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The understanding of hematology is dependent upon 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 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 germline or acquired after birth, can cause hematologic disorders. These may be mutations that change the DNA sequence, including single base changes, deletions, insertions, and duplications, or they may be epigenetic changes that affect gene expression without any change in the DNA sequence.

The detection of mutations that cause a variety of diseases is now possible and has become a routine method for the diagnosis of some disorders. Large-scale DNA sequencing can be 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 mouse 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 upon 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, hemophilias 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 artificial chromosomes; bp, base pairs; cDNA, complementary DNA; CNV, copy number variant; CpG, cytosine phosphate guanine; ENU, N-ethyl-N-nitrosourea; G6PD, glucose-6-phosphate dehydrogenase; HNPCC, hereditary nonpolyposis colorectal cancer; lncRNA, long noncoding RNA; miRNA, microribonucleic acid; mRNA, messenger ribonucleic acid; mtDNA, mitochondrial DNA; NADH, nicotinamide adenine dinucleotide (reduced form); PACs, P1-derived artificial chromosomes; PCR, polymerase chain reaction; 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 artificial chromosome.


*In the previous edition, this chapter was written by Ernest Beutler and portions of that chapter have been retained.




Many of the hematologic diseases described in this text have a genetic basis. Often the disease is caused by a mutation in a single gene. Some of these disorders, such as sickle cell disease (Chap. 49), thalassemia (Chap. 48), glucose-6-phosphate ...

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