Genetic and metabolic test selection

Overview & Definition

Picture the four-year-old in your general paediatric clinic with unexplained global developmental delay and a normal microarray, the neonate in the NICU with hypotonia, seizures and an uninformative septic screen, and the baby brought back at two weeks because a spot of blood from the heel-prick at 72 hours has returned an elevated octanoylcarnitine. The shared question is which tube to fill, in which child, in which window, and what to do with the answer. That question is what this page owns — not the platforms in depth (owned by the chromosomal microarray, exome and genome sequencing page) and not the diseases themselves, but the act of choosing and interpreting the test in a real child. [1] [10]

Genetic test selection is the request-side skill of matching a clinical question to a platform — karyotype for suspected aneuploidy or balanced rearrangements; chromosomal microarray for copy-number variants in developmental delay, intellectual disability, autism with dysmorphism, and multiple congenital anomalies; whole-exome and whole-genome sequencing for the single-nucleotide variants, small indels and (for genome) the non-coding variants that cause most Mendelian disease. Metabolic test selection is the parallel skill of matching a metabolic suspicion to the right analyte in the right sample in the right window — plasma amino acids, urine organic acids, the acylcarnitine profile, lactate and pyruvate, transferrin isoforms for congenital disorders of glycosylation, and very-long-chain fatty acids for peroxisomal disease. Newborn bloodspot screening is a third and distinct entity: a population screen, not a diagnostic test, run from a heel-prick onto a dried blood spot, that flags the infant who needs a confirmatory diagnostic test. [1] [12] [14]

The discipline that ties all three together is the Wilson and Jungner principles of screening — the condition must be an important health problem, there must be an accepted treatment, facilities for diagnosis and treatment must be available, there must be a recognisable latent or early symptomatic stage, and there must be a suitable test — applied honestly, so that a screen does not become a diagnostic label and a diagnostic test does not become a screen. [12]