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CHAPTER 10 GENETICS AND HEMATOLOGIC

DISORDERS
GENETIC PRINCIPLES AND Many of the hematologic diseases described in this text have a genetic basis.
MOLECULAR BIOLOGY 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 dehydrogenase (G6PD) deficiency (Chap. 47),
and factor V Leiden (Chap. 130), are common, whereas others, such as
Lynn B. Jorde* congenital dyserythropoietic anemia type I (Chap. 39), chronic gran-
ulomatous disease (Chap. 66), and afibrinogenemia (Chap. 125), are
rare. All are caused by mutations in a gene that result in the formation
SUMMARY of a defective protein or an insufficient amount of a normal protein.
The principal focus of this chapter is such genetic disorders. However,
The understanding of hematology is dependent upon an appreciation of a number of acquired hematologic diseases, including lymphomas, leu-
genetic principles and the tools that can be used to study genetic variation. kemias, and other clonal hematologic diseases, are the consequence of
All the genetic information that makes up an organism is encoded in the acquired damage to the genetic apparatus. Understanding these diseases
DNA. This information is transcribed into mRNA, and then the triplet code of requires an appreciation of how the genetic apparatus functions.
those mRNAs is translated into protein. Changes that affect the DNA or RNA All of the information required for the development of a complete
sequence or its expression, either in the germline or acquired after birth, can adult organism is encoded in the DNA of a single cell—the zygote. This
cause hematologic disorders. These may be mutations that change the DNA information, designated the genome, includes the data needed for the
sequence, including single base changes, deletions, insertions, and duplica- synthesis of all enzymes; all the plasma proteins, including the clotting
tions, or they may be epigenetic changes that affect gene expression without factors, complement components, and the transport proteins; all the
membrane proteins, including receptors; and all of the cytoskeletal pro-
any change in the DNA sequence. teins. The units of information into which the genome is organized are
The detection of mutations that cause a variety of diseases is now possible the genes, which are composed of sequences of DNA. By serving as the
and has become a routine method for the diagnosis of some disorders. Large-scale blueprints of proteins in the body, genes ultimately influence all aspects
DNA sequencing can be used to identify disease-causing genes and to carry of body structure and function. There are approximately 21,000 protein-
out genetic testing. The development of methods to disrupt or prevent expres- coding genes and an additional 10,000 genes that do not encode pro-
sion of specific genes has made it possible to produce mouse models of human teins but affect the regulation of genes. An error in one of these genes
1
hematologic diseases, and such models have the potential to serve as means to often leads to a recognizable genetic disease. To date, more than 20,000
better understand pathophysiology and to study treatment strategies. genetic traits and diseases have been identified and cataloged.
Inheritance patterns depend upon the biologic effect and chromosomal
location of the mutation. Common autosomal recessive hematologic diseases DNA, RNA, AND PROTEINS: HEREDITY AT THE
include sickle cell disease, the thalassemias, and Gaucher disease. Hereditary MOLECULAR LEVEL
spherocytosis, thrombophilia caused by factor V Leiden, most forms of von DNA
Willebrand disease, and acute intermittent porphyria are characterized by DNA has three basic components: the pentose sugar molecule, deoxyri-
autosomal dominant inheritance. Mutations that cause glucose-6-phosphate bose; a phosphate molecule; and four types of nitrogenous bases. Two of
dehydrogenase deficiency, hemophilias A and B, and the most common form the bases, cytosine and thymine, are single carbon-nitrogen rings called
of chronic granulomatous disease, are all carried on the X chromosome and, pyrimidines. The other two bases, adenine and guanine, are double car-
therefore, manifest X-linked inheritance, with transmission of the disease bon-nitrogen rings called purines. The four bases are commonly repre-
state from a heterozygous mother to her son. Understanding the genetics of a sented by their first letters: A, C, T, and G.
disorder is necessary for accurate genetic counseling. Watson and Crick demonstrated how these molecules are phys-
ically assembled together as DNA, proposing the double-helix model,
in which DNA appears like a twisted ladder with chemical bonds as
its rungs (Fig. 10–1). The two sides of the ladder are made up of the
2,3
sugar and phosphate molecules, held together by strong phosphodiester
Acronyms and Abbreviations: BACs, bacterial artificial chromosomes; bp, base bonds. Projecting from each side of the ladder, at regular intervals, are
pairs; cDNA, complementary DNA; CNV, copy number variant; CpG, cytosine phosphate the nitrogenous bases. The base projecting from one side is bound to the
guanine; ENU, N-ethyl-N-nitrosourea; G6PD, glucose-6-phosphate dehydrogenase; base projecting from the other by a weak hydrogen bond. Therefore, the
HNPCC, hereditary nonpolyposis colorectal cancer; lncRNA, long noncoding RNA; nitrogenous bases form the rungs of the ladder; adenine pairs with thy-
miRNA, microribonucleic acid; mRNA, messenger ribonucleic acid; mtDNA, mitochon- mine, and guanine pairs with cytosine. Each DNA subunit—consisting
drial DNA; NADH, nicotinamide adenine dinucleotide (reduced form); PACs, P1-derived of one deoxyribose molecule, one phosphate group, and one base—is
artificial chromosomes; PCR, polymerase chain reaction; RISC, RNA-induced silencing called a nucleotide.
complex; RNAi, RNA interference; rRNA, ribosomal ribonucleic acid; RT-PCR, reverse DNA directs the synthesis of all the body’s proteins. Proteins are
transcriptase polymerase chain reaction; SCID, severe combined immunodeficiency; composed of one or more polypeptides (intermediate protein com-
siRNA, small interfering ribonucleic acid; SNP, single nucleotide polymorphism; STR, pounds), which are, in turn, composed of sequences of amino acids.
short tandem repeat; tRNA, transfer ribonucleic acid; YAC, yeast artificial chromosome. The body contains 20 different types of amino acids, which are specified
by the four nitrogenous bases. To specify (code for) 20 different amino
acids with only four bases, different combinations of bases, occurring in
* In the previous edition, this chapter was written by Ernest Beutler and portions groups of three, are used. These triplets of bases are known as codons.
of that chapter have been retained. Each codon specifies a single amino acid in a corresponding protein.

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