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Loong et al. J Transl Genet Genom 2023;7:27-49 https://dx.doi.org/10.20517/jtgg.2022.20 Page 41

Cascade testing
Once a disease-causing variant is identified in a proband, steps are taken for their family members to
undergo similar genetic testing and phenotypic evaluation, with appropriate consent, because the patient’s
immediate family members are at increased risk of harboring the same disease-causing variant . From a
[6]
macro perspective, cascade testing can save a healthcare system, owing to early detection and management
of high-risk individuals. This sequence significantly decreases morbidity and mortality and reduces the
resources required to manage these patients . One signature example is familial hypercholesterolemia,
[128]
where cascade testing is a proven, cost-effective means for disease early detection .
[129]
Cascade testing begins with the immediate family members, followed by the second-, then third-degree
relatives, until all at-risk family members are identified and tested to the extent possible. The clinician and
geneticist work with the proband to this end. This procedure establishes a well-annotated pedigree tree and
[112]
improves the confidence of ICC diagnosis . While cascade testing is critical upon discovering a disease-
causing variant, there remain significant barriers and challenges to its practice. These challenges include
ensuring the confidentiality of the index case (proband), the non-acceptance of such testing among family
members, cultural and ethical considerations, insurance coverage, and resource considerations in these
families . Appropriate measures must be taken to explain the purpose and obtain informed consent before
[130]
[131]
approaching family members for genetic testing .
Incidental secondary genetic findings
While analyzing genomic results, disease-causing variants for unrelated medical conditions may be
identified incidentally. These are more likely to occur with WES/WGS sequencing. The variants may not
relate to the original phenotype with which the patient presented. Relevant consent and genetic counseling
must be clearly and expressly carried out before genetic testing in anticipation of these outcomes. In various
cases, these incidental findings would belong under predictive diagnostic testing. Care must be applied to
ensure adherence to country-specific regulations for genetic testing .
[132]
The ACMG lays out clear guidelines for returning incidental medically-actionable disease-causing variants
in 73 genes . These guidelines focus on highly penetrant genetic disorders using established management
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guidelines to prevent or significantly reduce mortality and morbidity. Examples of the ACMG medically-
actionable incidental findings gene list include BRACA1 and BRACA2 for hereditary breast cancer, ATP7B
for Wilson’s disease, and NF2 for neurofibromatosis type II . Following the discovery of incidental
[133]
pathogenic variants in the genes highlighted by the ACMG committee, the multidisciplinary team initiated
phenotypic testing, cascade testing, and guideline-based interventions, depending on appropriate consent.
Other pathogenic variants on genes not included in the ACMG list are under constant evaluation, and
additional studies are required to identify the relevant incidental findings to be reported.

Patient management
After confirming a diagnosis of ICC, the long-term management of the patient and any affected family
member takes the form of a multidisciplinary approach. This management begins with cardiologists and
genetic counselors directing the patients’ evidence-based management, social workers assisting with long-
term socioeconomic issues, and many allied health professionals. Genotype-positive and phenotype-
negative family (pre-clinical) members are under increased surveillance to monitor phenotype
progression .
[134]

Phenotype-positive, genotype-negative individuals are managed based on their clinical presentation and the
latest guidelines. For specific ICCs, prognostic implications are offered. For example, better long-term
outcomes are reported in genotype-negative DCM patients . These are also used for decision-making, such
[37]