Discussion
Reanalysis of WES can increase the molecular diagnostic yield up to 10-20% due to factors such as newly discovered disease genes and upgraded variant classifications of disease genes (7,8). Reanalysis of the patient’s WES identified biallelic variants in a candidate geneNHLRC2 . Variants in this gene have only been reported in association with a severe condition characterized by fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA)(9). Although WES reanalysis has not yet resulted in a confirmed diagnosis or change in the patient’s neurological management, it has provided an additional yet unrelated risk factor and revealed a potential candidate gene that could be researched further. Thus, exome reanalysis, one of the first steps in undiagnosed rare genetic diseases, can change clinical management due to new findings and ultimately benefit patients and their families. A caveat to consider is that reanalysis can increase the probability of incidental/secondary results; therefore, careful pre-test counselling remains essential.
In the present case, the secondary findings of the BRCA1 andBRCA2 pathogenic variants have important implications for the patient and their immediate family members. For the proband, regular and lifetime surveillance with imaging could pose a challenge due to her intellectual disability; thus, risk-reductive interventions, such as prophylactic bilateral mastectomy and salpingo-oophorectomy, could offer the best protection against developing cancer. Historical data demonstrates that DH individuals had an approximately 10-year earlier onset of first cancer compared to single heterozygous females (4).
Given our patient’s severe intellectual disability and complete dependence for activities of daily living, there is no prospect of independent life or starting a family. Her family therefore wondered about earlier than typical prophylactic surgical interventions. However, the risks and potential complications of these invasive surgeries, such as pain, infection, and more importantly long term effects including premature menopause, increased risks of osteoporosis, and cardiovascular disease ultimately affecting the quality of life, outweigh the minimal difference in cancer prevention (10,11). Counselling on earlier interventions by referral to a gynecologist has been critical in managing the family’s expectations focusing on balancing current needs of the patients versus future expectations. The family have therefore agreed to forego any prophylactic surgical interventions until later in life with proper counselling.
Currently, the treatment plan focuses on the patient’s quality of life, specifically managing the hormonal impact on her seizures. Focusing on menstrual history, the patient has regular menstrual cycles however, at times experiences vomiting, which has led to increases in seizure activity compared to perimenstrual baseline. Notably, combined hormonal contraceptive use is well established as a risk reduction method (estimated 40 to 50%) for ovarian cancer, including BRCA1/2carriers (2). Although, there is no associated risk increase or reduction in breast cancer in BRCA1/2 carriers using combined hormonal contraceptives (2). Thus, the patient was initially trialed on a combined hormonal contraceptive and later progestin-only pills, but due to side effects such as agitation and breast growth, the contraceptives were discontinued. As a result, a monthly leuprorelin injection, a gonadotropin-releasing hormone (GnRH) analogue, is being trialed. Additionally, the patient’s mother charts her behaviors, mood, and seizures around her menses to determine if this is a viable option.
The secondary findings also prompted the cascade testing of at-risk relatives who may have the familial pathogenic variant and require increased surveillance and early interventions. Several family members are currently pursuing genetic counselling and BRCA1 andBRCA2 variant testing to determine their carrier status.