Neurogenetic conditions and precision diagnosis: Case

Case discussion

Why a normal microarray does not end the investigation

This girl has an unexplained neurodegenerative or metabolic process with regression, drug-resistant epilepsy, and a movement disorder after a period of normal development. The clinical lesson is that a normal chromosomal microarray does not exclude a genetic cause, because the microarray detects copy-number variants and not the single-nucleotide variants and small insertions or deletions that an exome reads. 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. The pattern of normal early development followed by regression, in a child of unaffected parents, is the classic indication for trio exome or genome sequencing, because a de novo variant is the likely mechanism and only trio testing captures it. [9][3]

Deep phenotyping before the genome is read

Before the test is ordered I would complete the phenotyping, because the phenotype raises the yield of every genome read and may itself reveal a treatable diagnosis. I would characterise the seizure semiology and the movement disorder, code the phenotype in Human Phenotype Ontology terms, and run targeted investigations including a cerebrospinal fluid glucose to test for glucose transporter one deficiency and a creatine peak on magnetic resonance spectroscopy to test for a creatine disorder, because both are treatable and both fit this picture. Glucose transporter one deficiency presents with epilepsy and a paroxysmal movement disorder and responds to a ketogenic diet, and a low cerebrospinal fluid glucose would make it the working diagnosis even before the genome returns. [11]

The test to order, and why a trio

I would order a trio exome, sequencing the proband and both parents together, because the regression after normal development in a child of unaffected parents points to a de novo dominant variant, and trio design is what distinguishes 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 rises with a trio and with periodic reanalysis, so I would tell the parents that there is a roughly one-in-three chance of an answer from the first test and a real chance of an answer over the following years even if the first read is negative. [3]

Interpreting the result and the variant of uncertain significance

Every variant is read through the American College of Medical Genetics five-tier framework of pathogenic, likely pathogenic, uncertain significance, likely benign, and benign, using population frequency, computational prediction, segregation, and functional evidence. If the laboratory returns a variant of uncertain significance, I would manage the child by the phenotype, segregate the variant through the family where possible, and reanalyse it as evidence accrues, and I would never report it to the family as the cause of the disease. Over-calling a variant of uncertain significance as pathogenic produces a wrong label, wrong recurrence counselling, and wrong therapy, and it is the single most common source of error in genomic medicine. [1]

Acting on the diagnosis and the plan if it is negative

If the exome confirms an SLC2A1 variant consistent with glucose transporter one deficiency, I would start the ketogenic diet, stop the non-contributory anticonvulsant escalation, counsel the family on the prognosis and recurrence risk, and link them to a support network. A molecular diagnosis changes management in two directions: it directs therapy toward a treatable cause, and it withdraws non-contributory testing and enables accurate reproductive counselling. If the exome is negative, I would move to genome sequencing, which captures the non-coding and structural change and the repeat expansions that the exome misses, and I would arrange periodic reanalysis of the data, because new gene-disease associations are published continuously and an uninterpretable variant may be reclassified within one to two years. I would give the family a clear plan with scheduled review, so that the door to a diagnosis stays open. [11][9][3]