GeneSeq®: Cardio-Familial Aortopathy Profile

Whole blood

10 mL whole blood or 30 mL if ordering multiple tests

Yellow-top (ACD) tube or lavender-top (EDTA) tube

Confirm a clinical diagnosis of Aortopathy and identify presymptomatic family members, guiding prophylactic measures.

This analysis does not rule out germline mosaicism, the presence of large chromosomal aberrations (including deletions, insertions, and rearrangements), mutations in regions or genes not included in this test, and possible inter/intragenic interactions between sequence variants. False-positive or false-negative results may occur for reasons that include genetic variants, blood transfusions, bone marrow transplantation, mislabeled specimens, or erroneous representation of family relationships.

Mutation analysis is performed using the AgilentSure Select XT® enrichment method and the Illumina® next-generation sequencing platform. Regions of interest include all exons and splice junctions for each gene and limited regions for the following: APOB (556bp of exon 26) and MED12 (c.3020A>G). Sequencing reads are aligned withthe hg19 build of the human genome reference sequence. Analytical sensitivity is based on the depth of coverage across the regions of interest and is provided separately for each gene. Greater than 98% of target bases are synonymous variants not previously recorded at greater than or equal to 20x coverage. Sanger sequencing is used to confirm mutation identity and analyze regions with low coverage. Variants are reported using numbering and nomenclature recommended by the Human Genome Variation Society (HGVS). Variants known to be benign and synonymous variants not previously recorded in our internal variant data bases are not reported.

Aortopathy is characterized by aortic dilation, which can lead to life-threatening aneurysms and/or dissections. Thoracic aortic aneurysm and dissection (TAAD) may be seen in the context of several multisystem syndromes with overlapping symptoms, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and vascular-type Ehlers-Danlos syndromes (vt-EDS), but it can also occur in isolation. The genetic mutations responsible for syndromic forms of aortopathy and TAAD are known. They typically show autosomal dominant inheritance; however, a family history may not always be clear, since type, severity, and age of onset of symptoms can vary even within families. In addition, MFS, vt-EDS, and LDS may be caused by de novo mutations.

Genetic testing for familial aortopathy may:

• Confirm a clinical diagnosis of Marfan syndrome, Loeys-Dietz syndrome, vascular-type Ehlers-Danlos syndrome, or TAAD.

• Identify close relatives of an index patient who carry the mutation and are thus at high risk for TAAD and may require continual screening and lifestyle adjustments.

• In some cases, predict the severity of disease based on the exact mutation found.