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The understanding of hematology is more than ever dependent on an appreciation of genetic principles and the tools that can be used to study genetic variation. All the genetic information that makes up an organism is encoded in the DNA. This information is transcribed into messenger ribonucleic acid (mRNA), and then the triplet code of those mRNAs is translated into protein. Changes that affect the DNA or RNA sequence or its expression, either in the germ line or acquired after birth, can cause many hematologic disorders. These may be mutations that change the DNA sequence, including single base changes, deletions, insertion, and duplications, or they may be epigenetic changes that affect gene expression without any change in the DNA sequence. Insights into the genetic changes that may occur in the “dark matter” of DNA, the 98% of the genome that does not encode proteins, have also begun to come into clear view.

The detection of defined mutations that cause a variety of diseases is now possible and has become a routine method for the diagnosis of many hematological disorders. Increasingly, large-scale DNA sequencing is being used to identify disease-causing genes and to carry out genetic testing. The development of methods to disrupt or prevent expression of specific genes has made it possible to produce animal models of human hematologic diseases, and such models have the potential to serve as means to better understand pathophysiology and to study treatment strategies.

Inheritance patterns depend on the biologic effect and chromosomal location of the mutation. Common autosomal recessive hematologic diseases include sickle cell disease, the thalassemias, and Gaucher disease. Hereditary spherocytosis, thrombophilia caused by factor V Leiden, most forms of von Willebrand disease, and acute intermittent porphyria are characterized by autosomal dominant inheritance. Mutations that cause glucose-6-phosphate dehydrogenase deficiency (G6PD), hemophilia A and B, and the most common form of chronic granulomatous disease, are all carried on the X chromosome and therefore manifest X-linked inheritance, with transmission of the disease state from a heterozygous mother to her son. Understanding the genetics of a disorder is necessary for accurate genetic counseling.

Acronyms and Abbreviations

BACs, bacterial arti?cial chromosomes; bp, base pairs; cDNA, complementary DNA; CNV, copy number variant; CpG, cytosine phosphate guanine; ENU, N-ethyl-N-nitrosourea; G-6-PD, glucose-6-phosphate dehydrogenase; hereditary nonpolyposis colorectal cancer, HNPCC; lncRNA, long noncoding RNA; mRNA, messen­ger ribonucleic acid; LHON, Leber hereditary optic neuropathy; MERRF, myoclonic epilepsy with ragged-red fiber syndrome; miRNA, microribonucleic acid; mtDNA, mitochondrial DNA; NADH, nicotinamide adenine dinucleotide (reduced form); PACs, P1­derived arti?cial chromosomes; PCR, polymerase chain reaction; PNH, paroxysmal nocturnal hemoglobinuria; RISC, RNA-induced silencing complex; RNAi, RNA interference; rRNA, ribosomal ribonucleic acid; RT-PCR, reverse transcriptase polymerase chain reaction; SCID, severe combined immunodeficiency; siRNA, small interfering ribonucleic acid; SNP, sin­gle nucleotide polymorphism; STR, short tandem repeat; tRNA, transfer ribonucleic acid; YAC, yeast arti?cial chromosome.


Many of the hematologic diseases described in this ...

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