Neurogenetics
This domain tests inheritance pattern recognition, repeat expansion disorders, and a rational testing strategy rather than gene-list memorisation.
Inheritance patterns
Autosomal dominant: Huntington disease, neurofibromatosis type 1, Charcot-Marie-Tooth type 1, spinocerebellar ataxias. Autosomal recessive: Friedreich ataxia, Wilson disease, spinal muscular atrophy, most metabolic disease. X-linked: Duchenne dystrophy, fragile X syndrome. Mitochondrial: maternal transmission with variable heteroplasmy, as in MELAS, MERRF and Leber hereditary optic neuropathy.
Repeat expansion disorders
Huntington disease is a CAG expansion with paternal anticipation. Fragile X is a CGG expansion; premutation carriers can develop fragile X-associated tremor/ataxia syndrome in later life. Myotonic dystrophy is a CTG expansion, Friedreich ataxia a GAA expansion, and the spinocerebellar ataxias are mostly CAG repeats.
Testing principles
Choose a targeted test first when the phenotype is classic; move to panels or exome sequencing when it is not. Classify variants as pathogenic, likely pathogenic, variant of uncertain significance, likely benign or benign. Predictive testing in asymptomatic adults requires counselling and consent, and is generally deferred in minors.
Worked example
A 30-year-old has two years of chorea, irritability and cognitive decline. His father died at 55 with a similar illness. The pedigree suggests autosomal dominant inheritance, so test the HTT CAG repeat. Offer genetic counselling before testing, and remember each child has a 50 percent risk.
Traps
Ordering whole exome sequencing when a single gene test answers the question; missing maternal inheritance in mitochondrial disease; equating a variant of uncertain significance with a diagnosis; ignoring anticipation.