Validation of the BOADICEA model for predicting the likelihood of carrying pathogenic variants in eight breast and ovarian cancer susceptibility genes.

BOADICEA is a comprehensive risk prediction model for breast and/or ovarian cancer (BC/OC) and for carrying pathogenic variants (PVs) in cancer susceptibility genes. In addition to BRCA1 and BRCA2, BOADICEA version 6 includes PALB2, CHEK2, ATM, BARD1, RAD51C and RAD51D. To validate its predictions for these genes, we conducted a retrospective study including 2033 individuals counselled at clinical genetics departments in Denmark. All counselees underwent comprehensive genetic testing by next generation sequencing on suspicion of hereditary susceptibility to BC/OC. Likelihoods of PVs were predicted from information about diagnosis, family history and tumour pathology. Calibration was examined using the observed-to-expected ratio (O/E) and discrimination using the area under the receiver operating characteristics curve (AUC). The O/E was 1.11 (95% CI 0.97-1.26) for all genes combined. At sub-categories of predicted likelihood, the model performed well with limited misestimation at the extremes of predicted likelihood. Discrimination was acceptable with an AUC of 0.70 (95% CI 0.66-0.74), although discrimination was better for BRCA1 and BRCA2 than for the other genes in the model. This suggests that BOADICEA remains a valid decision-making aid for determining which individuals to offer comprehensive genetic testing for hereditary susceptibility to BC/OC despite suboptimal calibration for individual genes in this population.

Germline pathogenic variants associated with ovarian cancer: A historical overview.

The risk of ovarian, tubal, and peritoneal cancer is related to germline pathogenic variants, and over time, the number of known disease-associated genes has increased significantly. This study reviews the literature regarding the topic from a historical perspective. The aim is to present a timeline of the knowledge gained from the early 1900s until today. The findings are put into perspective by looking at the current gene panel used for screening for suspected hereditary ovarian cancer in Denmark compared to what is known internationally. In 1929, the first familial ovarian cancer incidents were registered, and in 1950, the involvement of a genetic component was suggested for the first time. During the 1970s, several studies reported an accumulation of ovarian cancer in certain families, and during this time, it was discovered that ovarian cancer was linked to both breast cancer and colorectal cancer. The inheritance of cancer disposition has been thoroughly investigated, leading to the discovery of the BRCA genes in the 1990s. Furthermore, new studies based on new genetic technologies have revealed several genes with germline pathogenic variants that increase the risk of ovarian cancer. The identification of these pathogenic variants has led to preventive measures and specific treatment of women with genetic disposition to ovarian cancer. In Denmark, consensus is to include at least ten genes in the screening panel for hereditary ovarian cancer, and in the future additional genes will probably be added.

Two maternal duplications involving the CDKN1C gene are associated with contrasting growth phenotypes.

BACKGROUND: The overgrowth-associated Beckwith-Wiedemann syndrome (BWS) and the undergrowth-associated Silver-Russell syndrome (SRS) are characterized by heterogeneous molecular defects affecting a large imprinted gene cluster at chromosome 11p15.5-p15.4. While maternal and paternal duplications of the entire cluster consistently result in SRS and BWS, respectively, the phenotypes associated with smaller duplications are difficult to predict due to the complexity of imprinting regulation. Here, we describe two cases with novel inherited partial duplications of the centromeric domain on chromosome 11p15 associated with contrasting growth phenotypes. FINDINGS: In a male patient affected by intrauterine growth restriction and postnatal short stature, we identified an in cis maternally inherited duplication of 0.88 Mb including the CDKN1C gene that was significantly up-regulated. The duplication did not include the long non-coding RNA KCNQ1OT1 nor the imprinting control region of the centromeric domain (KCNQ1OT1:TSS-DMR or ICR2) in which methylation was normal. In the mother, also referring a growth restriction phenotype in her infancy, the duplication was de novo and present on her paternal chromosome. A different in cis maternal duplication, 1.13 Mb long and including the abovementioned duplication, was observed in a child affected by Tetralogy of Fallot but with normal growth. In this case, the rearrangement also included most of the KCNQ1OT1 gene and resulted in ICR2 loss of methylation (LOM). In this second family, the mother carried the duplication on her paternal chromosome and showed a normal growth phenotype as well. CONCLUSIONS: We report two novel in cis microduplications encompassing part of the centromeric domain of the 11p15.5-p15.4 imprinted gene cluster and both including the growth inhibitor CDKN1C gene. Likely, as a consequence of the differential involvement of the regulatory KCNQ1OT1 RNA and ICR2, the smaller duplication is associated with growth restriction on both maternal and paternal transmissions, while the larger duplication, although it includes the smaller one, does not result in any growth anomaly. Our study provides further insights into the phenotypes associated with imprinted gene alterations and highlights the importance of carefully evaluating the affected genes and regulatory elements for accurate genetic counselling of the 11p15 chromosomal rearrangements.

[Fragile X chromosomes and fragile X syndrome]. / Fragilt X-kromosom og fragilt X-syndrom.

A case story is presented of a child diagnosed by chromosome analysis to be carrier of the fragile X chromosome at a low frequency in cultured lymphocytes. DNA analysis of the FMR1 gene at a later date did not reveal expansion of the FMR1 repeat, thereby refuting the diagnosis of fragile X syndrome. The discrepancy was discovered only when years later other family members came for counselling due to subsequent development of DNA-based analyses. It is recommended that persons and families investigated before DNA methods were used are re-evaluated and re-examined when relevant. Genetic diagnoses need regular revision, and information to families is important.