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Page 38 Loong et al. J Transl Genet Genom 2023;7:27-49 https://dx.doi.org/10.20517/jtgg.2022.20

Inherited aortopathies
MFS
MFS is an autosomal dominant multisystem connective tissue disorder associated with pathogenic variants
in FBN1 . It is characterized by aortic root aneurysm, aortic dissection, ectopia lentis (ocular lens
[97]
dislocation), and skeletal abnormalities usually involving disproportionate long bone overgrowth [98,99] . The
clinical diagnosis of MFS is made using the revised Ghent Nosology, which can diagnose or exclude Marfan
syndrome in 86% of cases [97,98] . With a positive diagnosis of MFS, early initiation of long-term beta-blocker
[100]
therapy is essential, with angiotensin-converting enzyme receptor blockers . Quinolone should be avoided
because it increases the risk of aortic dissection, especially in individuals with MFS . In addition to
[101]
medical therapy, surgical repair is considered for significant aortic root dilation, mitral valve regurgitation,
or other vascular abnormalities .
[100]
[102]
Up to 90% of MFS is caused by pathogenic variants in the FBN1 gene . FBN1 is a large structural
macromolecule found in the extracellular matrix, essential to the integrity and function of connective
tissues, especially in arteries, the perichondrium, and in components of the eye. While identifying FBN1
variants is not essential for the diagnosis, it is helpful to differentiate MFS from other inheritable syndromes
with similar clinical presentations [99,103] . For example, Loeys-Dietz syndrome and familial thoracic aortic
aneurysms and dissections have a similar clinical presentation of skeletal abnormalities and are genetically
associated with pathogenic variants in receptor genes TGFBR1 and TGFBR2 which have also been seen in
MFS . FBN1 variants can result in conditions other than MFS, including Weill-Marchesani syndrome,
[104]
familial thoracic aortic aneurysms/dissections, acromicric dysplasia, and geleophysic dysplasia, making the
[105]
clinical evaluation of the patient critical . Special care must be taken when investigating individuals
presenting with form fruste MFS, with atypical symptoms, or an incomplete presentation of typical MFS
symptoms . Genetic testing is warranted in individuals suspected to have MFS, especially when family
[106]
history is unknown or ambiguous.

CLINICAL FRAMEWORK FOR PATIENTS WITH ICCS
The NUHCS ICC program was launched in 2012. This project was initiated as a research program and
developed into a clinical workflow for diagnosing and managing individuals with ICC. Figure 1 summarizes
the workflow for ICC evaluation.

Patients were identified and invited into the study if they presented symptomatically at a healthcare
institute, if they were found to have phenotypes suggestive of ICC during general screening, or if they were
identified as part of a cascade testing workflow. These individuals were referred to the NUHCS ICC clinic
for further phenotyping and genotyping.

The phenotypic assessment was performed by clinicians using clinical examination, relevant blood tests,
electrocardiography (ECG), and cardiac imaging. Cardiac imaging included echocardiography, cMRI, or
computed tomography (CT) with contrast, depending on the assessed case. Following the investigations, the
clinicians offered the initial explanation of the ICC to the patient and referring cardiologist/physician, with
the strength of diagnosis graded according to international guidelines. Careful and accurate phenotyping is
essential for solid genotype-phenotype assessments, which are also required for the genetic variant curation
process.

Exome sequencing (WES) is performed for cases in the ICC clinic using next-generation sequencing, with a
FASTQ file generated from the sequencing procedure. Variant calling from the FASTQ file is performed
using the GATK pipeline (a bioinformatics tool that aligns the sequencing reads), presenting the overall