Choose and consent a genetic test after a normal microarray — OSCE

Candidate brief

You have this station to assess a 4-year-old with global developmental delay and a normal microarray, decide on the next genetic test, take consent for the full result space of an exome, and answer the family's questions. Treat this as a communication and decision-making encounter: explain the test choice, take explicit consent, address the possibility of an incidental secondary finding, and demonstrate the request-side discipline the station is testing. [1] [2]

Key teaching and management objectives

Begin by confirming the clinical picture and the prior. The child has global developmental delay with mild dysmorphism; the microarray from a year ago is normal. The Miller 2010 consensus establishes microarray as the first-tier test for this presentation with a yield of around 10 to 20 percent, but a normal microarray does not exclude a genetic diagnosis — it directs the next step. [1]

State the next test of choice: whole-exome sequencing as a trio, with both parents providing blood alongside the child. The Yang 2013 exome series gives a diagnostic yield of around 25 percent in ambulant children with a suspected monogenic disorder, and the trio sample roughly doubles the yield over proband-only testing because the de novo variant — present in the affected child and absent from both unaffected parents — is the single most powerful signal in interpretation. Repeating the microarray is not indicated; a karyotype is the wrong test for developmental delay. [2]

Take explicit consent for the full result space. An exome can return a diagnostic pathogenic variant in a known disease gene, a variant of uncertain significance whose clinical meaning is unresolved, an incidental actionable secondary finding on an ACMG-listed gene, or an unexpected finding such as non-paternity. Record the family's opt-in or opt-out for the secondary-findings list, which in the ACMG SF v3.2 update stands at 81 reportable genes covering hereditary cancer and cardiovascular risk syndromes among others. Explain that a secondary finding is a family finding, not the child's finding; that predictive testing is offered to at-risk adult relatives; and that a minor is not tested for an adult-onset condition without a childhood intervention, so siblings would not be tested for an adult-onset secondary finding now. [11]

Address the family's questions in plain language: an exome reads the roughly 20,000 genes of the coding genome; it cannot find everything (it does not find non-coding variants well, or repeat expansions); a negative result does not exclude a genetic cause and is reanalysed at one to two years as new genes are described and variants are reclassified; a variant of uncertain significance is reported as uncertain, not as a diagnosis, and should not drive surveillance until the evidence firms. Document the discussion, the opt-in or opt-out for secondary findings, and the plan for the result communication and the cascade testing. [11]

If the family asks about the newborn bloodspot screen for a younger sibling, explain that it is a screen, not a diagnosis: a heel-prick taken at 48 to 72 hours onto a Guthrie card, analysed by tandem mass spectrometry for dozens of metabolic, endocrine and haemoglobin conditions, with every abnormal result confirmed by a quantitative diagnostic test before a label is attached to a child. [12]

Marking domains

• Choice of next test and defence (4 marks). States trio whole-exome sequencing as the next test of choice after a normal microarray; defends against repeating the microarray and against a karyotype; quotes the Miller consensus and the Yang yield and the trio advantage.
• Consent for the full result space (3 marks). Names the four possible outcomes — diagnostic variant, variant of uncertain significance, incidental actionable secondary finding, unexpected non-paternity finding; records the family's opt-in or opt-out for the ACMG secondary-findings list (81 genes in v3.2); explains the rules around testing siblings for an adult-onset secondary finding.
• Family questions and plain-language explanation (2 marks). Explains what an exome can and cannot find; frames a negative result as a call for reanalysis; frames a variant of uncertain significance as unresolved rather than a diagnosis.
• Documentation and cascade (1 mark). Documents the discussion, the opt-in or opt-out, the plan for result communication and the cascade testing of at-risk relatives. [1] [2] [11]