Case Presentation
The patient is the second child of healthy nonconsanguineous parents of
mixed Belgian, Hungarian, English, and Scottish descent. The patient was
born at 37.5 weeks by induction due to maternal migraines following an
uncomplicated pregnancy. She had some mild respiratory distress at birth
which quickly improved. Her birth weight was 3.03 kg
(54th percentile). As an infant, she had feeding
difficulties with ineffective latching but gained weight appropriately
with bottle feeding. There is a history of torticollis at 4 months of
age.
She met motor milestones until 9 months of age, after which time
significant motor delays were observed. She walked at the age of 18
months with a crouched stance. Currently, at 16 years of age, she can
walk independently for short distances, with an unusual gait and a
kyphotic stance; she requires constant supervision. Her fine motor
skills never progressed beyond childhood and are limited. She had a few
words which she then lost, and she remains nonverbal. As an infant she
had startle behaviours, which were spasm-like; however, the
electroencephalograms (EEGs) did not suggest infantile spasms. At the
age of 6, she began to have absence episodes and partial and generalized
tonic-clonic seizures, which have continued since. Her epilepsy has been
classified as treatment resistant, due to failure of several
antiepileptic agents and she is currently controlled with a vagal nerve
stimulator. The patient was also diagnosed with celiac disease at 7
years of age due to persistent diarrhea leading to hypernatremia and
hospitalizations, and clinical response to a gluten-free diet (no biopsy
performed).
Genetic testing between 4 and 10 years of age was normal, including
chromosomal microarray analysis, Angelman, Rett syndrome testing,
comprehensive epilepsy panel and Mitochondrial DNA testing.
Subsequently, a clinical trio WES was arranged which did not identify
causative variants in genes to explain the patient’s presentation;
however, a paternal secondary finding of a pathogenic variant in theBRCA2 gene (c.475+1G>T) was identified. Three years
later, exome data reanalysis was offered to the patient’s family to help
provide a genetic diagnosis, given the rapid accrual of knowledge in
genomic medicine with new genes available for analysis. The exome
reanalysis identified biallelic variants (one on each copy) in a
candidate gene NHLRC2 . One of the variants was reported as
pathogenic (c.1750delC) and was inherited from her mother. The other
variant was reported as a variant of uncertain significance (c.2074
G>T) and was inherited from her father. The reanalysis of
the exome sequencing confirmed the previously identified BRCA2pathogenic variant and found a new pathogenic variant in theBRCA1 gene (c.5096G>A), which was again inherited
from the patient’s father. This c.5096G>A BRCA1variant was initially classified as a variant of uncertain significance
(5). However, in 2018, an analysis of a large cohort of 129 families,
using several analytical approaches, confirmed that
c.5096G>A BRCA1 variant is associated with
intermediate cancer risks (compared with the average BRCA1truncating variant) and thus was identified in our probands WES
reanalysis. Interestingly, this variant was found to have a lower
associated cancer risk (20% for risk for breast cancer and 6% for
ovarian cancer by age 70 for a female) than typical BRCA1pathogenic variants (5).
On family history, paternal grandmother had breast cancer in her 40s.
Maternal grandmother had colon cancer at age 64. There is no family
history of other malignancy. The patient’s mother has migraines. Her
father and paternal grandmother have Crohn’s disease. There are no
individuals with seizures, intellectual disability, or other
neurological issues in the family.
Gynecology consult was undertaken to review the genetics and other
clinical challenges. This initially focused on the patient’s
functionality, menstrual and hygiene challenges with her developmental
delay, with further discussions to focus on response to therapeutic
options in the patient and family context (6). One of the significant
challenges with decision-making for the family will be morbidity and
life expectancy with respect to surgery versus more conservative or
medical options.