Introduction
Germline pathogenic variants in breast cancer susceptibility genes 1 and2 (BRCA1 and BRCA2 ) are associated with hereditary breast and ovarian cancer syndrome (HBOC). Mutations in these genes significantly increase the risk for female and male breast cancers, ovarian cancer, and to a lesser extent, prostate cancer, pancreatic cancer, and melanoma (the cancer risk varies based on the gene affected) (1,2). Given these risks (along with poor prognosis in the event of a cancer diagnosis), cancer risk management is a priority in individuals with identified pathogenic variants. Breast cancer screening in women with BRCA1/2 pathogenic variants relies on annual clinical breast examination, mammography and breast MRI starting at 30 years of age. Bilateral prophylactic mastectomy is offered as an option to patients, as it decreases breast cancer incidence by 90% or more in patients with a BRCA1/2 mutation (1). Unfortunately, no screening test or algorithm has been shown to reduce mortality with ovarian cancer; serial transvaginal ultrasound and serum cancer antigen 125 (CA-125) have been proposed (2). In the absence of an effective screening program, the option of bilateral salpingo-oophorectomy offers the greatest risk reduction against developing ovarian cancer in women at high risk: the procedure has been shown to reduce the lifetime risk of ovarian cancer by about 80% (3).
The co-presence of mutations in both BRCA1 and BRCA2 genes (double heterozygous (DH)) is a rare event. Patients with DH mutations should be managed similar to BRCA1 mutation carriers rather thanBRCA2 mutation carriers due to factors such as lower age of diagnosis of breast and ovarian cancer with BRCA1 mutations (4). However, the available literature on patients presenting with DH mutations is sparse, and all pertains to adult cases.
We present a 15-year-old female with drug-resistant epilepsy, nonverbal intellectual disability whose initial genetic workup was nondiagnostic. The family consented to whole-exome sequencing (WES), including medically actionable secondary findings. The first exome analysis identified a secondary finding of a paternally inherited pathogenicBRCA2 variant. Exome reanalysis two years later showed biallelic variants of uncertain significance in a candidate gene as a potential explanation to her neurodevelopmental issues, NHL repeat-containing 2 (NHLRC2 ), and a novel secondary finding, a pathogenic BRCA1 variant, also paternal in origin.
This rare case highlights the management and approach to medically actionable secondary findings of WES in pediatric and adolescent patients. Furthermore, it expands on the implication of the commonality of WES’s incidental findings and if reanalysis of exome sequencing years down the line increases diagnostic yield.