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INTRODUCTION

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Chromosomal disorders can be classified into numerical and structural abnormalities of the chromosomes and are frequently encountered in clinical practice. They account for the majority of spontaneous abortions in the first trimester of pregnancy and are a major cause of congenital malformations, intellectual disability, and neurodevelopmental disorders.

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Aneuploidy is defined as the presence of an abnormal number of chromosomes in a cell, resulting from errors in chromosome segregation during meiosis and, less frequently, in mitosis. Most cases of aneuploidy of the autosomes are incompatible with life and lead to early pregnancy loss. The viable autosomal trisomies involve some of the smaller chromosomes, namely 21, 18, and 13. Aneuploidy of the sex chromosomes is tolerated more than aneuploidy of the autosomes. It is estimated that about 1 in 400 newborns has an abnormality of one of the sex chromosomes.

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Genomic disorders involve structural abnormalities of the chromosomes and have become increasingly recognized with advanced technologies, enabling recognition of submicroscopic losses and gains of genetic material; ie, DNA deletion and duplication rearrangements. The phenotype in these disorders can result from abnormal gene dosage of 1 or more of the genes in the deleted or duplicated interval or from interruption of a gene at a breakpoint junction. Many of the disorders have a specific constellation of physical findings and congenital malformations, which can be recognized clinically.

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Evaluation of chromosome number and structure should be considered in any child with multiple major and/or minor anomalies. For suspected aneuploidy such as proportionate short stature or primary amenorrhea in females (Turner syndrome) and small testes or significant gynecomastia in adolescent males (Klinefelter syndrome), an evaluation by G-banded karyotype study is warranted. Many clinicians recommend chromosomal microarray analysis (CMA), for assessment of children with intellectual disability and/or multiple congenital anomalies including congenital heart defects (CHD) (22q11.2 microdeletion syndrome). Other clinical indications for cytogenetic analysis include evaluation of stillbirths, as well as abortuses in recurrent cases, potentially due to a familial translocation.

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MECHANISMS OF ANEUPLOIDY AND GENOMIC IMBALANCE

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Nondisjunction, the failure of homologous chromosomes or sister chromatids to separate properly during cell division, results in gametes with abnormal chromosome numbers (Fig. 166-1). Fertilization of such gametes results in either monosomy (eg, Turner syndrome, 45,X) or trisomy (eg, Down syndrome). Advanced maternal age is associated with an increasing risk of meiotic nondisjunction, most likely due to the prolonged meiotic arrest of human oocytes. Occasionally, a fertilized ovum containing 3 copies of a chromosome resulting from a meiotic error loses 1 of the chromosomes in a process known as trisomy rescue. If the 2 retained chromosomes originate from the same parent, uniparental disomy results. Uniparental disomy (UPD) can cause disease by the copy number neutral genetic mechanisms of: (1) imprinting, an epigenetic mechanism dependent on the parent-of-origin of the mutation, and (2) reduction to homozygosity of recessive disease alleles present in 1 ...

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