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]