Cytogenetics, Genomic Medicine, and Bioinformatics
Cytogenetics and genomic medicine
Know the resolution and use of karyotyping, FISH, CMA (chromosomal microarray), and sequencing. Understand constitutional vs acquired abnormalities, mosaicism detection limits, and the interpretation of copy-number variants (benign, likely benign, VUS, pathogenic) using ClinGen/ACMG CNV frameworks. Be familiar with structural variant types (deletion, duplication, inversion, translocation, isochromosome) and the role of genomic medicine in diagnosis, carrier screening, and prenatal testing.
Bioinformatics
Understand the NGS pipeline: base calling, read alignment (reference genome, alignment scores), variant calling (SNV/indel, CNV, SV), annotation, filtering, and classification. Know quality metrics (Q30, depth, coverage uniformity, duplicate rate, contamination estimates) and the difference between analytical and clinical validity. Understand the role of reference databases (ClinVar, gnomAD, COSMIC) and the limitations of each.
Traps
Items confuse analytical sensitivity with clinical utility, over-trust a single database entry, or ignore the difference between a variant call and a validated result. Watch for questions about low-level mosaicism, the limits of CMA (balanced rearrangements are not detected), and the need for orthogonal confirmation of clinically actionable variants.
Rule of thumb
Match the technology to the question: CMA for genome-wide copy number, karyotype for balanced rearrangements and mosaicism, FISH for targeted loci, and sequencing for nucleotide-level resolution. Always confirm actionable findings with an orthogonal method.
Worked example
A CMA reports a 200-kb deletion of uncertain significance. Before calling it pathogenic, check population frequency, gene content, inheritance (parental studies), and overlap with known benign CNVs; classify using ClinGen scoring rather than size alone.