Single gene testing, such as for cystic fibrosis, myotonic dystrophy, and spinocerebellar ataxia

What it is

Targeted testing of one gene when the clinical phenotype names the gene
Contrast with a panel/exome, which is used when the phenotype is non-specific or genetically heterogeneous

Recognisable syndrome with one causative gene - CF (CFTR), HFE haemochromatosis, achondroplasia (FGFR3)
Repeat expansion disorders - Huntington, SCAs, myotonic dystrophy, Fragile X, Friedreich ataxia
Known familial variant -> predictive/cascade testing (test only for that variant - cheapest, fastest, unambiguous)
Pharmacogenomic testing - TPMT/NUDT15, DPYD, HLA-B57:01, HLA-B15:02
Confirming a newborn-screen or biochemical result

Cascade testing of first-degree relatives yields a carrier/affected result in ~50% per relative for an AD condition - the highest-yield genetic test in medicine
Diagnostic yield of targeted testing in a well-characterised phenotype far exceeds that of exome sequencing in an undifferentiated one

Match the mutation mechanism to the technology - the examinable point

Mutation type	Correct test	Why
Point mutation / small indel	Sanger sequencing, or targeted NGS	Reads base-by-base
Repeat expansion (CTG, CAG, GAA, CGG)	PCR + fragment length analysis; Southern blot or triplet-primed PCR for large expansions	*Sanger cannot size a large repeat - the polymerase stalls and the read fails*
Large deletion/duplication (exon-level)	MLPA or array/NGS copy-number analysis	Sequencing of a deleted allele just reads the normal one -> false "normal"
Whole-gene / contiguous deletion	Chromosomal microarray
Methylation/imprinting defect	Methylation-specific PCR (Prader-Willi, Angelman, Fragile X)	Sequence is normal
Mosaicism	Deep NGS on the affected tissue	Blood may be negative - e.g. TSC, McCune-Albright

*"The gene test was normal" is not the same as "the gene is normal"* - always ask which technique was used and what it cannot detect

Cystic fibrosis - extended CFTR variant panel first (covers F508del + common variants), then full CFTR sequencing + MLPA if only one or no variant found and the phenotype fits
Spinocerebellar ataxias and Huntington disease - PCR with fragment length analysis to size the CAG repeat; panel covers SCA1, 2, 3, 6, 7, 17 and others
Fragile X - PCR + methylation analysis (premutation vs full mutation)
Haemochromatosis - targeted C282Y/H63D genotyping only, after a raised transferrin saturation

Class	Meaning	Action
5 Pathogenic / 4 Likely pathogenic	Causative	Act on it
3 Variant of uncertain significance (VUS)	Unknown	*Never use to direct management or predictive testing* - manage on phenotype and family history; re-contact as classification changes
2 Likely benign / 1 Benign	Not causative	Look elsewhere

A negative targeted test excludes only that variant, in that gene, by that technique
Phase matters in AR disease: two variants must be in trans (on different alleles) - test the parents

Predictive testing for an untreatable late-onset disease (Huntington) requires a formal multi-session protocol, with psychological assessment, and is not performed on minors
Discuss: implications for relatives, reproductive options, insurance
- Australia: use of genetic test results in life insurance underwriting is banned - Treasury Laws Amendment (Genetic Testing Protections in Life Insurance) Act, Royal Assent 8 Apr 2026, applies to decisions made on or after 8 Oct 2026
  - Family history and existing diagnoses may still be used; private health insurance was always community-rated

State the phenotype on the request - the laboratory interprets variants against the clinical question
Test the affected relative first wherever possible; an unaffected person's negative result is uninformative unless the familial variant is known
Send to a NATA-accredited diagnostic laboratory - research and direct-to-consumer results must be confirmed diagnostically
Medicare rebates exist for some tests (e.g. eligible cancer-predisposition and pharmacogenomic tests); many others are hospital- or patient-funded
Refer to clinical genetics for: predictive testing, reproductive planning, VUS, atypical phenotypes, any Huntington-type disease

Confirmatory or segregation testing where needed
Cascade testing of at-risk relatives - the patient, not the doctor, contacts relatives
Reproductive options: preimplantation genetic testing, prenatal diagnosis (CVS/amniocentesis), donor gametes, non-invasive prenatal testing for paternally inherited variants

Anticipation - repeat expansion disorders (Huntington, myotonic dystrophy, Fragile X)
Imprinting - Prader-Willi/Angelman, Beckwith-Wiedemann
Mosaicism - TSC, McCune-Albright, segmental NF
Incomplete penetrance and variable expressivity - BRCA, HFE, TSC
Locus heterogeneity - retinitis pigmentosa, hereditary spastic paraparesis
Pharmacogenomics - TPMT/NUDT15, DPYD, CYP2D6, CYP2C19, HLA-B*57:01

Repeat expansion disorders show anticipation - repeat length inc through meiosis, so onset is earlier and disease more severe in successive generations
- Paternal transmission -> greater expansion in Huntington and SCAs
- Maternal transmission -> congenital myotonic dystrophy and Fragile X full mutation
Premutation carriers have their own phenotypes
- FMR1 premutation -> FXTAS (tremor/ataxia in older men) and primary ovarian insufficiency in women
Variant classification is not static - a VUS may be reclassified; establish who re-contacts the patient and when

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