Basic principles of genetic disease
- Benjamin A Raby, MD, MPH
Benjamin A Raby, MD, MPH
- Section Editor — Genetics
- Associate Professor of Medicine
- Harvard Medical School
The importance of genetics and genomics in clinical medicine is increasing.
This topic review presents an overview of the types of genetic and genomic disorders that can occur and the types of tools available to evaluate them, along with links to detailed reviews in UpToDate that discuss these concepts.
Terminology used to describe concepts in genetics and genomics is presented in a glossary. (See "Genetics: Glossary of terms".)
BASIC PRINCIPLES OF MOLECULAR GENETICS
Molecular genetics is discussed in greater detail separately. (See "Principles of molecular genetics".)
DNA, RNA, and protein: The building blocks of life — Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are linear, polymerized strands of linked nucleotides (figure 1 and figure 2 and figure 3). A nucleotide is a nucleoside, or a combination of a sugar (ribose or deoxyribose) and a base, that is linked to a phosphate group. RNA differs from DNA in that the hydrogen at the 2’ position in DNA is replaced by a less stable hydroxyl group in RNA. There are four DNA bases: adenine (A), cytosine (C), guanine (G), and thymidine (T). In RNA, thymidine is replaced by uracil (U). DNA or RNA polymers are formed by the linking of the 5’ phosphate of one nucleotide to the 3’ hydroxyl group of another.
- Dolgin E. Human genomics: The genome finishers. Nature 2009; 462:843.
- Verlaan DJ, Berlivet S, Hunninghake GM, et al. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet 2009; 85:377.
- Moffatt MF, Kabesch M, Liang L, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007; 448:470.
- Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411:599.
- Samson M, Libert F, Doranz BJ, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382:722.
- Southard AE, Edelmann LJ, Gelb BD. Role of copy number variants in structural birth defects. Pediatrics 2012; 129:755.
- Kruyer H, Milà M, Glover G, et al. Fragile X syndrome and the (CGG)n mutation: two families with discordant MZ twins. Am J Hum Genet 1994; 54:437.
- Bassett JH, Forbes SA, Pannett AA, et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 1998; 62:232.
- Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004; 428:486.
- Lupski JR, Reid JG, Gonzaga-Jauregui C, et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med 2010; 362:1181.
- BASIC PRINCIPLES OF MOLECULAR GENETICS
- DNA, RNA, and protein: The building blocks of life
- Organization of the human genome
- - Alleles, genotypes, and haplotypes
- - Identifying loci on chromosomes
- - Mitochondrial genes
- - Coding and noncoding genes
- Gene transcription
- Protein synthesis
- GENETIC VARIATION
- DNA sequence variation
- - Single nucleotide polymorphisms (SNPs)
- Nonsense mutation
- Missense mutation
- Splice site mutation
- Silent mutation
- Regulatory polymorphism
- Indels: Insertions and deletions
- Triplet-repeat expansion
- Structural genetic variation
- - Copy number variation
- - Chromosome translocations and inversions
- Epigenetic variation
- MEIOSIS: GAMETE FORMATION
- MODES OF INHERITANCE
- Mendelian inheritance
- - Autosomal dominant
- - Autosomal recessive
- - Sex-linked
- Situations affecting Mendelian inheritance
- - Penetrance
- Age-related penetrance
- Sex-influenced and sex-limited expression
- - Mosaicism
- - Anticipation
- - Imprinting
- THE ROLE OF GENETIC TESTING IN MODERN CLINICAL MEDICINE
- Perinatal screening
- Carrier testing
- Diagnostic testing
- Pharmacogenetic testing
- The future of genetic testing
- SUMMARY AND RECOMMENDATIONS