Abstract
The benefit of reporting unsolicited findings in Next Generation Sequencing (NGS) related to cancer genes in children may have implications for family members, nevertheless, could also cause distress. We aimed to retrospectively investigate germline variants in 94 genes implicated in oncogenesis, in patients referred to NGS testing for various rare genetic diseases and reevaluate the utility of reporting different classes of pathogenicity. We used in silico prediction software to classify variants and conducted manual review to examine unsolicited findings frequencies in 145 children with rare diseases, that underwent sequencing - using a 4813 gene panel. The anonymized reanalysis revealed 18250 variants, of which 126 were considered after filtering. Six pathogenic variants (in BRCA1,BMPR1A,FANCA,FANCC,NBN genes) with cancer related phenotype and three unsolicited variants (in BRCA2,PALB2,RAD50 genes) were reported to patients. Additionally, three unsolicited variants in ATR, BLM (in two individuals), and FANCB genes presented potential cancer susceptibility, were not reported to patients. In retrospect, 4.8% (7/145) of individuals in our cohort had unsolicited NGS findings related to cancer. More efforts are needed to create an updatable consensus in reporting variants in cancer predisposing genes, especially for children. Consent process is crucial to inform of both value and risk of additional genetic information.
Highlights
Www.nature.com/scientificreports guideline for diagnostic Next Generation Sequencing (NGS) in 2016 stated that laboratories should have a clearly defined protocol for addressing unsolicited and secondary findings[6]
We aimed to retrospectively investigate germline variants in 94 genes, causally implicated in oncogenesis, in patients referred for NGS testing for various rare genetic diseases, reevaluate them, and discuss the utility of reporting different classes of pathogenicity to the referring physician, families and patients
Six variants came from 5 individuals that had a cancer related syndrome as indication for analysis. These were: compound heterozygous variants in BRCA1 gene, identified as disease causing for Anemia Fanconi like syndrome; homozygous variant in NBN gene, was disease-causing for Nijmegen Syndrome; homozygous variant in FANCC gene, was disease-causing for Fanconi Anemia group C; homozygous variant in FANCA, was disease-causing for Fanconi Anemia group A and heterozygous variant in BMPR1A gene was disease-causing for Juvenile polyposis syndrome
Summary
Www.nature.com/scientificreports guideline for diagnostic NGS in 2016 stated that laboratories should have a clearly defined protocol for addressing unsolicited and secondary findings[6]. Interpretation of the ACMG recommendation vary between different laboratories in United States[7,8], while in Europe there is similar lack of consistency[5]. The disadvantage of a published minimum list is that it needs constant update, considering that cancer is one of the fields of medicine with the fastest development[11]. In this context, we aimed to retrospectively investigate germline variants in 94 genes, causally implicated in oncogenesis, in patients referred for NGS testing for various rare genetic diseases, reevaluate them, and discuss the utility of reporting different classes of pathogenicity to the referring physician, families and patients
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