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1298 ParT ElEvEN Diagnostic Immunology

Single Nucleotide Variant or Mutation Short Tandem Repeat (STR) Allele
10 20 30
–ggattacctg acccAccgct taatcattga Reference 2
–ggattacctCAGCAGccgcttaatcattgatt
–ggattacctg acccGccgct taatcattga c.15A>G
5
–ggattacctCAGCAGCAGCAGCAGccgcttaatcattgatt
Deletion
10 20 30
–ggattacctg acccACCgct taatcattga
Structural and Copy Number Variants (CNV)
–ggattacctg accc–––gct taatcattga c.15_17delACC
Deletion

Insertion
10 20 30
–ggattacctg accc-accgct taatcattga
–ggattacctg acccGaccgct taatcattga c.14_15insG
Duplication
Insertion/Deletion
10 20 30
–ggattacctg acccACCgct taatcattga
–ggattacctg acccGATgct taatcattga c.15_17delinsGAT
FIG 96.1 Classes of DNA Variation Important for Genetic Testing and Human Genetic Diseases.
DNA variations can be either benign or pathogenic, depending on whether they affect the underlying
functions of a genetic locus and the encoded proteins. An international standard nomenclature
is used to describe changes in the DNA. Structural variants have been found to be a common
cause of human genetic disorders.

includes a continuum of gene effects ranging from weak (common data and that each individual bears about 3.5 million simple
SNPs detected in disease association studies) to strongly deter- nucleotide variants and about 1000 structural variants, many of
minative (rare mutations detected in single gene disorders). which are unique to that person. Even given some technical
Genes can be mapped in relation to one another by a linkage reservations, the enormous extent of private variation has been
map. Genes that are physically close can be shown to be pre- clearly established.
dominantly coinherited. Linkage mapping played a large role in Linkage and LD mapping have been much less useful for the
the identification of the X-linked immunodeficiency genes identification of autosomal recessive genes responsible for many
(Chapters 22, 33–36). Beyond small families and at the population primary immunodeficiencies (PIDs) because the diseases are
level, the correlation of alleles among markers that are very close rare in the population and average families are not large enough
to each other in the genome is called linkage disequilibrium to narrowly localize the causative genes. Whole-genome and
(LD). LD occurs because the mutation that creates a polymor- exome sequencing technologies are being used to solve a great
5,6
phism occurs on a single chromosome with its whole complement fraction of remaining single-gene disorders, including PIDs.
of unique variants. This initial arrangement of alleles, however, The biggest difficulty with these conditions is that similar clinical
is broken up by recombination over time. Hence, only markers diseases can be caused by mutation in more than one gene locus
that are relatively close to each other continue to have significant (locus heterogeneity). Another challenge is that it may be difficult
LD. A large international project (HapMap) created a dense map to ascertain multiple extremely rare families with mutations in
of SNP markers allowing a comprehensive view of LD in several the same gene. Criteria for rare disease gene identification have
4
reference populations. This information has been efficiently been proposed and have helped harmonize standards for future
7
exploited in genetic epidemiology projects called genome- genome interpretation. Successful identification of pathogenic
wide association studies (GWAS; www.gwascentral.org), which variants, even those unique to single pedigrees, can be accom-
have characterized several thousand common variants that plished by combining DNA sequencing with complimentary
contribute to many common immunological diseases, such as functional technologies.
diabetes, rheumatoid arthritis (RA), and systemic lupus erythe-
matosus (SLE). Physical Maps and DNA Copy Number Variation
The advent of projects that assess whole exomes and genomes Physical maps are different from the genetic map in that they
in normal and disease populations, such as the 1000 Genomes describe how genes are arranged in the DNA on a scale as large
Project (www.1000genomes.org/), has focused much more as a whole chromosome and as fine as a single nucleotide. At
attention on rare genetic variation, particularly alleles with the coarsest level of the physical map, genes are placed in chromo-
frequency of 0.01–1.0%. It is also apparent that the extent of some segments corresponding to the Giemsa-stain banding
individual genetic variation was underestimated from previous pattern of metaphase chromosomes. A way to localize genes is