Paediatric Genomics —
Training activity: 9

Details

Interpret and report copy number variants, to include:

• Array abnormalities
• Karyotype abnormalities

Type

Developmental training activity (DTA)

Evidence requirements

Evidence the activity has been undertaken by the trainee​.

Reflection on the activity at one or more time points after the event including learning from the activity and/or areas of the trainees practice for development.

An action plan to implement learning and/or to address skills or knowledge gaps identified.

Considerations

• Local and national guidance
• The range of tools/resources available to perform variant analysis
• Use and application of evidence
• Recommendations for further evidence required to reclassify variants, particularly those of uncertain significance
• Role of the multidisciplinary team and its utility in classifying/reporting variants
• Nomenclature
• Possible segregation analysis
• Familial studies
• Reflex testing

Reflective practice guidance

The guidance below is provided to support reflection at different time points, providing you with questions to aid you to reflect for this training activity. They are provided for guidance and should not be considered as a mandatory checklist. Trainees should not be expected to provide answers to each of the guidance questions listed.

Before action

• What essential knowledge do you need before interpreting array and karyotype abnormalities? Consider the principles of array-based comparative genomic hybridization (aCGH) and karyotyping, the different types of CNVs (deletions, duplications, etc.), and the nomenclature used to describe these abnormalities.
• What do you anticipate learning from interpreting and reporting these CNVs? Think about the skills you hope to develop in assessing the clinical significance of CNVs, correlating cytogenetic and molecular findings, and writing clear and informative reports.
• What preparatory actions will you take for this experience? Will you review examples of array and karyotype reports?
• What potential difficulties might you encounter when interpreting and reporting CNVs? Consider challenges such as determining the pathogenicity of novel CNVs, interpreting variants of uncertain significance (VUS), or dealing with incidental findings. How do you plan to address these difficulties?

In action

• What is your current approach to interpreting copy number variant (CNV) data obtained from array-based comparative genomic hybridization (aCGH) or single nucleotide polymorphism (SNP) arrays and/or conventional karyotyping.
• What specific features are you focusing on (e.g., gains, losses, size, location, number of chromosomes involved)? Why are these features important?
• What decisions are you making as you assess the clinical significance of any identified CNVs?
• How are you considering factors such as gene content, inheritance, and presence in databases of known pathogenic or benign variants?
• How effectively are you able to identify and characterise the CNVs present in the array and/or karyotype data? Are you able to accurately determine their size, location, and potential impact?
• What challenges are you facing in this moment, such as interpreting variants of uncertain significance (VUS), or identifying potentially clinically relevant mosaicism?
• What insights are you gaining into the resolution and limitations of array and karyotyping technologies based on the specific cases you are reviewing? Are there instances where one technology provides more information than the other?
• If you encounter a CNV with unclear clinical significance, what immediate steps could you take to investigate it further?
• Do you need to discuss the interpretation of a complex case with a clinical geneticist or a more experienced colleague to ensure accurate assessment and reporting?
• Are you ensuring that your interpretation and any potential reporting of CNVs adhere to relevant professional guidelines and best practices for nomenclature and clinical interpretation?

On action

• Describe the range of copy number variants (CNVs) you interpreted.
  •  What types of abnormalities did you observe in the array data ?
  • What types of abnormalities were visible in the karyotypes (e.g., trisomies, monosomies, structural rearrangements)?
• What specific skills or knowledge did you develop regarding assessing CNV clinical significance (using size, gene content, and databases) and understanding the resolution and limitations of arrays compared to karyotyping?
  • What unexpected challenges or complex findings (e.g., VUS or rearrangements) did you encounter, and how did your real-time decision-making or data re-evaluation influence your final conclusions?
  • How has this experience deepened your understanding of the clinical importance of accurate CNV interpretation for the diagnosis and management of paediatric genetic disorders?
• What specific next steps will you take to advance your expertise in CNV interpretation, such as attending specialised workshops or reviewing literature on genotype-phenotype correlations?
  • What support or resources have you identified as beneficial for your development, such as up-to-date interpretation guidelines or collaborative opportunities with other laboratories?
  • How will you apply these learning actions to ensure your future handling of complex CNV cases remains current and aligned with best practice?

Beyond action

• Have you revisited the experiences of interpreting and reporting copy number variants (CNVs) from array and karyotype data?
• Evaluate how your ability to assess the clinical significance of CNVs has developed since this training activity.
• Are you now more proficient in using online databases and following best practice guidelines for variant interpretation?
• Compare this experience with other training activities involving the integration of diverse genomic data; what practices or behaviours have you assimilated into your routine work from these cross-modality activities?
• Review your reflections on multiple training activities involving data interpretation. Have you identified any consistent challenges you faced or strategies you found particularly helpful in reaching accurate conclusions?
• Discuss challenging CNV cases with clinical geneticists or senior colleagues. Has their input broadened your understanding of genotype-phenotype correlations and the clinical implications of different CNVs?
• Consider how your initial experiences with CNV interpretation have influenced your approach to analysing more complex genomic datasets, such as whole genome sequencing data. Are you now more attuned to identifying structural variants?
• How have you applied your skills in CNV interpretation in subsequent reporting or participation in multidisciplinary team meetings? Have you been able to contribute effectively to discussions about the clinical significance of CNVs?
• Can you now articulate the strengths and limitations of different cytogenetic techniques and explain the process of CNV interpretation?
• Identify future areas for development, such as specialising in the interpretation of specific types of structural variants or staying updated on new databases and algorithms for CNV analysis.

Relevant learning outcomes

#	Outcome
# 1	Outcome Apply appropriate testing strategies to patients referred for paediatric disorders.
# 3	Outcome Perform whole genome analysis for patients referred for paediatric disorders.
# 4	Outcome Interpret genomic variants, including copy number changes, and investigate the clinical significance of variants using bioinformatic tools using best practice guidelines.
# 5	Outcome Interpret and report genomic testing relevant to paediatric conditions, including appropriate recommendations for patient management.