Germline whole genome sequencing in pediatric oncology in Denmark:Practitioner perspectives

Background: With the implementation of a research project providing whole genome sequencing (WGS) to all pediatric cancer patients in Denmark (2016–2019), we sought to investigate healthcare professionals' views on WGS as it was actively being implemented in pediatric oncology. Methods: Semistructured interviews were carried out with pediatric oncologists, clinical geneticists, and research coordinating nurses (N = 17), followed by content analysis of transcribed interviews. Interviews were supplemented by ethnographic observations on Danish pediatric oncology wards. Additionally, questionnaires were distributed to healthcare professionals concerning when they found it appropriate to approach families regarding WGS. The response rate was 74%. Results: Healthcare professionals see imbalances in doctor–patient relationship, especially the double role doctors have as clinicians and researchers. Some were concerned that it might not be possible to obtain meaningful informed consent from all families following diagnosis. Still, 94% of respondents found it acceptable to approach families during the first 4 weeks from the child's diagnosis. Views on the utility of WGS, treatment adaptation, and surveillance differed among interviewees. Conclusion: Overall, healthcare professionals see dilemmas arising from WGS in the pediatric oncology clinic, and some advocate for further educational sessions with families and healthcare professionals. Despite concerns, healthcare professionals overwhelmingly supported early approach of families regarding WGS. Interviewees disagree on the benefits of surveillance based on genetic findings

Size matters in telomere biology disorders ‒ expanding phenotypic spectrum in patients with long or short telomeres

Abstract The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment

The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification

Abstract Background Exon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novo SMARCA4 exon 14 deletion. Methods The SMARCA4 deletion was identified by whole genome sequencing, and the effect on the RNA level was examined by gel‐ and capillary electrophoresis and nanopore sequencing. Results The deletion was in silico predicted to be truncating, but RNA analysis revealed two major transcripts with deletion of exon 14 alone or exon 14 through 15, where the latter was located in‐frame. Because the patient's phenotype matched that of other patients with pathogenic germline variants in SMARCA4, the deletion was classified as likely pathogenic. Conclusion We propose to include RNA analysis in classification of single‐exon deletions, especially if located outside of known functional domains, as this can identify any disparate effects on the RNA and DNA level, which may have implications for variant classification using the American College of Medical Genetics and Genomics guidelines