Genetics: Concept Checklist

Concepts covered across the module lectures, grouped by lecture. Tick each once you can explain it from memory.

L1 Genetic Tests - Clinical applications (17 Apr) L1 Genetics Genetic Tests - Clinical applications

• Scale of human genetic variation per individual and the filtering problem in genetic testing
• Allele frequency vs effect size: Mendelian variants vs common GWAS variants
• Five-tier variant classification and the variant of uncertain significance as the main diagnostic hurdle; SNPs vs CNVs
• Interpreting synonymous, missense and nonsense variants (CFTR examples)
• Genetic test modalities: single gene, targeted panel, WES, WGS, microarray; scope, cost and ideal use of each
• Three pillars of clinical utility: diagnosis/prognosis, reproductive decisions (PGD, prenatal diagnosis), therapy
• Cost-effectiveness of genetic testing relative to other specialised investigations
• Retinitis pigmentosa: phenotype, genetic and allelic heterogeneity, multiple inheritance modes
• Limitations of early microarray testing (known mutations only) and diagnostic yield in the NZ retinal audit
• NGS targeted panels in Māori and Polynesian patients and discovery of a founder mutation
• Luxturna: AAV-delivered RPE65 gene therapy mechanism
• The end-to-end genomic diagnostic pathway from phenotype to clinical action

L2 Genetics of autism (20 Apr) L2 Genetics Genetics of autism

• ASD: core domains, prevalence, spectrum, comorbidities and heritability estimates
• Framework for genetic work-up of a family with a child with ASD
• Recurrence risk of ASD, sex ratio, and sporadic de novo presentation on pedigree
• Proportion of ASD due to monogenic syndromes
• Fragile X syndrome: X-linked FMR1 CGG repeat expansion and repeat size classes
• Tuberous sclerosis: autosomal dominant TS1/TS2 genes, organ manifestations, clinical diagnostic criteria; why a negative sequencing test is not exclusionary
• Chromosomal anomalies and CNVs in ASD: microarray detection, 15q11-13 imprinted duplication, recurrent CNV regions
• Interpreting CNVs: inheritance from unaffected parents, non-penetrance and variable expression
• De novo mutations and mutational burden from exome sequencing; genes clustering in synaptic function and chromatin remodelling
• Genetic architecture of ASD: common inherited variation accounts for most liability vs small contribution of de novo variants
• Clinical genetic work-up of autism and why a highly predictive test is unlikely

L3 Genetics of diabetes and obesity (1 May) L3 Genetics Genetics of diabetes and obesity

• Evolutionary mismatch as the framework for modern metabolic disease
• Thrifty gene theory (selection) vs genetic drift (chance) as origins of metabolic traits
• Heritability of obesity, and monogenic (leptin pathway, MC4R) vs polygenic obesity
• How the obesogenic environment shifts the population distribution and increases penetrance of existing genetic risk
• Epigenetics: DNA methylation at CpG sites, intergenerational transmission (F0, F1, F2), epigenetic biomarkers such as AHRR and EWAS
• FTO variant: prevalence in Europeans, effect size, ghrelin-mediated mechanism
• Population differences in obesity-associated genes
• CREBRF variant in Pacific peoples: founder effect, large effect on weight, paradoxical protection against type 2 diabetes and gestational diabetes
• Genetic architecture of type 2 diabetes: many variants of modest effect, TCF7L2 and KCNQ1 as the largest, predominance of beta-cell/islet genes
• Polygenic risk scores for obesity: predictive value and avoiding genetic determinism
• From genetic pathophysiology to targeted drugs: PPARG and glitazones, KCNJ11 and sulphonylureas in MODY; pharmacogenetics of GLP-1 agonists

L4 Direct to consumer genetic tests - metabolism and athletics (1 May) L4 Genetics Direct to consumer genetic tests - metabolism and athletics

• Revision of clinical genetic test modalities and their uses
• What DTC genetic companies offer: trait reports vs health reports, scale and pricing
• DTC vs clinical genetics: SNP chip genotyping vs sequencing, counselling, focus, data destination
• DTC workflow from saliva to dashboard, and why it detects only common variants
• Monogenic (definitive) vs polygenic (probabilistic) DTC testing and polygenic risk scores
• Converting relative risk to absolute risk, and why “double the risk” misleads
• Sports genetics: limited predictive value of ACTN3/ACE vs utility in injury-risk screening
• Pharmacogenomics of CYP2C19: population differences in poor metabolisers, clopidogrel activation vs citalopram clearance
• Clinical friction: worried well, false security, GP workload, false positives from SNP arrays
• Data as the product: research consent, third-party sale, forensic use
• Genetic discrimination by insurers in NZ and legislative response
• Regulatory positions and clinical rules for handling DTC results: verify, beware artefacts and false negatives, refer by clinical criteria

L5 Genome damage and repair (11 May) L5 Genetics Genome damage and repair

• Baseline inherited and de novo variation per individual, and somatic mutation during cell division
• DNA replication error rate, effect of proofreading, and about one new mutation per genome per division
• Mutational hot spots: methylated CpG C-to-T mutation, higher rate in spermatogenesis, disease examples (FGFR3 achondroplasia)
• Mutagens overview: daily DNA damage, possible outcomes (repair, death, mutation), free radicals as common intermediates
• Ionising radiation: electromagnetic vs particulate, direct vs indirect (radical) action, lesions produced
• Radiation dose in NZ by source, ALARA, and the linear no-threshold model
• UV damage via pyrimidine dimers and free radicals
• Radon: source, lung cancer risk interaction with smoking, mitigation
• Chemical mutagens: Ames test, barbequed meat mutagenicity, four classes (base analogues, base-pairing agents, intercalators, crosslinkers/breaks)
• Diet, lifestyle and cancer risk (WCRF matrix and recommendations), strength of evidence vs size of risk, mechanistic links to genome instability
• p53 and cell cycle checkpoints; genome instability as an enabling characteristic of cancer
• Four DNA repair pathways (BER, NER, recombinational repair HR/NHEJ, MMR): lesions repaired and how they differ
• Diseases from repair defects: MYH, xeroderma pigmentosum, BRCA1/2, mismatch repair colorectal cancer; congenital repair disorders
• Consequences of DNA damage: arrest, apoptosis, or mutation; chromosomal instability in sporadic cancer