Introduction
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic variation in the fibrillin-1 gene (FBN1) on chromosome 15q21.1.  The three major clinical indicators for MFS include thoracic aortic aneurysm or dissection, ectopia lentis, and characteristic musculoskeletal features such as scoliosis, pectus anomalies, and arachnodactyly.  Missense, nonsense, and splice site variants within FBN1 have all been reported to cause MFS. While translocations have been reported in the literature to be pathogenic for MFS when causing a break point within the FBN1 gene, here, we report what is believed to be a novel case of a translocation that resulted in an atypical inheritance pattern of MFS.

Case Presentation
A 3-year-old female with a diagnosis of Marfan syndrome presented to our cardiovascular connective tissue clinic.  She was initially worked up by an outside genetics clinic when her mother raised concerns for MFS, based on features of hypotonia, flat feet, mild pectus excavatum, mild developmental delay, and long, thin fingers. Echocardiogram revealed mild mitral valve prolapse and a mildly dilated aortic root.  Family history revealed an affected maternal uncle and maternal great aunt who had previously had a positive FBN1 deletion detected on a Thoracic Aortic Aneurysm and Dissection (TAAD) panel. 

Diagnostic Workup
Chromosome microarray and TAAD panel performed at the outside clinic confirmed deletion of the FBN1 gene in the 3-year-old proband and defined breakpoints containing 18 genes across the 2448 kb deletion from 15q21.1-15q21.2. The microarray study also indicated a loss of 15q11.2, although this variation is not known to be pathogenic. The mother was negative for the 15q21 (FBN1) deletion but was positive for the 15q11.2 deletion. We pursued fluorescence in situ hybridization (FISH) on the proband and mother that revealed a unique translocation in the unaffected mother with one 15q21 (FBN1) locus translocated to chromosome 7p. This led to the affected child when she inherited the non-translocated chromosome 7 and the 15q21 (FBN1) deletion. Thus, individuals in the family inheriting the translocated 7 are protected from the Marfan phenotype. This supports the known inheritance pattern while allowing for uncharacteristic skipping of generations in this family. The proband is currently under standard ophthalmologic and cardiovascular treatment protocols for MFS.

Discussion
This case study demonstrates the benefits of FISH and other karyotype technologies to investigate atypical inheritance patterns for MFS. Relevant for this family, it also allows for reproductive testing options. Future study of this family can also help define the presentation associated with duplication of FBN1.