Genomic testing, variant interpretation, and counselling — formative SAQs

SAQ 1 (10 marks)

A four-year-old boy is referred for global developmental delay, mild dysmorphic features, and a paternal family history of learning difficulty. His chromosomal microarray returned normal. The paediatrician has now ordered trio exome sequencing. The parents ask what this test involves and what it might find. ^{[2] [9]}

a) Explain why a normal chromosomal microarray does not exclude a genetic diagnosis, and justify the escalation to exome sequencing. (3 marks) ^{[2] [9]}

b) Describe the ACMG/AMP five-tier variant classification framework, naming each tier and giving the approximate probability range for a variant of uncertain significance. (3 marks) ^[1]

c) Outline the domains you would cover in the pre-test counselling conversation, including the option of secondary findings and the management of a potential VUS. (2 marks) ^{[5] [9]}

d) Explain why trio sequencing (proband plus both parents) is preferred over proband-only sequencing, naming two advantages. (2 marks) ^[9]