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Chapter 21. Genetic Testing For Neurological Disorders

Aditi I. Dagli; Charles A. Williams

Many of the neurological disorders discussed in this book have a genetic etiology that can be diagnosed and/or confirmed by chromosomal or molecular testing. Due to advances in genetic technology, the range of testing options has increased dramatically in the last few years. Deciding which test to perform and how to interpret the results can be daunting. Accordingly, in this chapter we review the different types of clinically available genetic tests. These can be employed for general screening or for confirmation of a clinically diagnosed condition. The general portfolio of such testing is illustrated in Table 21-1, and this chapter will review these types of tests.

Table 21–1. Common Types of Genetic and/or Metabolic Tests That May Be Obtained During a Neurological Evaluation
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Table 21–1. Common Types of Genetic and/or Metabolic Tests That May Be Obtained During a Neurological Evaluation
Chromosome-Based Tests
  • Routine G-banded analysis
  • Single FISH probe study (eg, for Angelman syndrome)
  • Multiple probe FISH study (eg, subtelomeres)
  • Array-based comparative genomic hybridization (CGH)
Molecular Mutation-Based Tests
  • Single mutation study
  • Multiple mutation screens (eg, Charot-Marie-Tooth multigene panel)
  • Complete gene sequencing and/or gene deletion study (eg, Neurofibromatosis, type)
  • Trinucleotide repeat analysis (eg, for Fragile X)
  • DNA methylation study (eg, to rule out Prader-Willi syndrome)
  • Single nucleotide polymorphism (SNP) analysis (eg, to rule out uniparental disomy)
Mitochondrial-Based Tests
  • Mitochondrial DNA (mtDNA) sequence analysis
  • Southern blot study for mtDNA deletions and duplications
  • Electron transport function (ETF) assays
Metabolic Testing
  • Urine organic acids
  • Plasma amino acids
  • Plasma acylcarnitine profile
Other Tests
  • Enzyme Assay (eg, Lysosomal Enzymes)

A routine chromosome study (karyotype) involves evaluating the chromosomes during the metaphase period of cell mitosis, and the test is usually performed on blood cells. Lymphocytes are grown in culture and stained with a dye such as Giemsa to obtain a distinct pattern of light and dark bands. This banding pattern is unique to each of the 46 chromosomes, and helps to identify them on microscopic examination (Figure 21-1). A routine chromosome study can identify extra or missing chromosomes (eg, Down [47, XY+21] and Klinefelter [47, XXY] syndromes) as well as detect large inversions, translocations, deletions, duplications, and extra fragments (eg, marker chromosomes). The visual resolution of this study, however, is only at the 10 to 20 million base pair level (Table 21-2). Higher-resolution tests are available (as discussed below in Array-Based Comparative Genomic Hybridization) that detect much smaller changes in the chromosome.

Table 21–2. Sensitivity of Different Genetic Tests to Detect DNA Changes.
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Table 21–2. Sensitivity of Different Genetic Tests to Detect DNA Changes....
Type of testDetection size*
Routine chromosome study10-20 million
Individual FISH3-5 million
Subtelomere FISH panel3-5 million per probe
Array-based CGH:
Low resolution (~1200 probes)400,000-1.5 million
High resolution (~10-90,000 probes)(30,000-300,0000)
Gene analysis:
Gene deletion, gene duplication testing30,000-800,0000 depending on gene
Point mutation analysis

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