Neurogenetics
Neurogenetics
What Do You Need to Know?
- Autosomal dominant (AD): 50% offspring affected; one mutant allele sufficient; variable penetrance; male-to-male transmission possible (distinguishes from X-linked)
- Autosomal recessive (AR): 25% affected offspring from two carrier parents; consanguinity increases risk; carriers are asymptomatic
- X-linked recessive: males affected, females are carriers; NO male-to-male transmission; all daughters of an affected male are obligate carriers
- Mitochondrial inheritance: maternal only — affected mother passes to all children; heteroplasmy and threshold effect determine phenotype
- Trinucleotide repeat expansions: cause anticipation (earlier onset in successive generations); CAG repeats = polyglutamine = mostly AD; Friedreich ataxia (GAA) is the only common AR trinucleotide repeat disorder
- Genomic imprinting: Prader-Willi = paternal deletion 15q11–13 (“P for Paternal, P for Prader”); Angelman = maternal deletion 15q11–13 (“A for Angelman, M for Maternal”)
- Chromosomal microarray (CMA) is the recommended first-line genetic test for unexplained intellectual disability and autism; whole-exome sequencing (WES) is best for complex phenotypes
- Huntington disease: CAG repeat in HTT on 4p16.3; >40 repeats = fully penetrant; caudate atrophy; AD with anticipation (paternal transmission → larger expansions)
Central Dogma of Molecular Biology
DNA → RNA → Protein
- Transcription: DNA → pre-mRNA in the nucleus; RNA polymerase II reads the template strand (3′ to 5′) and synthesizes mRNA (5′ to 3′)
- RNA processing: 5′ cap + 3′ poly-A tail added; introns spliced out, exons joined to form mature mRNA
- Translation: mRNA → protein at ribosomes; codons (3 nucleotides) specify amino acids; AUG = start codon (methionine); UAA, UAG, UGA = stop codons
Gene Structure
- Promoter: upstream regulatory region; binding site for RNA polymerase and transcription factors
- Exons: coding sequences that are retained in mature mRNA (“EXons are EXpressed”)
- Introns: intervening noncoding sequences removed by splicing (“INtrons are IN the way”)
- UTRs (untranslated regions): 5′-UTR and 3′-UTR — regulate mRNA stability, localization, and translation efficiency
Post-Translational Modifications
- Glycosylation: addition of sugar moieties; important for protein folding and cell signaling
- Phosphorylation: addition of phosphate group by kinases; key regulatory mechanism (e.g., tau hyperphosphorylation in Alzheimer disease)
- Ubiquitination: tagging proteins with ubiquitin for proteasomal degradation (e.g., defective in Parkinson disease — parkin is an E3 ubiquitin ligase)
Types of Mutations
Classification of Mutations
| Mutation Type | Description | Example |
|---|---|---|
| Silent | Nucleotide change but same amino acid (codon degeneracy) | No clinical effect |
| Missense | Single nucleotide change → different amino acid | Sickle cell disease (Glu → Val); CADASIL (NOTCH3 cysteine mutations) |
| Nonsense | Single nucleotide change → premature stop codon | Duchenne muscular dystrophy (truncated dystrophin) |
| Frameshift | Insertion or deletion NOT a multiple of 3 → shifts reading frame | Duchenne (out-of-frame deletion) vs. Becker (in-frame deletion) |
| In-frame insertion/deletion | Insertion or deletion of 3n nucleotides; reading frame preserved | Becker muscular dystrophy (shortened but partially functional dystrophin) |
| Splice-site mutation | Disrupts intron-exon boundary → abnormal mRNA splicing | Some forms of SMA, familial dysautonomia (IKBKAP) |
| Trinucleotide repeat expansion | Dynamic mutation; repeat length increases across generations | Huntington (CAG), Fragile X (CGG), Friedreich ataxia (GAA) |
| Chromosomal deletion | Loss of a chromosome segment | DiGeorge (22q11.2 deletion), Williams (7q11.23) |
| Chromosomal duplication | Extra copy of a chromosome segment | CMT1A (PMP22 duplication) |
| Gene fusion | Two genes fused by translocation or deletion | BCR-ABL in CML; KIAA1549-BRAF in pilocytic astrocytoma |
Functional Consequences of Mutations
- Loss of function: reduced or absent protein function; most AR diseases (both alleles must be affected)
- Gain of function: protein acquires new or enhanced activity; typically AD (e.g., Huntington — toxic polyglutamine expansion)
- Dominant negative: mutant protein interferes with normal protein function; one bad copy poisons the complex (e.g., some collagen disorders, p53 mutations)
- Haploinsufficiency: one functional copy insufficient to maintain normal function; AD mechanism (e.g., NF1 — 50% neurofibromin is not enough)
Board Pearl
Duchenne vs. Becker dystrophy — the reading frame rule: Duchenne = out-of-frame (frameshift) deletion → no functional dystrophin → severe. Becker = in-frame deletion → shortened but partially functional dystrophin → milder. This is one of the most commonly tested mutation-type concepts on boards.
Patterns of Inheritance
| Pattern | Key Features | Board-Relevant Examples |
|---|---|---|
| Autosomal dominant | 50% offspring affected; vertical transmission; male-to-male transmission possible; variable penetrance and expressivity; de novo mutations common | Huntington, NF1, NF2, TSC, myotonic dystrophy, CADASIL, most SCAs, CMT1A |
| Autosomal recessive | 25% affected offspring; horizontal transmission (siblings affected); carriers asymptomatic; consanguinity ↑ risk; typically loss-of-function mutations | Friedreich ataxia, Wilson disease, SMA, most metabolic diseases, ataxia-telangiectasia |
| X-linked recessive | Males affected; carrier females usually asymptomatic; NO male-to-male transmission; affected father → all daughters are carriers, no sons affected | Duchenne/Becker, Kennedy disease (SBMA), Fragile X, Fabry disease, adrenoleukodystrophy |
| X-linked dominant | Affects both sexes; often lethal in males; affected females show variable expression due to X-inactivation | Rett syndrome (MECP2), incontinentia pigmenti (IKBKG), Aicardi syndrome |
| Mitochondrial | Maternal inheritance only; affected mother → all children at risk; affected father → no children affected; heteroplasmy (variable mutation load); threshold effect | MELAS, MERRF, LHON, Kearns-Sayre, NARP |
| Genomic imprinting | Gene expression depends on parent of origin; same chromosomal deletion → different disease depending on which parent it came from | Prader-Willi (paternal 15q11–13), Angelman (maternal 15q11–13) |
Board Pearl
Male-to-male transmission EXCLUDES X-linked inheritance. If a pedigree shows an affected father with an affected son, the disease must be autosomal (dominant or recessive), not X-linked. This is one of the most commonly tested pedigree interpretation rules.
Board Pearl
Prader-Willi vs. Angelman — same deletion, different parent: Both involve deletion of 15q11–13. Prader-Willi = loss of paternal copy → hypotonia, obesity, hypogonadism, intellectual disability (“P for Paternal, P for Prader”). Angelman = loss of maternal copy (UBE3A gene) → severe intellectual disability, seizures, happy demeanor, puppet-like gait (“A for Angelman, M for Maternal”).
Genetic Testing Modalities
| Test | Resolution | Detects | Key Indications |
|---|---|---|---|
| Karyotype | ~5 Mb | Aneuploidies, large structural rearrangements (translocations, large deletions) | Down syndrome, Turner, Klinefelter; balanced translocations |
| FISH | ~100 Kb–5 Mb | Targeted detection of known deletion/duplication using fluorescent probe | DiGeorge (22q11.2), Prader-Willi/Angelman (15q11–13); confirmatory test |
| Chromosomal microarray (CMA/SNP array) | ~5–10 Kb | Copy number variants (microdeletions/duplications); loss of heterozygosity (LOH); cannot detect balanced translocations | First-line test for unexplained intellectual disability, autism, multiple congenital anomalies |
| Single-gene sequencing | Single nucleotide | Point mutations, small insertions/deletions in one specific gene | When a specific gene is suspected (e.g., HTT for Huntington) |
| Gene panel | Single nucleotide | Mutations in multiple genes related to a phenotype | Epilepsy panel, neuropathy panel, ataxia panel; cost-effective for defined phenotypes |
| Whole-exome sequencing (WES) | Single nucleotide | ~1.5% of genome (all exons); captures ~85% of disease-causing mutations | Complex/undiagnosed phenotypes; parent-child trios increase diagnostic yield (~25–40%) |
| Whole-genome sequencing (WGS) | Single nucleotide | Entire genome including noncoding regions, structural variants | Most comprehensive; identifies intronic variants and structural variants missed by WES; still largely research |
Board Pearl
Chromosomal microarray (CMA) is the recommended first-line genetic test for children with unexplained intellectual disability, autism spectrum disorder, or multiple congenital anomalies — NOT karyotype. CMA has ~15–20% diagnostic yield vs. ~3% for karyotype. However, CMA cannot detect balanced translocations or low-level mosaicism — karyotype is still needed for these.
Trinucleotide Repeat Disorders
Overview
- Trinucleotide repeats are dynamic mutations — repeat length tends to increase in successive generations
- Anticipation: longer repeats → earlier onset and more severe disease in each generation
- CAG repeats (coding region) → polyglutamine (polyQ) tract → typically gain-of-function toxicity; mostly AD
- GAA repeats (intronic) → loss of function (reduced transcription); Friedreich ataxia is AR
- CGG/CTG repeats (UTR/noncoding) → variable mechanisms (RNA toxicity, methylation, silencing)
High-Yield Trinucleotide Repeat Table
| Disease | Repeat | Gene / Protein | Locus | Inheritance | Key Features |
|---|---|---|---|---|---|
| Huntington disease | CAG | HTT / huntingtin | 4p16.3 | AD | >36 repeats abnormal; >40 fully penetrant; caudate atrophy; chorea, psychiatric, dementia; paternal anticipation |
| Fragile X syndrome | CGG | FMR1 / FMRP | Xq27.3 | X-linked | >200 = full mutation (methylation → silencing); most common inherited cause of intellectual disability; long face, large ears, macroorchidism |
| Fragile X premutation | CGG | FMR1 | Xq27.3 | X-linked | 55–200 repeats; FXTAS in older males (tremor, ataxia, white matter lesions); premature ovarian insufficiency (POI) in females |
| Friedreich ataxia | GAA | FXN / frataxin | 9q21.11 | AR | Only common trinucleotide repeat that is AR; spinocerebellar ataxia + hypertrophic cardiomyopathy + diabetes; dorsal column & spinocerebellar tract degeneration; absent reflexes + extensor plantar responses |
| Myotonic dystrophy type 1 (DM1) | CTG | DMPK | 19q13.32 | AD | Multisystem: myotonia, distal weakness, cataracts, cardiac conduction defects, frontal balding, testicular atrophy, insulin resistance; maternal anticipation → congenital DM1 |
| SCA1 | CAG | ATXN1 | 6p22.3 | AD | Cerebellar ataxia + pyramidal signs + neuropathy |
| SCA2 | CAG | ATXN2 | 12q24.12 | AD | Cerebellar ataxia + slow saccades (distinguishing feature) |
| SCA3 (Machado-Joseph) | CAG | ATXN3 | 14q32.12 | AD | Most common SCA worldwide; bulging eyes, dystonia, spasticity, peripheral neuropathy |
| SCA6 | CAG | CACNA1A | 19p13.13 | AD | Pure cerebellar ataxia; small expansions (21–33 repeats); late onset; very slowly progressive |
| SCA7 | CAG | ATXN7 | 3p14.1 | AD | Cerebellar ataxia + retinal degeneration (pigmentary maculopathy) — unique among SCAs |
| DRPLA | CAG | ATN1 | 12p13.31 | AD | Ataxia + chorea + seizures + dementia; more common in Japanese population |
| Kennedy disease (SBMA) | CAG | Androgen receptor (AR) | Xq12 | X-linked recessive | Bulbospinal muscular atrophy; proximal weakness, bulbar involvement, gynecomastia, sensory neuropathy, tongue fasciculations; slowly progressive |
Board Pearl
Friedreich ataxia is the ONLY common trinucleotide repeat disorder that is autosomal recessive. All other major trinucleotide repeat diseases are AD or X-linked. The GAA expansion in frataxin (intronic) causes loss of function — unlike CAG (polyglutamine) disorders which are gain-of-function. Classic triad: ataxia + cardiomyopathy + diabetes. Exam finding: absent deep tendon reflexes + extensor plantar responses (combined dorsal column and corticospinal tract disease).
Clinical Pearl — Anticipation by Parent of Origin
The parent who transmits the larger expansion varies by disease: Huntington disease — paternal transmission causes greater expansion (spermatogenesis has more cell divisions); Myotonic dystrophy type 1 — maternal transmission causes greater expansion (congenital DM1 is almost always maternally inherited — floppy baby, respiratory failure, facial diplegia). Fragile X — maternal transmission expands premutation to full mutation (no male-to-full transmission because the premutation does not expand during spermatogenesis).
Non-Trinucleotide Repeat Genetic Neurologic Diseases
Key Board-Relevant Genetic Diseases
| Disease | Inheritance | Gene / Protein | Locus | Key Features |
|---|---|---|---|---|
| Alzheimer disease (early-onset familial) | AD | APP / amyloid precursor protein | 21q21.3 | Onset <65 years; Down syndrome patients (trisomy 21) have extra APP copy → early Alzheimer |
| Alzheimer (early-onset) | AD | PSEN1 / presenilin-1 | 14q24.2 | Most common cause of early-onset familial AD; most aggressive; onset 30s–50s |
| Alzheimer (early-onset) | AD | PSEN2 / presenilin-2 | 1q42.13 | Rarest cause of familial AD; Volga-German families |
| Alzheimer (risk factor) | Risk allele | APOE ε4 | 19q13.32 | Strongest genetic risk factor for late-onset AD; 1 allele = 3× risk, 2 alleles = 12× risk; ε2 is protective |
| CADASIL | AD | NOTCH3 | 19p13.12 | Recurrent subcortical strokes + migraine with aura + white matter disease + dementia; granular osmiophilic material (GOM) on skin biopsy |
| Wilson disease | AR | ATP7B | 13q14.3 | Copper accumulation; Kayser-Fleischer rings, hepatic disease, dystonia/tremor, psychiatric symptoms |
| CMT1A | AD | PMP22 duplication | 17p12 | Most common CMT; demyelinating neuropathy; pes cavus, stork legs; duplication → overexpression of PMP22 |
| CMT1B | AD | MPZ / myelin protein zero | 1q23.3 | Demyelinating neuropathy; similar to CMT1A but less common |
| HNPP | AD | PMP22 deletion | 17p12 | Hereditary neuropathy with liability to pressure palsies; recurrent compressive neuropathies; deletion (vs. duplication in CMT1A) |
| Duchenne / Becker MD | X-linked recessive | DMD / dystrophin | Xp21.2 | Duchenne = absent dystrophin (frameshift); Becker = reduced/truncated dystrophin (in-frame) |
| Spinal muscular atrophy (SMA) | AR | SMN1 | 5q13.2 | Loss of SMN1; severity inversely correlated with SMN2 copy number; nusinersen (antisense oligonucleotide), onasemnogene (gene therapy), risdiplam (oral) |
Board Pearl
CMT1A = PMP22 duplication; HNPP = PMP22 deletion — same gene, opposite dosage. Both are on chromosome 17p12. CMT1A (too much PMP22) causes chronic demyelinating neuropathy. HNPP (too little PMP22) causes episodic compressive neuropathies. This reciprocal duplication/deletion from unequal crossing over is a classic board question.
Chromosomal Disorders with Neurologic Manifestations
| Disorder | Karyotype | Key Neurologic Features | Other Features |
|---|---|---|---|
| Down syndrome | Trisomy 21 | Intellectual disability; early-onset Alzheimer disease (APP gene on Ch 21 → amyloid overproduction); infantile spasms; increased seizure risk | Cardiac defects (AV canal), atlantoaxial instability, hypothyroidism, duodenal atresia, leukemia |
| Edwards syndrome | Trisomy 18 | Severe intellectual disability; neural tube defects | Clenched fists (overlapping fingers), rocker-bottom feet, cardiac defects; most die within first year |
| Patau syndrome | Trisomy 13 | Holoprosencephaly; severe intellectual disability; midline facial defects (cleft lip/palate, cyclopia) | Polydactyly, cardiac defects, cutis aplasia; most die within first year |
| Turner syndrome | 45,X | No intellectual disability; visuospatial processing deficits; social cognition difficulties | Short stature, webbed neck, shield chest, coarctation of aorta, streak gonads |
| Klinefelter syndrome | 47,XXY | Learning difficulties (language-based); mild intellectual disability in some | Tall stature, gynecomastia, hypogonadism, infertility |
| DiGeorge / 22q11.2 deletion | del(22)(q11.2) | Learning disability; psychiatric illness (~25% develop schizophrenia); velopharyngeal insufficiency | Cardiac defects (conotruncal), hypocalcemia (absent parathyroids), T-cell deficiency (thymic aplasia), cleft palate |
| Williams syndrome | del(7)(q11.23) | Intellectual disability with relative strength in verbal/social skills (“cocktail party personality”); visuospatial deficits | Elfin facies, supravalvular aortic stenosis, hypercalcemia; deletion includes elastin gene |
| Cri-du-chat syndrome | del(5p) | Severe intellectual disability; high-pitched cat-like cry (due to laryngeal abnormality) | Microcephaly, wide-set eyes, low-set ears |
Clinical Pearl — Down Syndrome and Alzheimer Disease
Virtually all patients with Down syndrome develop Alzheimer neuropathology (amyloid plaques and neurofibrillary tangles) by age 40, due to lifelong overproduction of amyloid-beta from the extra copy of APP on chromosome 21. Clinical dementia onset is typically in the 50s. This is one of the strongest pieces of evidence supporting the amyloid hypothesis of Alzheimer disease.
Genetic Counseling Concepts
Key Terminology
- Penetrance: proportion of individuals with a given genotype who express the phenotype
- Complete penetrance (100%) = all carriers show disease (e.g., Huntington with >40 repeats)
- Reduced penetrance = some carriers never develop clinical disease (e.g., BRCA1, Huntington 36–39 repeats)
- Expressivity: range of phenotypic severity among individuals who express the genotype
- Variable expressivity = same mutation → different severity (e.g., NF1 — some have mild café-au-lait spots only, others have severe plexiform neurofibromas)
- Anticipation: earlier onset and/or increased severity in successive generations; hallmark of trinucleotide repeat disorders
- De novo mutations: new mutations not present in either parent; no family history does NOT exclude a genetic disease (e.g., ~50% of NF1, ~2/3 of TSC are de novo)
- Variants of uncertain significance (VUS): genetic variant detected on sequencing with insufficient evidence to classify as pathogenic or benign; do NOT use for clinical decision-making; may be reclassified over time
- Pleiotropy: single gene affecting multiple organ systems (e.g., myotonic dystrophy — muscle, heart, eyes, endocrine)
- Genetic heterogeneity:
- Locus heterogeneity: same phenotype caused by mutations in different genes (e.g., CMT caused by >80 different genes)
- Allelic heterogeneity: same phenotype caused by different mutations in the same gene
Heteroplasmy and Threshold Effect (Mitochondrial)
- Heteroplasmy: coexistence of mutant and wild-type mtDNA within the same cell
- Threshold effect: clinical disease manifests only when the proportion of mutant mtDNA exceeds a tissue-specific threshold (typically 60–90%)
- Tissues with highest energy demand (brain, muscle, heart) are most vulnerable → explains CNS and muscle predominance in mitochondrial diseases
- Mitotic segregation: during cell division, mtDNA distributes unevenly to daughter cells → explains variable expression even within the same family
Clinical Pearl — Genetic Testing in Neurologic Practice
When a VUS is reported, clinicians should not use it to confirm a diagnosis or guide treatment. Family segregation studies (testing affected and unaffected relatives) can help reclassify VUS over time. The yield of whole-exome sequencing in undiagnosed neurologic disease is approximately 25–40% when performed as a parent-child trio, compared to ~25% for proband-only testing.
Quick Reference — High-Yield Neurogenetics Summary
Inheritance Pattern Quick-Recall
| Inheritance | Distinguishing Clue | Board-Favorite Examples |
|---|---|---|
| AD | Vertical transmission; 50% affected; male-to-male OK | Huntington, NF1/2, TSC, CADASIL, most SCAs, CMT1A, myotonic dystrophy |
| AR | Horizontal (siblings); 25% affected; consanguinity | Friedreich ataxia, Wilson, SMA, most leukodystrophies, Tay-Sachs |
| X-linked recessive | Males only; NO male-to-male; carrier mothers | Duchenne/Becker, Kennedy (SBMA), Fragile X, Fabry, ALD |
| X-linked dominant | Often male-lethal; affected females | Rett, incontinentia pigmenti, Aicardi |
| Mitochondrial | Maternal only; variable severity | MELAS, MERRF, LHON, Kearns-Sayre |
| Imprinting | Parent-of-origin matters | Prader-Willi (paternal), Angelman (maternal) |
Trinucleotide Repeat Quick-Recall
| Repeat | Location | Mechanism | Diseases |
|---|---|---|---|
| CAG | Coding (exon) | Polyglutamine → gain of function; toxic aggregation | Huntington, SCAs (1, 2, 3, 6, 7), DRPLA, Kennedy (SBMA) |
| CGG | 5′-UTR | Methylation → gene silencing (full mutation); RNA toxicity (premutation) | Fragile X syndrome; FXTAS (premutation) |
| CTG | 3′-UTR | RNA toxicity (CUG-repeat RNA sequesters MBNL1) | Myotonic dystrophy type 1 (DM1) |
| GAA | Intronic | Impaired transcription → loss of function (reduced frataxin) | Friedreich ataxia (the ONLY common AR trinucleotide repeat disorder) |
References
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw Hill; 2023.
- Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. 11th ed. McGraw Hill; 2022.
- Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 8th ed. Elsevier; 2016.
- Bird TD. Hereditary Ataxia Overview. In: Adam MP, et al., editors. GeneReviews. University of Washington, Seattle; 2023.
- Paulson H. Repeat expansion diseases. Handb Clin Neurol. 2018;147:105–123.
- Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–764.
- Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–894.
- Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256(Suppl 1):3–8.
- Darras BT. Spinal muscular atrophies. Pediatr Clin North Am. 2015;62(3):743–766.
- Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370(25):2418–2425.