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50 Clinical Neurogenetics Brent L 50 Clinical Neurogenetics Brent L. Fogel, Daniel H. Geschwind CHAPTER OUTLINE research has permitted dissection of the cellular machinery supporting the function of the brain and its connections while establishing causal relationships between such dysfunction, GENETICS IN CLINICAL NEUROLOGY human genetic variation, and various neurological diseases. In GENE EXPRESSION, DIVERSITY, AND REGULATION the modern practice of neurology, the use of genetics has DNA to RNA to Protein become widespread, and neurologists are confronted daily with data from an ever-increasing catalog of genetic studies TYPES OF GENETIC VARIATION AND MUTATIONS relating to conditions such as developmental disorders, Rare versus Common Variation dementia, ataxia, neuropathy, and epilepsy, to name but a few. Polymorphisms and Point Mutations The use of genetic information in the clinical evaluation of Structural Chromosomal Abnormalities and Copy neurological disease has expanded dramatically over the past Number Variation (CNV) decade. More efficient techniques for discovering disease genes Repeat Expansion Disorders have led to a greater availability of genetic testing in the clinic. CHROMOSOMAL ANALYSIS AND ABNORMALITIES Approximately one-third of pediatric neurology hospital admissions are related to a genetic diagnosis, and there are DISORDERS OF MENDELIAN INHERITANCE now hundreds of individual genetic tests available to the prac- Autosomal Dominant Disorders ticing neurologist, including several related to common dis- Autosomal Recessive Disorders eases. This number continues to increase rapidly (Fig. 50.1), Sex-Linked (X-Linked) Disorders but is rapidly being supplanted by the clinical availability of exome and genome sequencing, allowing neurologists to MENDELIAN DISEASE GENE IDENTIFICATION BY rapidly survey every gene in human genome for disease- LINKAGE ANALYSIS AND CHROMOSOME MAPPING causing mutations. NON-MENDELIAN PATTERNS OF INHERITANCE As neuroscience and genetic research have progressed, we Mitochondrial Disorders have been led to a deeper understanding of the sources and Imprinting nature of human genetic variation and its relationship to clini- Uniparental Disomy cal phenotypes. In the past there has been a tendency to consider genetic traits as either present or absent, and corre- COMMON NEUROLOGICAL DISORDERS AND COMPLEX spondingly, patients were either healthy or diseased; this is the DISEASE GENETICS traditional view of Mendelian, or single gene, conditions. Common Variants and Genome-Wide Association Although certain relatively rare neurological diseases— Studies Friedreich ataxia or Huntington disease (HD), for example— Rare Variants and Candidate Gene Resequencing can be traced to a single causal gene, the common forms of Copy Number Variation and Comparative Genomic other diseases such as Alzheimer dementia, stroke, epilepsy, Hybridization or autism usually arise from an interplay of multiple genes, each of which increases disease susceptibility and likely inter- GENOME/EXOME SEQUENCING IN CLINICAL PRACTICE acts with environmental factors. Subsequently, the realm of AND DISEASE GENE DISCOVERY the “sporadic” and the “idiopathic” has been challenged by FUTURE ROLE OF SYSTEMS BIOLOGY IN NEUROGENETIC the identification of genetic susceptibility factors, which has DISEASE sparked a flurry of investigation into a variety of genes and genetic markers that confer a risk of illness yet are not wholly ENVIRONMENTAL CONTRIBUTIONS TO NEUROGENETIC causative. Disease status may lie on the end of a continuum DISEASE of individual variation and thus can be considered a quantita- GENETICS AND THE PARADOX OF DISEASE DEFINITION tive rather than purely qualitative trait (Plomin et al., 2009). So, rather than using what might be considered an arbitrary CLINICAL APPROACH TO THE PATIENT WITH cutoff point, such as a specific number of senile plaques or SUSPECTED NEUROGENETIC DISEASE neuritic tangles that define affected or unaffected patients, one Evaluation and Diagnosis might instead think in terms of a continuum of pathology that Genetic Counseling relates to different levels of burden or susceptibility. Prognosis and Treatment As we continue to discover more genes involved either directly or indirectly in neurological disease pathogenesis, the amount of information available to the clinician grows, as do the challenges in interpreting this in a meaningful way for an individual patient. Much of this information, particularly with respect to genetic risk, is not a matter of a positive or negative GENETICS IN CLINICAL NEUROLOGY result, but instead is a feature to be incorporated into the Since the discovery of the structure of deoxyribonucleic acid clinical framework supporting an overall diagnosis. While (DNA) and the elucidation of the genetic mechanisms of modern neurologists need not also be geneticists, it is essential heredity, clinical neurology has benefited from advances in that they possess a firm understanding of the basics of human genetics and neuroscience. This clinically relevant basic genetics in order to be fully prepared to confront the litany of 648 Descargado de ClinicalKey.es desde Univ Antioquia septiembre 06, 2016. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2016. Elsevier Inc. Todos los derechos reservados. Clinical Neurogenetics 649 2500 50 2250 2000 1750 1500 1250 1000 750 500 250 0 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 Fig. 50.1 Rapid growth of clinical testing for genetic disease. This graph plots the number of genetic diseases for which clinical testing was available over the period of 1993–2013, illustrating an approximate 20-fold increase in the number of testable disorders. (Data from GeneTests. Available at http://www.genetests.org/.) diagnostic information available today. This is becoming more contains one or more promoters, DNA sequences that allow for true as the use of clinical exome and genome sequencing the binding of a cellular protein complex that includes RNA becomes increasingly widespread. In this chapter we will polymerase and other factors that faithfully copy the DNA in discuss these essential basics and present examples of how the 5′ to 3′ direction in a process known as transcription. The genetic information has informed our understanding of resulting single-stranded molecule contains a ribose sugar unit disease definition and etiology, show how it is utilized in the in its backbone and thus the resulting molecule is termed practice of neurology today, and how it will be used even more ribonucleic acid, or RNA. RNA also differs from the template extensively in the future. Given the massive acceleration in DNA by the incorporation of uracil (U) in place of thymine technology, from microarrays to the methods enabling com- (T), as it also pairs efficiently with adenine, and thymine serves plete and efficient human genome sequencing, this future is a secondary role in DNA repair that is not necessary in RNA. closer than most realize and the era of genomic medicine is The sequence of the RNA matches the sense DNA strand and fast approaching. is therefore complementary to (and hence derived from) the antisense strand. GENE EXPRESSION, DIVERSITY, Transcribed coding RNA must be processed to become AND REGULATION protein-encoding messenger RNA (mRNA), a term used to dif- ferentiate these RNAs from all other types of RNA in the cell. The basic principles of molecular genetics are outlined in Fig. To become mature, RNA is stabilized by modification at the 50.2 and Table 50.1, and more detailed descriptions can be ends with a 7-methylguanosine 5′ cap and a long poly-A 3′ found elsewhere (Alberts et al., 2008; Griffiths et al., 2002; tail. A further critical stage in the maturation of the RNA mol- Lodish et al., 2008; Strachan and Read, 2003). To briefly sum- ecule involves a rearrangement process termed RNA splicing marize, deoxyribonucleic acid (DNA), found in the nucleus of (Fig. 50.3). This is necessary because the expressed coding all cells, comprises the raw material from which heritable sequences in DNA, called exons, of virtually every gene are information is transferred among individuals, with the sim- discontinuous and interspersed with long stretches of gener- plest heritable unit being the gene. DNA is composed of a ally nonconserved intervening sequences referred to as introns. series of individual nucleotides, all of which contain an identi- This, along with other mechanisms, likely plays an evolution- cal pentose (2′-deoxyribose)-phosphate backbone but differ ary role in the development of new genes by allowing for the at an attached base that can be adenine (A), guanine (G), shuffling of functional sequences (Babushok et al., 2007). thymine (T), or cytosine (C). A and G are purine bases and Nascent RNA molecules are recognized by the spliceosome, a pair with the pyrimidine bases T and C, respectively, to form protein complex that removes the introns and rejoins the a double-stranded helical structure which allows for semicon- exons. Not every exon is utilized at all times in every RNA servative bidirectional replication, the means by which DNA derived from a single gene. Exons may be skipped or included is copied in a precise and efficient manner. In total, there are in a regulated manner through alternative splicing, which approximately 3.2 billion base pairs in human DNA. By con- occurs in nearly 95% of all genes to create different isoforms vention, a DNA sequence is described by listing the bases as of that mRNA. The dynamic nature
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