Neurogenetic conditions and precision diagnosis: SAQ

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 pattern of normal early development followed by regression, with a normal microarray, 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. The normal initial tests do not exclude a genetic cause, and the move from serial single-gene testing to tiered genomic testing is exactly how the diagnostic odyssey is ended for this family. [3][9]

Question 1 (10 marks)

Outline your diagnostic approach, the genomic test you would order next and why, how you would interpret a variant of uncertain significance, and what you would tell the parents about the chance of a diagnosis. [3]

I would begin with deep phenotyping, taking a three-generation pedigree with consanguinity and parental ages, characterising the seizure semiology and the movement disorder, coding the phenotype in Human Phenotype Ontology terms, and completing the phenotyping with a cerebrospinal fluid glucose and a creatine peak on magnetic resonance spectroscopy, because glucose transporter one deficiency and a creatine disorder are both treatable and both fit this picture. I would then 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. A normal microarray does not exclude a single-gene disorder, because the microarray detects copy-number variants and not the coding single-nucleotide variants that an exome reads. [3][11]

The diagnostic yield of trio exome in neurodevelopmental disorders is around thirty-six per cent, and it rises further when the result is periodically reanalysed, 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. I would set expectations that a variant of uncertain significance may be returned, that it is a statement of insufficient evidence rather than a soft diagnosis, and that it is managed by the phenotype and reanalysed, never reported as the cause of the disease. Every variant is read through the American College of Medical Genetics five-tier framework of pathogenic, likely pathogenic, uncertain significance, likely benign, and benign, and a diagnostic call requires the variant to match the clinical picture. [3][1]

Question 2 (10 marks)

Explain how a molecular diagnosis changes management, using the treatable neurogenetic conditions as examples, and outline your plan if the exome is negative. [9]

A molecular diagnosis changes management in two directions. It directs therapy toward a treatable cause, and in this child glucose transporter one deficiency is the leading treatable candidate, presenting with epilepsy and a paroxysmal movement disorder and responding to a ketogenic diet that supplies the brain with ketone bodies as an alternative fuel, supported by a low cerebrospinal fluid glucose. If the exome confirmed an SLC2A1 variant, I would start the ketogenic diet, stop the non-contributory anticonvulsant escalation, and counsel the family on the prognosis. Other treatable conditions that a molecular diagnosis can unlock include creatine transporter deficiency responding to creatine, dopa-responsive dystonia responding to levodopa, pyridoxine-dependent epilepsy responding to pyridoxine, and biotinidase deficiency responding to biotin, and the mutation-specific therapies for spinal muscular atrophy and Duchenne muscular dystrophy require a confirmed molecular diagnosis before they can be given. [11][9]

The second direction is the withdrawal of non-contributory testing and the redirection of care, because a confirmed diagnosis ends the diagnostic odyssey, enables accurate recurrence-risk and reproductive counselling, and links the family to a support network, a natural-history study, and a clinical trial. If the exome is negative, I would not discharge the child as undiagnosed. 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 a variant that is uninterpretable today 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. [9][3][7]