Neurogenetic conditions and precision diagnosis: Viva

Q1. The microarray is normal but you still think this is genetic. Why?

Because a chromosomal microarray detects copy-number variants, such as deletions and duplications, and not the single-nucleotide variants and small insertions or deletions that an exome reads. A normal microarray therefore rules out a pathogenic copy-number change but does not rule out a single-gene disorder, which is the more likely mechanism in a child with regression, drug-resistant epilepsy, and a movement disorder after normal development. The microarray is the right first-tier test for a copy-number burden, and a normal result simply moves the investigation to the next tier. ^[9][3]

Probe: What is the yield of the microarray? Around fifteen to twenty per cent for unexplained developmental disability, which is why it is first-tier for copy-number variants but not the whole answer for a single-gene picture like this. ^[3]

Q2. What test do you order next, and why does a trio matter?

A trio exome, sequencing the proband and both parents together. The regression after normal development in a child of unaffected parents points to a de novo dominant variant, and trio design is what allows the laboratory to distinguish a de novo change from an inherited one at the variant level. The pooled diagnostic yield of exome in neurodevelopmental disorders is around thirty-six per cent, and it is higher with a trio because the parental samples resolve segregation and support a confident pathogenic call. ^[3]

Probe: What if only the child can be sampled? A proband-only exome still works but the yield is lower and the interpretation is harder, because a variant of unknown inheritance is harder to classify. Wherever possible I would obtain parental samples, even after the event, to convert a proband-only result into an effective trio. ^[1]