Paeds · genetics-dysmorphology-and-metabolism
Genomic testing, variant interpretation and counselling
Also known as Genomic medicine · Next-generation sequencing in paediatrics · ACMG/AMP variant classification · Secondary findings in genomic sequencing · Pre- and post-test genetic counselling
A fellowship approach to genomic testing in paediatrics: choose the right test from the hierarchy of karyotype, chromosomal microarray, gene panel, exome, and whole-genome sequencing; apply the ACMG/AMP five-tier variant classification framework to interpret results; manage variants of uncertain significance and secondary findings; and deliver pre- and post-test genetic counselling that equips families for diagnosis, uncertainty, and cascade testing — because the diagnostic yield of genome sequencing in rare paediatric disease now reaches 40 to 50 percent.
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Target exams
Red flags
- A child with unexplained global developmental delay, intellectual disability, or autism with dysmorphic features who has not had chromosomal microarray — the first-tier genomic test
- A critically ill infant in the NICU or PICU with a suspected genetic disorder and no diagnosis after 48 to 72 hours — consider rapid trio genome sequencing
- Multiple congenital anomalies in a newborn or child — chromosomal microarray and exome or genome sequencing are indicated
- A normal chromosomal microarray does not exclude a single-gene disorder — proceed to exome or genome sequencing if the phenotype fits
- A variant of uncertain significance (VUS) should never be used as the sole basis for clinical management decisions
- A pathogenic or likely pathogenic result obligates cascade testing of parents, siblings, and at-risk relatives
- A non-diagnostic exome should be re-analysed every 2 to 3 years as new genes are discovered and variant databases expand
Life stages
Care settings
Clinical exam formats
Board mappings
- Indications for chromosomal microarray and exome sequencing
- ACMG/AMP variant classification tiers
- Pre- and post-test genetic counselling
- Bayesian variant interpretation and evidence codes
- Secondary findings and the ACMG SF v3.0 gene list
- Rapid genomic sequencing in critically ill children and cascade testing
- Choosing the right genomic test for a child with developmental delay
- Counselling a family on a VUS or secondary finding
- Coordinating diagnostic and family testing
- Long case of a child undergoing genomic investigation
- Discussing a molecular diagnosis, secondary findings, and reproductive risk with parents
- Genomic medicine in paediatrics
- Communication of complex and uncertain results
- Ethics of genetic testing in children
- Genomic test hierarchy and diagnostic yield
- ACMG/AMP variant classification framework
- Secondary findings and consent
- Counselling a family on a genomic test result
- Discussing uncertainty and secondary findings
- Genomic testing in developmental disability
- Variant interpretation and classification
- Genetic counselling and family testing
- Genomic medicine
- Variant of uncertain significance management
- Ethics of genetic testing and counselling
- Genomic testing in rare paediatric disease
- ACMG/AMP variant classification
- Multidisciplinary care of the genetically diagnosed child
The fellowship mark goes to the candidate who thinks in three layers at once. The first layer is the test and its yield: what question is being asked, which test answers it, and what the diagnostic probability is before the sample is sent. The second is the variant and its classification: the ACMG/AMP framework that converts raw sequence data into a probabilistic call, and the distinction between a pathogenic finding that drives management and a VUS that does not. The third is the family: the consent conversation that precedes testing, the disclosure that follows, the cascade testing of relatives, and the re-analysis that keeps the result alive as knowledge grows. [1] [3]
Overview & Definition
Genomic testing in paediatrics encompasses the range of laboratory techniques used to identify genetic variation underlying congenital anomalies, developmental disorders, and inherited diseases. The hierarchy runs from the traditional karyotype, which detects large-scale chromosomal rearrangements visible under a microscope, through chromosomal microarray (CMA), which detects sub-microscopic copy-number variants (CNVs) at far higher resolution, to next-generation sequencing technologies — gene panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS) — that read the DNA letter by letter and can identify single-nucleotide variants, small insertions and deletions, and some structural rearrangements. [2] [9]
The clinical application of these technologies depends on a structured variant interpretation process that converts millions of sequence differences into a small number of clinically actionable calls. The American College of Medical Genetics and Genomics and the Association for Molecular Pathology published the consensus standards for this process in 2015, establishing a five-tier classification framework — pathogenic, likely pathogenic, variant of uncertain significance, likely benign, and benign — that every clinical genomics laboratory now applies. This framework, combined with structured pre- and post-test genetic counselling, defines the modern practice of genomic medicine in paediatrics. [1] [10]
References10ShowHide
- [1]Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 2015.PMID 25741868
- [2]Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet, 2010.PMID 20466091
- [3]Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med, 2013.PMID 23788249
- [4]Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med, 2017.PMID 27854360
- [5]Miller DT, Lee K, Chung WK, et al. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med, 2021.PMID 34012068
- [6]Smedley D, Smith KR, Martin A, et al. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report. N Engl J Med, 2021.PMID 34758253
- [7]Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill newborns: a retrospective analysis of diagnostic and clinical trajectories. Lancet Respir Med, 2015.PMID 25937001
- [8]Jansen S, Vissers LELM, de Vries BBA The Genetics of Intellectual Disability. Brain Sci, 2023.PMID 36831774
- [9]Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med, 2021.PMID 34211152
- [10]Tavtigian SV, Harrison SM, Boucher KM, et al. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat, 2020.PMID 32720330