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Kenneson et al. J Transl Genet Genom 2024;8:285-97 https://dx.doi.org/10.20517/jtgg.2024.22 Page 293

likely to be entered into the registry. This is supported by the observation that a smaller percentage of
patients diagnosed in the earlier time period had cardiac manifestation as their first manifestation compared
to those born and diagnosed in the later decades. Since it is possible that milder cases may be more difficult
to recognize and therefore take longer to diagnose, this may skew the results for the earlier time periods
toward longer diagnostic odysseys. In addition, births in 2010-2019 may include children who have not yet
been diagnosed, which may skew results for this time period toward shorter diagnostic odysseys. Thus,
more studies are needed to assess whether or not the diagnostic journey has shortened over the years.

BTHS is not currently included in newborn screening tests, despite data demonstrating that early BTHS
diagnosis is critical for favorable prognosis as mortality is especially high during infancy . Newborn
[26]
screening in the United States is guided by the principles defined by Wilson and Jungner in 1968, which
[27]
includes an acceptable screening test and consensus on how to treat patients with the disorder . For
newborn screening to be conducted ethically without rigorous informed consent of the parents, it is
necessary that the test and consequent follow-up offer clinical benefit to the child . However, in the past
[28]
few decades, there has been increasing interest in population-based screening for disorders that do not meet
the classic criteria, with emphasis on benefits beyond those to the child, such as avoidance of the diagnostic
odyssey, provision of reproductive information to the family, and opportunities to study the impact of early
treatment [28,29] . It has been suggested that screening for disorders that do not meet the classic criteria be
conducted after the newborn period and with explicit informed consent from the parents in a second tier of
[30]
screening , and this approach is currently being piloted in a research setting . As new technology and
[28]
methods emerge with the potential for early detection of BTHS, adding BTHS to newborn screening panels
should be considered.

Clinical manifestations
The prevalence of cardiomyopathy in individuals with BTHS has been reported to be about 90%-95% [16,31,32] .
In the present study, however, the frequency of individuals with BTHS who had a documented cardiac
disorder was 80.7%. Three of the individuals in our analysis who did not have a cardiac disorder reported
that they were genetically diagnosed after another family member was diagnosed with BTHS and two of the
individuals were less than six months old. When these five individuals were excluded, the frequency of
cardiac disorders increased to 84.5%, which is still lower than previous reports. Likewise, the frequency of
neutropenia/frequent infections in our study (67.2%) is less than previous reports of 84%-86% [17,31] . Steward
et al. analyzed data from individuals who were diagnosed clinically, while Rigaud et al. included individuals
who were diagnosed through family-based testing, as in our BRR data [17,31] . The studies by Rigaud et al. and
Kang et al., however, included clinical assessment of individuals, while our study is based on self-report [31,25] .
Lack of clinical assessment, inclusion of individuals diagnosed through family screening, and biases in self-
reported data may explain the lower frequency of these manifestations in our analysis.

Because cardiomyopathy is a predominant clinical feature of BTHS, with >70% of affected individuals
reporting cardiomyopathy as a manifestation in various reports [16,25,31-33] , cardiologists may be more aware of
BTHS than other specialists. In our analysis, cardiac disorders were the most common presenting
manifestation for individuals with BTHS but accounted for 57% of individuals with BTHS. The second most
common presenting manifestation was feeding difficulty, weight loss, and/or failure to thrive. Furthermore,
two-thirds of registry participants reported a GI disorder, the most common being chronic constipation,
chronic diarrhea, dysphagia, feeding difficulties, and GERD. The number of patients with chronic
constipation or diarrhea is higher than expected based on general population data . Nutritional challenges
[34]
and GI disorders in BTHS have not been thoroughly described in most previous natural history reports. In
fact, our results support the elevation of nutritional and GI issues as cardinal characteristics of the disorder,
as over half of BTHS-affected individuals report experiencing them at some point in life.