Novel Generation-Skipping Inheritance Pattern of Marfan Syndrome Due to FBN1 Insertional Translocation: Diagnostic Utility of FISH and Implications for Genetic Counseling.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic variants in the fibrillin-1 (FBN1) gene on Chromosome 15q21.1. A 3-year-old female presented to the clinic with MFS and a family history of an affected maternal uncle and maternal great-aunt. The proband and the uncle had a positive thoracic aortic aneurysm and dissection (TAAD) panel for MFS revealing an FBN1 deletion. This was confirmed on proband's chromosome microarray; however, the mother was negative for the FBN1 deletion. Fluorescence in situ hybridization (FISH) was used in this case to show a unique chromosome rearrangement in the unaffected mother with an insertional translocation of the 15q21.1 loci (FBN1) to Chromosome 7p. This led to an affected child who inherited the nontranslocated Chromosome 7 and the 15q21 (FBN1) deletion. Thus, individuals in the family inheriting Chromosome 7 with the FBN1 insertional translocation are protected from the MFS phenotype. This supports the known autosomal dominant inheritance pattern while allowing for uncharacteristic skipping of generations of MFS in this family.