Neurogenetic conditions and precision diagnosis

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Target exams

Red flags

• A child with unexplained global developmental delay, intellectual disability, regression, or early-onset drug-resistant epilepsy should be offered chromosomal microarray and exome or genome sequencing early, not after years of negative single-gene tests; exome reaches a diagnostic yield of around thirty-six per cent in neurodevelopmental disorders
• A molecular diagnosis that predicts a treatable condition is a treatment trigger, not merely a label: glucose transporter one deficiency responds to the ketogenic diet, creatine transporter deficiency to creatine, dopa-responsive dystonia to levodopa, and biotinidase deficiency to biotin
• A negative exome is never the end of the investigation: trio sequencing, periodic reanalysis as knowledge grows, and genome sequencing each recover additional diagnoses over the following years
• Do not over-interpret a variant of uncertain significance as pathogenic; manage the child by their phenotype and reanalyse the variant over time
• Sporadic severe neurodevelopmental disease in a child of unaffected parents is overwhelmingly driven by a de novo dominant variant, which only trio sequencing captures
• In the acutely ill infant with an unexplained encephalopathy or refractory seizures, rapid whole-genome sequencing returns a diagnosis within days and changes acute management, including the start of treatable-condition therapy and the withdrawal of invasive testing

Life stages

Care settings

Clinical exam formats

Board mappings

• Recognises that chromosomal microarray followed by exome or genome sequencing is the first-tier investigation for a child with unexplained developmental delay, intellectual disability, regression, or early-onset drug-resistant epilepsy, replacing serial single-gene testing
• States that exome sequencing reaches a diagnostic yield of around thirty-six per cent in neurodevelopmental disorders, that trio sequencing of the proband and both parents is superior to proband-only testing because it captures de novo dominant variants, and that a negative test is followed by periodic reanalysis
• Identifies the treatable neurogenetic conditions unlocked by a molecular diagnosis, including glucose transporter one deficiency treated with the ketogenic diet, biotinidase deficiency with biotin, and dopa-responsive dystonia with levodopa
• Applies the American College of Medical Genetics five-tier variant classification framework of pathogenic, likely pathogenic, uncertain significance, likely benign, and benign, and explains how a variant of uncertain significance is managed by the phenotype rather than over-interpreted as causal
• Selects between chromosomal microarray, exome, genome, and rapid whole-genome sequencing using the phenotype, acuity, and prior testing, and justifies rapid whole-genome sequencing in the acutely ill infant where a diagnosis within days changes management
• Coordinates deep phenotyping, trio genomic testing, variant interpretation, return of results with genetic counselling, periodic reanalysis, reproductive counselling, and enrolment in gene-specific trials and natural-history studies
• The tiered testing ladder of chromosomal microarray at around fifteen to twenty per cent yield, then trio exome at around thirty-six per cent, then genome sequencing, and the principle that reanalysis recovers additional diagnoses over time
• The American College of Medical Genetics five-tier variant classification and the correct management of a variant of uncertain significance, and the dominance of de novo change in sporadic severe neurodevelopmental disease
• The treatable neurogenetic conditions and their targeted therapies, and the role of rapid whole-genome sequencing in the acutely ill infant
• Takes a three-generation pedigree with consanguinity and parental ages, performs deep phenotyping with dysmorphology and Human Phenotype Ontology coding, and selects the correct tier of genomic test
• Counsels the family on the yield, the chance of an uncertain result, the possibility of an incidental secondary finding, recurrence risk, and the option of reanalysis, and returns results with a clinical geneticist
• Translates the molecular diagnosis into management by starting treatable-condition therapy, stopping non-contributory invasive testing, arranging reproductive counselling, and linking the family to support networks and trials
• Level 1: Recognition that unexplained developmental delay or early-onset epilepsy warrants early chromosomal microarray and exome or genome sequencing rather than prolonged single-gene testing
• Level 2: Application of trio sequencing, the American College of Medical Genetics variant classification framework, and the management of a variant of uncertain significance, with an awareness of the treatable conditions
• Level 3: Coordination of rapid whole-genome sequencing in the acutely ill infant, periodic reanalysis, genetic counselling, reproductive planning, and gene-specific therapy and trial enrolment
• Chromosomal microarray as first-tier testing for copy-number variants with a yield of around fifteen to twenty per cent, and exome as first-tier for neurodevelopmental disorders with a yield of around thirty-six per cent
• The American College of Medical Genetics five-tier variant classification, the meaning and management of a variant of uncertain significance, and the importance of de novo dominant variants in sporadic disease
• The treatable neurogenetic conditions including glucose transporter one deficiency and the ketogenic diet, creatine transporter deficiency and creatine, pyridoxine-dependent epilepsy, and biotinidase deficiency
• Structured assessment of a child with an undiagnosed neurodevelopmental disorder including pedigree, deep phenotyping, and the selection and interpretation of genomic testing
• Communication of an uncertain or complex genomic result to a family, including a variant of uncertain significance and an incidental finding, with honesty about uncertainty and a plan for reanalysis
• Recognition of the treatable conditions unlocked by a molecular diagnosis and the integration of genetics, neurology, metabolism, and counselling services
• United States practice of chromosomal microarray and exome or genome sequencing as first-tier testing for paediatric neurodevelopmental disorders, with rapid whole-genome sequencing established in the neonatal and paediatric intensive care unit
• The American College of Medical Genetics variant classification framework and the recommended secondary findings list, and the management of a variant of uncertain significance
• The treatable neurogenetic conditions and the gene-modifying therapies for spinal muscular atrophy and Duchenne muscular dystrophy that depend on a confirmed molecular diagnosis
• Recognition that early tiered genomic testing ends the diagnostic odyssey in paediatric neurogenetic disease and that a molecular diagnosis changes management by enabling targeted therapy and genetic counselling
• Selection of chromosomal microarray, exome, genome, and rapid whole-genome sequencing using phenotype and acuity, with trio sequencing to capture de novo change
• Multidisciplinary coordination of phenotyping, variant interpretation, counselling, reanalysis, reproductive planning, and enrolment in gene-specific therapy and natural-history studies
• Canadian practice of tiered genomic testing and the Care4Rare and rare-disease strategy frameworks, with rapid whole-genome sequencing in the acutely ill child
• The American College of Medical Genetics variant classification, the management of a variant of uncertain significance, and the treatable conditions unlocked by precision diagnosis
• Coordination of clinical genetics, neurology, metabolism, and counselling, with attention to equitable access for remote and indigenous communities and reanalysis over time