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Uptodate CLINICAL GENETICS MEDICAL GENETICS UpToDate CLINICAL GENETICS 2015 Index • Genetic and environmental causes of birth defects • Microdeletion syndromes (chromosomes 1 to 11) • Microdeletion syndromes (chromosomes 12 to 22) • Microduplication syndromes • Primary care of the adult with intellectual disability • Intellectual disability (mental retardation) in children 1 • Intellectual disability (mental retardation) in children 2 • Microcephaly in infants and children • Microcephaly/ A clinical genetics approach • Macrocephaly in infants and children/ Etiology and evaluation • Sex chromosome abnormalities • Pulmonic stenosis (PS) in children • Evaluation of male infertility Derleme Dr. Yavuz ŞAHİN Genetic and environmental causes of birth defects http://www.uptodate.com/contents/genetic-and-environmental... Official reprint from UpToDate® www.uptodate.com ©2015 UpToDate® Genetic and environmental causes of birth defects Author Section Editor Deputy Editor Harry Ostrer, MD Louise Wilkins-Haug, MD, PhD Vanessa A Barss, MD, FACOG All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Feb 2015. | This topic last updated: Jan 20, 2015. INTRODUCTION — A major birth defect is one of medical, surgical or cosmetic significance. The prevalence of these defects is 2 to 4 percent among live born infants and does not vary among ethnic groups (table 1). Birth defects may be isolated or multiple and can affect one or more organ systems. Both genetic and environmental factors play a role in their pathogenesis. As an example, parents with a birth defect, a previously affected child, or a family history of birth defects are at higher risk of having a baby with the same, or a different, anomaly. Other risk factors include maternal age, illness, drug use, exposure to infectious or environmental agents, and the physical features of the intrauterine environment. The relative contribution of various etiologies to the overall frequency of birth defects is estimated to be [1]: ● Unknown cause, including suspected polygenic and multifactorial causes (65 to 75 percent) ● Genetic: single gene disorders (15 to 20 percent), chromosomal abnormalities (5 percent) ● Environmental exposures (eg, maternal medical conditions, substance abuse, infection, drugs, chemicals, radiation, hyperthermia; mechanical constraints on fetal development) (10 percent) COMMON FEATURES OF CHROMOSOMAL DISORDERS — There are certain common characteristics of the syndromes that are produced by constitutional chromosomal abnormalities: ● Greater than 90 percent of embryos/fetuses with constitutional chromosomal abnormalities do not survive to term. In trisomy 21, as an example, 40 percent of fetuses are lost after 12 weeks of gestation. Even higher embryonic and fetal loss rates are found with monosomy X. ● Multiple organ systems tend to be involved, especially the central nervous system. Intellectual disability, in particular, is a common abnormality in viable infants. ● The longevity and fertility of individuals with these conditions tend to be reduced. As an example, the risk of malignancy is increased for certain chromosomal disorders, such as trisomy 21, deletions of the long arm of chromosome 13; deletions of the short arm of chromosome 11, and 46,XY gonadal dysgenesis. STRUCTURAL CHROMOSOMAL ABNORMALITIES — Chromosomal abnormalities affect approximately 1 in 200 newborn infants [2,3]. These defects may be either sporadic or heritable and are due to a number of different etiologies. (See "Basic principles of genetic counseling for the obstetrical provider" and "Basic principles of genetic disease".) Nondisjunction — The most common sporadic chromosomal abnormalities result from loss or gain of a chromosome, usually from nondisjunction. Nondisjunction refers to the process whereby paired chromosomes fail to separate during cell division so that both chromosomes go to one daughter cell and none to the other. Thus, after fertilization, one daughter cell inherits three chromosomes of the affected chromosome and becomes trisomic (eg, trisomy 21 or Down syndrome), while the other daughter cell inherits only one chromosome resulting in monosomy (figure 1 and figure 2). Cytogenetic surveys of spontaneous abortions during the first trimester of pregnancy demonstrated that approximately one-half 1 of 36 19.03.2015 10:55 Genetic and environmental causes of birth defects http://www.uptodate.com/contents/genetic-and-environmental... were associated with trisomic or monosomic abortuses [4,5]. (See "Congenital cytogenetic abnormalities".) Trisomic embryos have been described for almost all of the autosomes. Some trisomies (eg, trisomy 13, 18, 21, and those involving the sex chromosomes) can result in live births [6], while others (eg, trisomy 16) are detected only in abortuses. The risk of trisomy of the autosomal and sex chromosomes increases with maternal age, but the magnitude of this risk varies somewhat depending on the chromosome (table 2) [7-9]. The incidence of monosomy X (Turner syndrome) does not increase with maternal age. The extra chromosome of a trisomic group is maternal in origin in the vast majority of cases. This suggests a defect in chromosome segregation during oogenesis, rather than defective spermatogenesis. Prolonged retention of oocytes or sperm in the reproductive tract before fertilization does not seem to be a cause of nondisjunction leading to Down syndrome or of major birth defects [10], but altered recombination appears to have a role [11,12]. In this model, age-related perturbations in the meiotic machinery cause homologues with susceptible crossover configurations to segregate incorrectly. Distal crossovers may be unable to lock homologues together, allowing them to move independently and possibly drift together to the same spindle pole; pericentromeric crossovers may lock homologues too tightly, so they are unable to separate from one another and thus migrate together to the same spindle pole. Nonallelic homologous recombination — Other sporadic chromosomal defects occur through abnormalities in recombination, which refers to the natural process of breaking and rejoining DNA strands during meiosis to produce new combinations of genes and, thus, generate genetic variation. Nonallelic homologous recombination (NAHR) typically involves the exchange of unequal amounts of genetic material during pairing between homologous chromosomes. Thus, the gene copy number is altered or hybrid genes are formed with novel properties. Single-gene phenotypes (ie, a trait or series of traits that can be attributed to mutation in a single gene), are produced that may be transmitted in a Mendelian fashion. For the X and Y chromosomes, the frequency of new unequal recombinational events is approximately 1:30,000 [13]. Structural variation of chromosomes can increase the frequency of unequal recombination. Unequal recombination may delete or disrupt one or more genes; in the latter case, two or more Mendelian phenotypes can be produced. This condition is called a "contiguous gene syndrome" [14]. (See "Congenital cytogenetic abnormalities".) Inversions — Chromosome inversions are the result of abnormal recombinational events. There are two types of inversion (figure 3): ● Paracentric, involving both sides of the centromere. ● Pericentric, involving only one side [15,16]. Paracentric chromosomes form inversion loops to pair with their normal chromosome partners. If crossing over occurs outside the inversion loop, then no abnormal products are formed. If the breakage and recombination occur within the loop, the products have both duplicated and deleted segments, a phenomenon that is referred to as "recombination aneusomy" [17]. The phenotype may be abnormal if the duplicated and deleted regions in the offspring are large in size. The sites of recombination may vary from one gamete to another, so that each offspring may appear to be a sporadic case with a novel phenotype. Deletions and duplications — Deletions are missing portions of a chromosome, while duplications involve an extra copy of a portion of the chromosome. Deletion carriers are effectively monosomic for the genes in the missing segment, whereas duplication carriers are trisomic for the duplicated genes. 2 of 36 19.03.2015 10:55 Genetic and environmental causes of birth defects http://www.uptodate.com/contents/genetic-and-environmental... Deletions and duplications are generally described by their location (eg, duplication 4p) or by the two chromosomal break points defining the defective area (4p15.2,16.1). If the deletion is a common one, it may be defined by an eponym (5 p minus is known as Cri du Chat syndrome). Larger deletions and duplications can be identified cytogenetically because these banding patterns are unique to each chromosome. However, microdeletions and microduplications may be too small to be detected by traditional cytogenetic techniques and may require molecular techniques. Common microdeletions/duplications can be identified by fluorescence in situ hybridization (FISH) using a probe for the deleted or duplicated genes or by array genomic hybridization using microarrays (DNA chips). Some deletions occur more frequently than would be expected by chance alone and cause several specific contiguous gene deletion syndromes. DiGeorge syndrome, as an example, usually results from a microdeletion of the long arm of chromosome 22 (22q11.2) and is associated with phenotypic abnormalities due to defects of the fourth branchial arch and adjacent structures
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