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.