Genetic testing in neurology has evolved into a layered ecosystem of methodologies — Sanger sequencing, next-generation sequencing (NGS) panels, whole-exome and whole-genome sequencing, repeat-expansion-specific assays, mitochondrial DNA testing, copy-number variant detection, and long-read sequencing. Choosing the right test depends on which disease (or category of disease) you suspect, what variant types that disease produces, what each test type detects (and misses), and what insurance will cover. This section is a practical workup guide — what to order, in what order, and how to interpret results. Clinical disease syndromes are covered in the relevant clinical chapters (Movement Disorders, Cognitive, Neuromuscular, etc.); here, the focus is on the lab side.

How This Section Is Organized

The genetics section is split into two parts:

Part 1 — Approach to Genetic Testing

Foundational pages on the test types, when to order each, and the practical considerations of ordering genetic testing in clinical practice.

• Types of Genetic Tests — Sanger sequencing, NGS panels, whole-exome and whole-genome sequencing, repeat expansion testing, mitochondrial DNA testing, copy-number variant detection, methylation testing, karyotype, long-read sequencing. What each detects, what each misses, turnaround and cost.
• When to Order Each Test — decision framework for choosing single-gene vs panel vs WES vs WGS vs disease-specific assay. Algorithm for the most common ordering decisions.
• Counseling, VUS & Practical Considerations — pre-test genetic counseling, variants of uncertain significance, reanalysis, ACMG variant classification, cost and insurance, sponsored testing programs, and recent advances.

Part 2 — Disease-Specific Workup

One page per phenotype category. Each page covers the major hereditary diseases in that category, the highest-yield first-line test for each, reflex testing if first-line is negative, and treatment-driven testing relevance.

• Movement Disorders — Huntington disease, spinocerebellar ataxias, Friedreich ataxia, Wilson disease, familial Parkinson disease, hereditary dystonia, NBIA, Kennedy disease, DRPLA
• Stroke & Cerebrovascular — CADASIL, CARASIL, COL4A1/A2, cavernous malformations, hereditary hemorrhagic telangiectasia, moyamoya, Fabry-related stroke
• Cognitive & Dementia — familial Alzheimer disease, APOE, frontotemporal dementia, C9orf72, prion disease, ALSP
• Motor Neuron Disease — familial ALS, SOD1 (tofersen-eligible), SMA, Kennedy disease
• Peripheral Neuropathy — Charcot-Marie-Tooth, hereditary spastic paraplegia, hereditary sensory and autonomic neuropathies, hATTR amyloidosis, Fabry
• Muscular Dystrophies & Myopathies — Duchenne/Becker, myotonic dystrophy types 1 and 2, FSHD, limb-girdle, congenital muscular dystrophy, Pompe, centronuclear myopathy
• Mitochondrial Disorders — MELAS, MERRF, LHON, Kearns-Sayre, NARP/MILS, Leigh syndrome, POLG-related disease
• Leukodystrophies & White Matter Disease — X-linked ALD, MLD, Krabbe, Alexander, PMD, vanishing white matter, AGS, cerebrotendinous xanthomatosis, ALSP
• Epilepsy Genetics — epileptic encephalopathies, Dravet, GLUT1 deficiency, tuberous sclerosis, genetic generalized epilepsies, progressive myoclonic epilepsies, neuronal ceroid lipofuscinoses
• Metabolic & Storage Disorders + Neurocutaneous — Fabry, Pompe, Gaucher, Niemann-Pick C, Tay-Sachs, MPS, urea cycle, CTX, NF1, NF2, TSC, VHL, Sturge-Weber

Some Disease–Gene Pairs to Memorize

These are the highest-yield single-gene tests in adult neurology. For each, the disease is unambiguous enough that a single-gene test is the correct first move.

• CADASIL → NOTCH3 (full-gene sequencing, exons 2–24 with cysteine-altering variants)
• MELAS → m.3243A>G targeted testing first, then whole mtDNA sequencing + nuclear panel
• Huntington disease → HTT CAG repeat (RP-PCR; Southern blot for very large expansions) — NOT detected by standard NGS panels
• Friedreich ataxia → FXN GAA repeat — triplet-primed PCR + long-range PCR (or Southern blot) is the standard clinical assay; long-read sequencing is an emerging adjunct for sizing and interruption detection
• C9orf72 ALS/FTD → hexanucleotide repeat expansion — specialized RP-PCR or Southern blot, NOT standard NGS
• DMD → DMD MLPA first (~70% of variants), then sequencing
• SMA → SMN1 exon 7 deletion by MLPA; SMN2 copy number drives treatment selection
• CMT → PMP22 duplication first (CMT1A is the commonest form), then CMT NGS panel
• X-ALD → plasma very-long-chain fatty acids (VLCFA) first, then ABCD1 sequencing
• Fabry → α-Gal A enzyme activity (males) + GLA sequencing (mandatory in females — enzyme can be normal)
• Familial AD → APP / PSEN1 / PSEN2 sequencing
• SOD1-ALS → SOD1 sequencing → tofersen eligibility
• hATTR polyneuropathy → TTR sequencing → patisiran / vutrisiran / inotersen eligibility for the polyneuropathy; tafamidis is FDA-approved for ATTR-cardiomyopathy only (US) and is relevant when hATTR includes cardiac involvement

Pre-Test Quick Checklist

1. Define the clinical phenotype precisely — the narrower the differential, the better the test choice.
2. Identify the suspected variant type(s) — point mutation, expansion, deletion, mosaic, methylation? This selects the assay.
3. Check what testing has already been done — avoid duplicating panels; reanalyze previous data if appropriate.
4. Consider trio testing if WES is the right call and parents are accessible.
5. For predictive testing: refer for formal genetic counseling first.
6. Check for sponsored testing programs for the suspected disease — they may cover the cost.
7. Confirm sample requirements — most tests are blood; some need muscle (mitochondrial deletions, CPEO/KSS), urine sediment (mtDNA heteroplasmy), skin biopsy (mosaic NF1 / Sturge-Weber), or affected tissue.
8. Set expectations with the patient and family about VUS frequency and turnaround.

Pitfalls and Pearls

• Repeat expansions are NOT detected by standard NGS — order the disease-specific repeat assay.
• Single-gene Sanger is correct only when the gene is unambiguous.
• Mitochondrial blood testing is often negative with positive muscle / urine — heteroplasmy is tissue-specific.
• For X-linked disease in females, enzyme activity can be normal — order gene sequencing.
• VUS is not a diagnosis — counsel families clearly; reanalyze every 2–3 years.
• Pre-test counseling is mandatory for predictive testing (HD, familial AD, familial FTD, familial ALS).
• Sponsored testing programs are widely available — check before paying out-of-pocket.
• Treatment-driven testing: order specific gene tests when the result changes therapy eligibility (SOD1, SMN1, DMD, TTR, GLA).

References

1. Rexach J, Lee H, Martinez-Agosto JA, et al. Clinical application of next-generation sequencing to the practice of neurology. Lancet Neurol. 2019;18(5):492-503.
2. Klein CJ, Foroud TM. Neurology individualized medicine: when to use next-generation sequencing panels. Mayo Clin Proc. 2017;92(2):292-305.
3. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants (ACMG/AMP). Genet Med. 2015;17(5):405-424.