---
module: 069-02
language: en
chapter: 69
title: "Genomic Medicine, Genetic Diagnosis, Counselling, and Precision Care"
module_title: "History, examination, diagnostic strategy, differential diagnosis, and common disease"
source_sha256: 5b3c27d01f451a23e3e6ff6686d7f0e95d3655f06f474cb021a4bc3f757bbb65
---
# Genomic diagnosis in practice

## Diagnostic approach
### Start with phenotype and family, not sequencing
### Define the question, document findings
### Match test to suspected variant class
### Prepare for results affecting relatives
### Negative may lower probability without excluding

## Three-generation pedigree
### Record relatives, pregnancies, ages, causes of death
### Ask consanguinity, donor conception, adoption
### Do not infer parentage or gender from role
### Look for transmission patterns
#### Vertical, sibling, sex bias, maternal line
#### Multiple primaries, early onset
### Family history is dynamic
#### Small families, surgery, early death hide syndromes
#### Records confirm whether diseases match
### Test the affected relative first
#### Unaffected first may be uninformative

## Phenotyping and examination
### Record positive and relevant negative findings
### Measure growth, proportions, skin, neurology
### Photographs need specific consent
### Dysmorphology identifies patterns
#### Many features are familial variants
#### Coherent minor anomalies raise plausibility
#### Compare with appropriate references and parents
### Search for treatable complications
#### Diagnosis matters when it guides care

## Choosing the test
### Karyotype: aneuploidy, large rearrangements
### Microarray: submicroscopic copy-number change
#### Misses balanced translocations, small variants
### Single gene when phenotype points to one
### Panels for heterogeneity, content varies
### Exome and genome sequencing
#### Miss some repeats, methylation, mosaicism
### Specialised assays for specific classes
### Confirm report scope and parental samples

## Biochemical genetics
### Crises: encephalopathy, acidosis, hyperammonaemia
### Stabilise without waiting for molecular diagnosis
### Critical samples during illness
#### Treatment takes priority over yield
### Normal newborn screen does not exclude
### Pattern guides substrate, cofactor, catabolism
### Functional evidence can establish pathogenicity

## Interpreting results
### Pathogenic result needs concordance
#### Established gene, mechanism, zygosity, phenotype
### Pathogenicity differs from causality
### Segregation supports or weakens
#### De novo strong, mosaicism possible
#### Non-segregation does not disprove
### No predictive testing on a VUS
### Reanalysis and recontact policies
### True negative needs known familial variant
#### Otherwise often uninformative

## Common presentations
### Delay with anomalies: microarray and sequencing
#### Repeat testing may need separate assays
### Hereditary cancer assessment
#### Tumour screening needs germline confirmation
#### Moderate-risk genes, uncertain management
### Inherited cardiac disease
#### Silent, age-dependent phenotype
#### Negative panel does not stop surveillance
### Prenatal: screening versus diagnosis
#### Cell-free DNA confounders
#### Ultrasound phenotype guides test choice

## Incidental and uncertain findings
### Unrelated variants, carrier status, relationships
### Pre-test discussion of categories and records
### Benefits versus anxiety, insurance, conflict
### No childhood testing for adult-onset without benefit
### Diagnosis is iterative
#### No assay compensates for an undefined question