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INTRODUCTION

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Cytogenetics is a field of genetics involved with the study of chromosomes. Clinical cytogenetics aims to delineate the gross chromosomal abnormalities, both in number and structure, associated with certain malformation syndromes. Approximately 1% of live-born babies have a cytogenetic abnormality, making this field particularly relevant in the pediatric population and the clinical practice of pediatrics. Cytogenetics includes routine analysis of G (Giemsa)-banded chromosomes, fluorescence in situ hybridization (FISH), and whole-genome array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays. Whole-genome sequencing (WGS), which has been viewed traditionally as a molecular technique targeting single nucleotide variants (SNVs), is gradually being introduced into the cytogenetics field because of its potential to analyze copy number variants (CNVs) as well as structural variants (SVs). WGS can be implemented postnatally as well as prenatally, from fetal DNA in maternal blood. Whole-exome sequencing (WES) focuses on the coding sequences of all genes in the human genome (~1% of the human genome). It detects small changes in DNA including SNVs and indels (insertions and deletions <50–100 bp). WES has been particularly useful clinically for elucidating the etiologic molecular diagnosis in pediatric patients whose phenotype remained a diagnostic dilemma and for finding dual molecular diagnoses in patients with blended phenotypes.

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Numerical abnormalities of chromosomes, such as trisomy 21 (Down syndrome), Turner syndrome (monosomy X), and Klinefelter syndrome (47,XXY), can be detected by analysis of chromosomes under a light microscope and preparation of a karyotype, a standardized photomicrograph of chromosome pairs ordered from largest to smallest (with the exception of chromosome 21, which is smaller than chromosome 22). The karyotype allows for visualization of large (generally involving >5 megabases [Mb] of DNA) structural abnormalities of chromosomes, such as reciprocal translocations, Robertsonian translocations, and ring chromosomes. In addition, large terminal deletions at either end of a chromosome (eg, 5p deletion or cri du chat syndrome) and large interstitial deletions within the arms of a chromosome (eg, del(17)p11.2 associated with Smith-Magenis syndrome) can also be visualized on routine karyotype. However, smaller deletion and duplication CNVs require higher resolution techniques that can be either targeted to a specific region, as with FISH technology, or multiple loci based, as with microarrays and next-generation sequencing technologies.

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Indications for use of cytogenetics in a pediatric population include recognizable syndromes, multiple congenital malformations, developmental delay, short stature and primary amenorrhea in girls, and intellectual disability. Cytogenetics is also widely used in oncology to help with diagnosis, a treatment plan, and prognosis.

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CHROMOSOME ANALYSIS

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Abnormalities of chromosome number and structure can result during either type of cell division, mitosis or meiosis. Mitosis is the ordinary somatic cell division by which the body grows, differentiates, and renews tissues. Mitotic division results in 2 diploid daughter cells that are genetically identical to the parent cell. To prepare for mitotic division, genomic DNA is duplicated during interphase, in the S (synthesis) phase of the cell cycle. The duplication results in 2 sister chromatids held together at the centromere. Mitosis then ensues, with its 4 stages: prophase, metaphase, anaphase, and telophase. Prophase is marked by gradual condensation of the chromosomes ...

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