Genetic and metabolic test selection — branching viva

Opening question

This 4-year-old with global developmental delay and mild dysmorphism has a normal chromosomal microarray from a year ago. Both parents are available and willing to provide blood. Walk me through your next genetic test of choice, the platform, the sample strategy, and why you would not repeat the microarray or send a karyotype. [1] [2]

Branch 1 — why the trio matters

You have chosen trio whole-exome sequencing. Explain to me why a trio sample is preferred over proband-only, what signal the trio unlocks, and by roughly how much it changes the diagnostic yield. Tell me what you would do if only one parent were available. [2]

Branch 2 — the critically ill infant

Step sideways to the NICU. A term infant presents at 48 hours with hypotonia, intractable seizures and an uninformative septic and metabolic screen. Defend the choice of rapid whole-genome sequencing over sequential single-gene testing in this infant, and quote the diagnostic yield and the management impact from the evidence. [8]

Branch 3 — the heel-prick and the abnormal screen

Back to the maternity unit. A term neonate's newborn bloodspot screen returns a markedly elevated octanoylcarnitine. Explain why the screen is taken at 48 to 72 hours, why the screen is not a diagnosis, and the confirmatory diagnostic pathway you would now run. Tell me what counts as a poorly taken spot. [12]

Branch 4 — the incidental finding and consent

The exome on your original 4-year-old returns a pathogenic variant in BRCA1, reported as an incidental actionable secondary finding. Tell me what consent should have been taken before the test, how you would counsel the family now, and whether and when you would test this child's siblings. Name the policy that governs the reportable genes. [11]

Closing — the five-step framework

Step back. Give me the five-step framework you would apply to any genetic or metabolic test request — justify, choose, sample, consent, cascade — and tell me how each step prevents the avoidable harms in this topic. [1] [12]