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Trio exome sequencing — RACP Paediatrics MCQ

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HardGeneticsTrio exome sequencingRACP Paediatrics

A 2-year-old has severe global developmental delay, epilepsy and two congenital anomalies. Chromosomal microarray and Fragile X testing are non-diagnostic, and phenotype-directed metabolic testing is normal. There is no single recognisable syndrome. What is the highest-yield next genetic investigation?

Educational content. Not a substitute for clinical judgement or local policy.

Reveal the answer and explanation

Correct answer: E — Order clinical trio exome or genome sequencing through genetics

Explanation lettering: C = shown as A · E = shown as C · A = shown as E

A is correct because exome or genome sequencing is recommended as a first- or second-tier test for children with unexplained congenital anomalies or developmental disability; trio analysis improves de novo and segregation interpretation. B repeats a completed copy-number test without a new indication. C cannot resolve most sequence-level causes and is lower yield after a normal array unless a chromosomal mechanism is specifically suspected. D lacks validated consent, analysis and confirmatory clinical interpretation. E denies a meaningful diagnostic yield and potential management, recurrence-risk and family benefits. ACMG guidance is jurisdiction-neutral and aligns with Australian clinical-genomics practice.

Reference: NSW Centre for Genetics Education, genomic testing for paediatric intellectual disability and childhood syndromes: https://www.genetics.edu.au/SitePages/Genomic-testing-Intellectual-disability-childhood-syndromes.aspx; ACMG evidence-based guideline, exome and genome sequencing in paediatric congenital anomalies or developmental disability: https://pubmed.ncbi.nlm.nih.gov/34211152/