the developing placenta and is accepted as an initial screen for select aneuploidy conditions. In cases where a high risk for an abnormality is identified, then diagnostic testing such as karyotyping or chromosomal microarray analysis of amniotic fluid or chorionic villus samples is recommended.

According to estimates from the Centers for Disease Control and Prevention (CDC), congenital malformations occur in approximately 3% of newborns in the United States. Congenital anomalies affecting major organ systems can result from chromosomal imbalances that affect the dosage or copy number of developmental genes that are located in the affected region. This chapter will focus on genetic disorders and syndromes with underlying chromosomal abnormalities that typically manifest themselves in the newborn period. In addition, it will discuss the shift in genetic evaluation and diagnosis in both prenatal and postnatal cases, to the use of microarray and next generation sequencing-based diagnostic techniques.

Human Karyotype

Chromosomes consist of single molecules of DNA whose structure is maintained by association with histones and other proteins. Chromosomes from dividing cells can be visualized under the light microscope as linear structures with two arms joined by a centromere . The short arm is designated the p arm and the long arm is designated the q arm . The ends or tips of the p and q arms are known as telomeres . The chromosome complement, or karyotype, in human cells normally consists of 46 chromosomes, with 22 pairs of autosomes (numbered in general from largest to smallest) and one set of sex chromosomes–two X chromosomes in genetic females (46,XX) and an X chromosome and a Y chromosome in genetic males (46,XY) ( Fig. 28.1 ). After treatment with special dyes, each pair shows a distinctive size, centromeric position, and staining or banding pattern allowing it to be identified and classified. Human cells were first determined to have 46 chromosomes in 1956, and the presence of recurrent numerical abnormalities in syndromes including Down, Turner, and Klinefelter syndrome were identified soon after.

Fig. 28.1, G-banded human female karyotype. The 46 chromosomes are arranged in 23 pairs, each with a specific banding pattern. (Courtesy UCLA Cytogenetics Laboratory.)

Karyotype analysis is performed in cells undergoing mitosis, or cell division, in which the chromosomes condense and can be stained and visualized. At this stage, each chromosome consists of two sister chromatids, which are the products of DNA replication. Karyotype analysis can be successfully performed on cell types that can be stimulated to divide and grow in culture, such as peripheral blood lymphocytes, skin fibroblasts, and amniocytes, or cell types that are normally undergoing rapid cell division, such as bone marrow or chorionic villi. Historically, several different staining methods have been described. However, G-banding (Giemsa staining) is most commonly used. At the highest resolution, G-banding can allow the detection of structural rearrangements as small as 5 to 10 million base pairs or 5 to 10 megabase (Mb) pairs, though the maximum attainable resolution varies by preparation and by specimen type.

Prior to fertilization, gamete formation, either spermatogenesis or oogenesis, is accomplished by a process known as meiosis . In the first part of meiosis (meiosis I), homologous chromosomes align as pairs and cross over, exchanging genetic material, also known as recombination . In this stage, named reduction division, the recombined pairs separate and the typical diploid content (46 chromosomes) of the cell is reduced by half to a haploid complement of 23 chromosomes. In the next stage, meiosis II, the sister chromatids of each chromosome separate, similar to mitosis. The full diploid state of the cell (46 chromosomes) will be restored at the time of fertilization.

An imbalance of genetic material, or aneuploidy, occurs from a net loss or gain of genetic material during sperm or egg formation or less commonly, after fertilization during the initial divisions of the embryo. This missing or extra genetic material can be small pieces or parts of chromosomes (partial or segmental aneuploidy) or an entire chromosome itself. The classic recognizable aneuploidy syndromes involve trisomy (three copies of a full chromosome) such as those of chromosomes 13, 18, and 21, or monosomy (only a single copy) of a complete chromosome, such as the X chromosome. Aneuploidy can result from nondisjunction, a failure of normal chromosome separation. In such cases, a pair of homologs or sister chromatids does not separate in meiosis, and one daughter cell receives both copies of that pair, while the other cell receives none. This event can occur in either stage of gamete division, meiosis I or meiosis II. Most human meiotic nondisjunction arises during oocyte formation, specifically in maternal meiosis I. The occurrence of meiotic nondisjunction increases significantly with maternal age. Therefore, prenatal karyotyping from amniocentesis or chorionic villus sampling (CVS) is offered to women aged 35 years or older.

Noninvasive prenatal screening (NIPS), also known as noninvasive prenatal testing (NIPT) or cell-free DNA (cfDNA) screening, is a relatively new technology that analyzes the cell-free fetal DNA fraction (derived from placental trophoblasts) circulating in maternal peripheral blood and can be offered starting at 9 to 10 weeks of gestation. While NIPS was initially recommended for women at high risk for carrying a fetus with a chromosome abnormality, recent guidelines recommend that it should be offered to all pregnant women regardless of age or other risk factors. The technical approaches and analyses vary by platform, but in general NIPS uses next-generation sequencing to assess the copy number of different chromosome regions in cfDNA. It is performed as an initial screen for common aneuploidy conditions, with some laboratories screening for rarer aneuploidies, as well as microdeletion/microduplication syndromes (see additional details below) and other segmental aneuploidies. An important metric to consider when counseling patients with abnormal NIPS results is the positive predictive value (PPV), which is the probability that a positive test result represents a true positive . While NIPS has high PPV for common aneuploidies such as trisomy 21, the PPV is significantly lower for rarer conditions such as microdeletions, and appropriate follow-up testing and genetic counseling are critical. In addition, since the risk of trisomy increases with maternal age, the PPV of NIPS is age-dependent. For patients where NIPS shows a high risk of a chromosomal abnormality in the fetus, or with atypical/inconclusive results, diagnostic testing such as karyotyping or chromosomal microarray analysis of amniotic fluid or chorionic villus specimens is recommended.

Nondisjunction can also occur later, in mitosis, with uneven division of genetic material during an early embryonic cell division. This can result in two cell lines: one trisomic lineage that is potentially viable and one monosomic line. If this event occurs after the first postzygotic division, cells with a normal chromosome complement may also coexist with cells containing an aneuploid complement, as a mosaic chromosome constitution. This is considered a possible mechanism for the occurrence of mosaic Down syndrome, where a percentage of the cells in the patient have three copies of chromosome 21, and the remainder of the cells have the expected two copies. Mosaicism is also seen with sex chromosome aneuploidies, most notably mosaic Turner syndrome, where a subset of the cells examined show a 45,X complement and another population of cells from the patient may have a normal 46,XX or XY complement.

Partial aneuploidy may result from several mechanisms and may be inherited or can occur de novo seen only in the patient. For carriers of a balanced translocation, who have a rearrangement or exchange of material between chromosomes, the carrier parent has no net loss or gain of genetic material (balanced) and is usually phenotypically normal. However, segregation of these abnormal derivative chromosomes during meiosis can lead to offspring having an unbalanced rearrangement and its phenotypic consequences. Unbalanced rearrangements or translocations can also arise sporadically. This is often seen in recurrent deletion syndromes caused by the loss of genetic material from specific chromosomes (e.g., 1p–, 4p–, 5p–), with a resulting, often recognizable, phenotype.

Other chromosome microdeletions resulting in partial aneuploidy, have been mechanistically tied to aberrant recombination due to the presence of segmental duplications, or large “blocks” or segments of DNA that contain chromosome-specific repetitive sequences. In these cases, the highly homologous repeats can mediate misalignment and nonallelic homologous recombination between two homologs. Segmental duplications are present in regions of the genome prone to rearrangements, such as the pericentromeric regions of 7q11, 15q11, 17q12, and 22q11, leading to the phenotypes seen in Williams–Beuren syndrome, Prader–Willi or Angelman syndrome, Charcot–Marie–Tooth disease or hereditary neuropathy with liability to pressure palsies, and the recurrent 22q11.2 deletion syndromes, respectively.

Fluorescence in situ hybridization (FISH)

While deletions and duplications larger than 5 Mb may be observed by standard chromosome analysis, smaller rearrangements are generally not visible. These submicroscopic deletions and duplications are often referred to as copy number variants (CNVs). CNVs may be detected by fluorescence in situ hybridization or FISH, which utilizes fluorescently labeled DNA molecules (“probes”) that bind to a specific region of interest in the genome, followed by visualization of the hybridization patterns using fluorescence microscopy. FISH has many advantages including rapid turnaround time (same-day or overnight for certain specimen types), improved resolution compared to karyotype (can detect changes as small as 100 to 200 kb, depending on probe design), high sensitivity for mosaicism, and the ability to interrogate non-dividing tissues, which means FISH may be performed on a wide variety of specimen types. However, a limitation of FISH is that it is only informative for the specific regions being targeted and therefore requires prior knowledge of specific conditions to test for; even then, it may miss atypical rearrangements of these regions that are outside the region targeted by the FISH probes.

Chromosomal Microarray Analysis (CMA)

Another technology which has facilitated the identification of CNVs is chromosomal microarray analysis, which can identify submicroscopic losses and gains of chromosomal material (typically less than 5 Mb) that cannot be seen by standard karyotyping. Chromosomal microarrays use DNA probes which are arrayed on a glass slide or other solid support, and patient DNA is fragmented and fluorescently labeled before being hybridized to the array ( Fig. 28.2 ). Microarray testing can be performed for either a targeted region, or more commonly, in a genome-wide fashion. One approach known as array comparative genomic hybridization (array CGH or aCGH) involves hybridizing both patient and control DNA, each labeled with different colored dyes, followed by comparison of the relative fluorescence intensities, identifying regions where the patient DNA shows a copy number loss or gain relative to the control. Another commonly used technique is single nucleotide polymorphism (SNP) chromosomal microarray, which includes probes targeting polymorphic regions in the human genome and involves an in silico comparison of fluorescence intensities to a set of control data. The resolution of an array depends on the density of probes; most genome-wide array platforms can detect copy number variants as small as 50 to 100 kb (kilobases). Targeted arrays with a high density of probes surrounding genes of interests may be able to detect smaller variants, such as those involving a single exon of a gene.

Fig. 28.2, Example of a typical workflow for chromosomal microarray analysis. Patient DNA is fragmented and labeled, before being hybridized to an “array” of oligonucleotide probes on a solid support such as a glass slide. Following a period of hybridization and further processing, the arrays are scanned and the relative fluorescence intensity is measured. Normalization may be performed by concurrent hybridization of a control sample labeled with a different color (array CGH) or by a computational, in silico comparison to a set of controls (e.g., SNP microarray). CGH , comparative genomic hybridization; SNP , single nucleotide polymorphism.

Microarray-based methods are focused on detecting copy number changes, while structural rearrangements that do not affect copy number such as balanced translocations or inversions are not detectable by this method. With a single test, microarrays can detect copy number variants in a genome-wide approach, revealing disorders usually identified by cytogenetic analysis and multiple individual FISH studies. The use of high-resolution microarrays in infants with multiple congenital anomalies has, in many cases, led to the identification of a specific genotype, with clinical evaluation then further defining the associated phenotype. In addition, SNP arrays include probes that can detect known polymorphisms present in the human genome, which may help identify regions of homozygosity, uniparental disomy (UPD), identity-by-descent, triploidy, mosaicism, chimerism, or maternal cell contamination.

In the postnatal setting, for patients with developmental delays/intellectual disability, autism spectrum disorder, or multiple congenital anomalies, CMA allows an increased diagnostic yield (approximately 15% to 20%) compared to G-banded karyotypes. In the prenatal setting, in cases with ultrasound abnormalities and a normal karyotype, CMA provides additional information in 6% to 7% of cases. Whereas microarray analysis can afford a robust and exceptional level of resolution from a diagnostic perspective, one major difficulty with interpretation of the results lies in assigning causality and clinical significance to the multiple alterations that are detected in each individual. Toward this end, the use of online databases (e.g., Database of Genomic Variants, http://dgv.tcag.ca/dgv/app/home ) with information on normal variation in multiple ethnic populations and testing the infant’s unaffected parents can help in discerning whether a copy number change is likely the cause of the patient’s clinical features.

Trisomies

Down Syndrome (Trisomy 21)

Lejeune, Gautier, and Turpin (1959) demonstrated that trisomy of human chromosome 21 caused the constellation of findings recognized as Down syndrome ( Fig. 28.3 ). This chromosome disorder was the first to be described and is the most common viable autosomal trisomy, occurring in approximately 1 in 700 live births in the United States. The vast majority (>90%) occur secondary to meiotic nondisjunction, and a pronounced maternal age effect is encountered. Approximately 4% of cases are caused by a translocation that could be either de novo or inherited from a balanced translocation-carrier parent that subsequently becomes unbalanced causing trisomy in the fetus. Typically, the translocated chromosome 21 rearranges with another acrocentric chromosome, often chromosome 14, resulting in a Robertsonian translocation ( Fig. 28.4 ). Mitotic nondisjunction, or mosaic Down syndrome, has been demonstrated in approximately 3% to 5% of cases as well, with variable features ranging from normal to a typical Down syndrome phenotype.

Fig. 28.3, Child with Down syndrome (trisomy 21). Some of the typical features such as epicanthal folds, flattened nasal bridge, posterior rotated ears, and fifth finger clinodactyly are demonstrated.

Fig. 28.4, Karyotypes that may be found in patients with Down syndrome or DS. (A) This case shows an extra copy of chromosome 21 (arrow), with 47 chromosomes total [47,XX,+21]. Standard trisomy is seen in ~95% of DS cases. (B) This case still shows three copies of chromosome 21, but the extra copy of 21 is present on chromosome 14 (arrow) in a (14;21) Robertsonian translocation, and there are 46 chromosomes total [46,XY,der(14;21)(q10;q10),+21]. Robertsonian translocations are observed in approximately 4% of DS. (Courtesy UCLA Cytogenetics Laboratory .)

Clinical Features

It is the more common occurrence of Down syndrome in babies of older mothers that led to the recommendation for prenatal karyotyping for advanced maternal age (>35 years at the time of conception). Diagnostic samples are usually obtained by amniocentesis after 15 weeks' gestation or CVS at 10 to 12 weeks' gestation. Maternal serum analyte testing is recommended for prenatal screening purposes for all pregnant women, with results showing low alpha fetoprotein, low unconjugated estriol, and elevated total human chorionic gonadotropin levels. Noninvasive prenatal screening is also accepted as an initial study for fetal aneuploidy and is particularly robust for detecting trisomy 21. Associated ultrasonographic findings for Down syndrome, including a cardiac defect, shortened long bones, underdeveloped fetal nasal bone, nuchal translucency or thickening, echogenic small bowel, and duodenal atresia (“double-bubble” sign), may be seen in 50% to 60% of fetuses.

Most patients with Down syndrome, if it is not diagnosed prenatally, are usually recognized at birth because of the well-established phenotypic features. The constellation of associated physical findings includes brachycephaly, the presence of a third or confluent fontanelle, upward-slanted palpebral fissures, epicanthal folds, Brushfield spots in the irises, flattened nasal root, small posteriorly rotated ears with overfolded superior helices, prominent tongue, short neck with excess nuchal skin, single palmar creases, brachydactyly, fifth-finger clinodactyly, exaggerated gap between the first and second toes, open field hallucal pattern, and hypotonia (see Fig. 28.3 ). Often the physical features conform to an easily distinguishable phenotype, but in some cases prematurity or ethnic variation can make a clinical diagnosis less straightforward. An immediate karyotype is indicated to confirm the diagnosis and its mechanism (e.g. trisomy or translocation) and to provide accurate recurrence risk counseling for the family. Malformations involving many organ systems have been described in Down syndrome, and whether the diagnosis is known prenatally or determined in the newborn period, several clinical investigations are warranted when this diagnosis is suggested. The most common malformation is congenital heart disease (seen in over 50% of cases), which may require surgical intervention. Atrioventricular canal defects are often encountered (~40%), although ventricular septal defects (VSDs), atrial septal defects (ASDs), tetralogy of Fallot, and patent ductus arteriosus (PDA) are all described in the disorder. An echocardiogram is indicated in all cases, and medical and surgical interventions for cardiac lesions are routine. Gastrointestinal malformations, especially duodenal atresia (2% to 5%), in addition to Hirschsprung disease and less frequently encountered conditions, such as esophageal atresias, fistulas, and webs throughout the tract have been described. It is critical to carefully monitor the baby's feeding and bowel function before considering discharge from the nursery.

Although growth parameters can be within the normal range at birth, significantly decreased postnatal growth velocity is encountered in these patients. Separate growth curves have been devised for patients with Down syndrome because growth retardation involving height, weight, and head circumference has been well documented. However, the most recent health supervision guidelines for patients with Down syndrome recommend that patients be assessed on the basis of the World Health Organization or Centers for Disease Control and Prevention growth curves. An initial ophthalmologic evaluation is also indicated in the first few months of life and then annually, because strabismus, cataracts, myopia, and glaucoma have been shown to be more common in children with Down syndrome. In addition, hearing loss of heterogenous origin is present in approximately half of patients, with middle ear disease contributing to this problem.

Spinal cord compression caused by atlantoaxial subluxation from ligamentous laxity and subsequent neurologic sequelae can be a complication of the disorder. Radiographs are obtained in the early childhood years when there is concern for myopathic symptoms related to spinal cord compression (weakness, abnormal reflexes, incontinence, etc.). Physicians should be vigilant in evaluating the cervical spine, especially before procedures requiring positioning for anesthesia. Other associated disorders that merit screening are hypothyroidism in approximately 5% of patients, seen with the presence of thyroid autoantibodies. Initial evaluation occurs with newborn screening programs, followed by additional measurement of thyroid-stimulating hormone and free thyroxine levels at 6 months, 12 months, and then yearly thereafter. Hematopoietic abnormalities are common, and a complete blood count with differential should be performed at birth and later in infancy in accordance with published guidelines. Approximately 5% to 10% of newborns develop transient myeloproliferative disorder (TMD), which usually resolves spontaneously, but in 20% to 30% of cases these children will go on to develop myeloid leukemia of Down syndrome (ML-DS) by age 2 to 4 years. Overall, the relative risk of leukemia is elevated in children with Down syndrome, who have a greater than 100-fold increased risk for myeloid leukemia (in particular, acute megakaryoblastic leukemia) and a 27-fold increased risk for acute lymphoblastic leukemia or ALL, in particular B-ALL. Children with ML-DS show significantly better outcomes than non-DS children with AML, while children with DS-ALL have worse outcomes compared to non-DS cases, due to higher relapse rates, increased risk of infection, treatment-related mortality, and induction failure. Survival of patients with Down syndrome is shorter after a diagnosis of acute lymphoblastic leukemia than in diploid patients. There is also an increased risk of iron-deficiency anemia, with recommended screening to include annual hemoglobin level measurement starting at 12 months of age then annually thereafter. If the hemoglobin level is low, then a complete blood count with iron studies should be performed.

Patients with Down syndrome demonstrate a wide range of developmental abilities, with highly variable personalities and behavioral phenotypes as well. Central hypotonia with concomitant motor delay is most pronounced in the first 3 years of life, as are language delays. Therefore, immediate and intensive early intervention and developmental therapy are critical for maximizing the developmental outcome. A range of intellectual ability has been described, with conflicting data on genetic and environmental modifiers of outcome. Seizure disorders occur in 5% to 10% of patients, often manifesting themselves in infancy.

The most common causes of death in patients with Down syndrome are related to congenital heart disease, infection (e.g., pneumonia) that is thought to be associated with defects in T-cell maturation and function, and malignancy. Once medical and surgical interventions for the correction of associated congenital malformations are complete and successful, the long-term survival rate is good. However, less than half of patients survive to 60 years, and less than 15% survive past 68 years—and neurodegenerative disease with features of Alzheimer disease is encountered in many patients older than 40 years. Men with Down syndrome are almost always infertile, whereas small numbers of affected women have reproduced.

In counseling the family of a newborn in whom Down syndrome has been diagnosed, it is important to include the organ systems affected in the baby and the severity of each malformation when one is defining a prognosis. Above all, the wide variability of the phenotype should be emphasized, with a care plan tailored to the needs of the individual patient.

Genetic Counseling

In cases with non-translocation Down syndrome (including mosaic cases) parental karyotypes are generally not analyzed, because the karyotypes are normal in virtually all cases. After having one child with Down syndrome, a mother's recurrence risk for another affected child is approximately 1% higher than her age-specific risk. This fact is especially significant in younger mothers, whose age-specific risks are low. If a de novo translocation resulting in Down syndrome is found, the recurrence risk is less than 1%. If the mother is found to carry a constitutional balanced Robertsonian translocation, the risk of another translocation Down syndrome fetus is approximately 15% at the gestational age when amniocentesis is offered and 10% at birth. However, if the father is the translocation carrier, the recurrence risk is significantly smaller, approximately 1% to 2%. While array-based diagnostic techniques will identify the copy number change associated with the trisomy, structural rearrangements such as Robertsonian translocations are not detected. In this situation, a karyotype will provide information regarding the mechanism of the trisomy, which is needed for accurate recurrence risk counseling.

Trisomy 18 (Edwards Syndrome)

Trisomy 18 is encountered in 1.07 cases per 10,000 live births and 4.08 cases per 10,000 births overall, and it is associated with a high rate of intrauterine demise. It is estimated that only 5% of conceptuses with trisomy 18 survive to birth. The rates of pregnancy loss have been estimated between 70% and 72% in cases with a viable fetus at 12 weeks, and 59% between 24 weeks and term. Findings on prenatal ultrasonography can raise suspicion for the disorder—growth retardation, oligohydramnios or polyhydramnios, heart defects, myelomeningocele, clenched fists, and limb anomalies. Diagnostic testing is recommended when prenatal ultrasonography findings are suggestive of this condition. Maternal serum screening can show low values for alpha fetoprotein, unconjugated estradiol, and total human chorionic gonadotropin. The PPV of NIPS for trisomy 18 is currently 45% for a 36 year-old woman at 16 weeks’ gestation ( https://www.perinatalquality.org/Vendors/NSGC/NIPT/ ), thus high resolution anatomy ultrasounds and diagnostic testing by amniocentesis are currently recommended for follow up.

Clinical Features

The classical phenotypic features reported at birth include intrauterine growth restriction (1500 to 2500 g at term), small narrow cranium with prominent occiput, open metopic suture, low-set posteriorly rotated ears, and micrognathia with small mouth. Characteristic clenched hands with overlapping digits, an excess of arches on dermatoglyphic examination, hypoplastic nails, and “rocker-bottom” feet or prominent heels with convex soles ( Fig. 28.5 ) are described. Additional malformations encountered in this syndrome include congenital heart disease (ASD, VSD, PDA, pulmonic stenosis, aortic coarctation) in over 70% of patients, cleft palate, clubfoot deformity, renal malformations, brain anomalies, choanal atresia, eye malformations, vertebral anomalies, hypospadias, cryptorchidism, and limb defects, especially radial ray defects.

Fig. 28.5, Newborn with trisomy 18, showing prominent occiput, characteristic facial appearance, and clenched hands.

Historically, the prognosis in this disorder is extremely poor with survival estimates of 37.2% at 28 days and 13.4% at one year. Death is related to central apnea, infection, and congestive heart failure. The newborn period is characterized by poor feeding and growth, typically requiring tube feedings. Universal poor growth and profound intellectual disability have been documented, with developmental progress typically leveling at that of a 6 to 8-month-old infant. Malignant tumors such as hepatoblastoma and Wilms tumor have been described in some survivors. There is emerging evidence that various interventions can improve the survival and quality of life for the child and the family, and this should be discussed with the parents during a prenatal or postnatal visit.

Families have indicated a desire to be able to take the infant home and spend time as a family, understanding the dismal prognosis. Many institutions have determined specific protocols typically based on each infant’s clinical findings such as their ability to breathe without mechanical ventilation, for example, when considering surgical interventions such as cardiac repair. In general, those who do not require mechanical ventilation have less complex cardiac defects and do not show other major malformations, (e.g. omphalocele) benefit the most from intervention. However, it is important to evaluate each infant on an individual basis during such considerations and have a team-based plan involving neonatology, cardiology, cardiac surgery, genetics, and other appropriate specialists when considering intervention.

Genetic Counseling

The estimate of the recurrence risk for trisomy 18 in a future pregnancy is a 1% risk over the maternal age-specific risk for any viable autosomal trisomy. Trisomy occurring from a structural rearrangement, such as a translocation, warrants parental karyotype analysis before the recurrence risk can be assessed.

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