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Page 288 Kenneson et al. J Transl Genet Genom 2024;8:285-97 https://dx.doi.org/10.20517/jtgg.2024.22

defined as having a cardiac disorder if they reported cardiomyopathy, cardiac arrest, cardiac failure, or an
implantable device.

Fatigue
Fatigue was evaluated via the clinical survey (“Has the participant experienced excessive fatigue in the past
12 months?” or report of a diagnosis of chronic fatigue in the clinical history questions). Additionally, the
Patient-Reported Outcomes Measurement Information System Fatigue Short Form 8A (PROMIS-F SF-
8A) was used to assess fatigue more comprehensively. The questionnaire contains 8 items with a 5-point
[24]
Likert-rating scale (e.g., “Not at all,” “A little bit,” “Somewhat,” “Quite a bit,” “Very much”). Examples of
items include: “During the past 7 days, I have trouble starting things because I am tired,” “In the past 7 days,
to what degree did your fatigue interfere with your physical functioning?” A summative raw score was
computed for each participant and then converted into the corresponding T-score based on the PROMIS
[24]
scoring tables .

RESULTS
Clinical survey data were available for 115 BRR participants with BTHS, including 114 males and 1 female.
Characteristics of the study population are provided in Table 1. Ten males were deceased at the time of data
analysis: four from arrhythmia and/or heart failure, three from stroke, two from sepsis, and one from
electromechanical dissociation following transplant. Twenty of the participants indicated they were related
to another participant in the BRR. Twenty-five males in the BRR had had at least one heart transplant, with
two participants having received two heart transplants.

We analyzed the data regarding initial presenting manifestations. Four BRR participants reported that they
had no manifestations at diagnosis but were instead diagnosed due to the presence of another affected
individual in the family. Table 2 provides the presenting manifestations and age at first manifestation as
reported by 102 participants. The most commonly reported presenting manifestations were
cardiomyopathy/heart failure and feeding difficulty/weight loss/failure to thrive, reported by 57% and 25%
of BRR participants, respectively. Of those who reported cardiomyopathy/heart failure as a presenting
manifestation, 96% reported the onset of this clinical phenotype before one year of age. Overall, the initial
clinical manifestation occurred by one year of age in 89% of cases. Only 4 cases reported a first
manifestation onset at greater than 5 years of age: two with feeding difficulty/weight loss/failure to thrive
and two with low muscle tone.

Age at diagnosis was available for 100 participants [Table 3]. Ninety of these participants were the first
person in the family to be diagnosed (probands), while 10 were diagnosed after a positive family history.
Those with a family history were more likely to be diagnosed earlier. We also looked at the time to diagnosis
from first manifestation for 89 probands for whom we had complete data on age at first manifestation, age
at diagnosis and presenting manifestation. Time from first manifestation to diagnosis is presented according
to first manifestation [Table 4] and year of birth [Table 5].

Overall, the frequency of a reported history of the following conditions included cardiac disorder (80.7%),
GI disorders (68.7%), and neutropenia or frequent infections (67.2%). The most commonly reported GI
disorders were chronic constipation (n = 16), chronic diarrhea (n = 20), dysphagia (n = 7), feeding
difficulties (n = 51), and gastroesophageal reflux (GERD) (n = 25).

Of the 22 individuals with BTHS who reported no cardiac disorders, there was a mean age of 21.4 years (SD
= 15.8) at the most recent survey data entry. Two individuals were under the age of 6 months, with the rest