--- module: 069-01 language: en chapter: 69 title: "Genomic Medicine, Genetic Diagnosis, Counselling, and Precision Care" module_title: "Mechanistic foundations, classification, normal variation, and clinical presentation" source_sha256: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410 --- # Genomic foundations and presentation ## Framing genomic medicine ### Links sequence, structure, regulation, environment, phenotype ### Genetic contribution does not mean inevitability ### Congenital is not necessarily inherited ### Build a defensible causal model from variation ## Genome organisation ### Antiparallel strands, complementary bases #### Support replication and repair ### Regulatory elements set when and where #### Promoters, enhancers, silencers, splice sites ### Alternative promoters, splicing, polyadenylation ### Chromatin states are dynamic #### Methylation, histone marks, 3D contacts #### Epigenetic states persist without sequence change ### Meiosis pairs, recombines, segregates homologues #### Nondisjunction gives aneuploid gametes #### Mitotic error after fertilisation gives mosaicism ### Mitochondrial genome inherited via the ovum #### Heteroplasmy and threshold effects #### High energy demand organs affected ## Variant scale and consequence ### Single-nucleotide variants and indels #### In-frame or frameshift ### Repeat expansions lengthen across generations ### Copy-number variants, inversions, translocations ### Synonymous is not always silent ### Non-coding variants disrupt regulation ### Structural variants change dosage or create fusions ### Loss of function #### Both copies lost, or haploinsufficiency ### Gain of function and dominant negative ### Same gene, different mechanisms, different disease ### Five-tier classification #### Uncertain significance is not a diagnosis ## Inheritance patterns ### Autosomal dominant #### One-in-two transmission #### Reduced penetrance, variable expressivity #### Germline mosaicism raises recurrence ### Autosomal recessive #### One-in-four each pregnancy, independent #### Consanguinity raises shared rare allele chance ### X-linked #### Hemizygous individuals express recessive variant #### Skewed X inactivation in heterozygotes ### Y-linked paternal, mitochondrial maternal ### Imprinting: parent of origin sets syndrome ### Anticipation from unstable repeats #### Ascertainment can mimic it ## Beyond single genes ### Polygenic traits: many small effects ### Heritability is population-specific #### Not individual determination ### Multifactorial threshold models #### Recurrence not a Mendelian ratio ### Polygenic scores modify probability #### Performance falls in unlike populations #### Risk of widening inequity ## Penetrance and variability ### Penetrance by defined phenotype and age ### Expressivity is degree or pattern ### Age-dependent penetrance: carriers may develop disease ### Modifiers, sex, environment, chance ### Pleiotropy across systems ### Locus versus allelic heterogeneity ### Somatic mosaicism #### Blood testing may miss tissue variants #### Earlier event, broader distribution ### Gonadal mosaicism allows recurrence ## Clinical presentations ### Prenatal: anomaly, growth, screening, fluid ### Childhood: anomalies, delay, seizures, crises ### Adult: cardiac, cancer, neurological, renal ### Negative family history can mislead ### Germline versus somatic tumour variants #### Confirm in a non-tumour sample ### Pharmacogenomics shapes metabolism and reactions #### Genotype does not replace monitoring ## Language and uncertainty ### Use neutral terms, never "defective" ### Separate carrier, predisposition, diagnosis, disease ### Probabilities per pregnancy or interval ### Reason from variant to presentation with evidence ### Bounded uncertainty with a plan #### Segregation, functional study, reinterpretation