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Page 44 Loong et al. J Transl Genet Genom 2023;7:27-49 https://dx.doi.org/10.20517/jtgg.2022.20

Singapore. The moratorium aims to deter individuals from undergoing clinical genetic tests for any medical
indications or participating in precision medicine research due to concerns about insurability. Under this
moratorium, insurance companies in Singapore are not allowed to use predictive genetic test results to
[144]
assess or decide the outcome of insurance applications under various circumstances . A summary of the
moratorium is provided in Table 2.

Case studies of ICC patients from our clinic
In this section, we discuss three case examples of ICC. We present a case of cardiomyopathy, LQTS, and
Marfan syndrome. These exemplify the real-life application of the workflow described in the above sections.

Case 1: A patient with DCM
The proband was a 24-year-old female at the time of presentation at the ICC clinic after a referral by her
primary cardiologist given a family history of SCD. She has three brothers, one of whom passed away from
SCD at age 22 shortly before the visit. Thus, she had a strong family history of DCM, with her father and
deceased brother having the condition, both diagnosed through echocardiography measurements. Her
family history was highly suggestive of ICC, so she was referred to the ICC clinic. [proband’s father’s echo
(Supplementary Material 1)]

At the time of presentation, the proband was asymptomatic. Her transthoracic echocardiogram revealed a
mildly dilated left ventricle with an ejection fraction of 52% on transthoracic echocardiography [proband’s
echo (Supplementary Material 2), Figure 2A]. Due to the familial history and clinical suspicions of DCM,
the proband underwent WES.

A rare variant was found on the TNNC1 gene upon genetic testing and variant curation. This gene TNNC1
is commonly implicated in DCM and HCM in an autosomal dominant inheritance pattern. The variant, in
this case, was: NM_003280.3:c.452A>T (p.Asp151Val) . This variant was classed as likely pathogenic by
[145]
[112]
our variant curation [ACMG guidelines: PM1, PM2, PP1, PP3 (Moderate)] . The base position is strongly
conserved, and the base change is not present in gnomAD or local databases (SG10K_pilot database) with
adequate sequence coverage . Pathogenic variants in the TNNC1 gene have been linked to DCM and
[111]
HCM according to various databases such as OMIM, and it was labeled as "definite" according to curation
by the ClinGen consortium . The TNNC1 domain has 34 missense/in-frame variants (five pathogenic and
[75]
29 VUS), and the pathogenicity of the missense variant = 14.7%. In addition, clear segregation was
established according to cascade testing results of the patient’s first-degree family members. In silico
prediction tools, SIFT and DAMN, also offered pathogenic predictions on the variant. The variant was
further confirmed through gold-standard Sanger sequencing. Eventually, cascade testing was initiated to
examine other family members of the proband. The proband’s father, who bore the same variant in
TNNC1, showed clinical features of DCM: dilated ventricles with a low ejection fraction of 35% [Figure 2A]
and multiple hospital admissions for acute decompensated heart failure. We did not initiate testing on her
deceased brother. Cascade testing for the patient’s two other brothers and mother revealed the absence of
the TNNC1 variant [Figure 2B]. Clinically, they did not present with signs or symptoms of DCM or other
significant cardiovascular conditions. Serial transthoracic echocardiograms of the proband’s two living
brothers were normal. We took this information to represent genotype-phenotype segregation,
strengthening the status of the variant as the disease-causing “pathogenic” variant.

The proband’s subsequent transthoracic echocardiogram three years after her initial presentation showed a
worsening left ventricular ejection fraction of 37%. She was started on guideline-directed heart failure
medications and remained asymptomatic in her follow-up visits with her primary cardiologist.