Refinement of Connective Tissue Disorder Diagnosis From Marfan to Loeys-Dietz Syndrome Type 4-End of a 30-Year Diagnostic Odyssey.

Characterization of the molecular basis of connective tissue disorders causing aortopathy is important for clinical management. We report a 4-generation family with autosomal dominant inheritance of a connective tissue disorder causing aortic dilatation and/or dissection. Linkage analysis performed in the 1990s had suggested Marfan syndrome, but the molecular basis proved elusive over two decades. Reanalysis of genome sequence data using software to detect copy number variation (CNV) identified a 19 kb deletion including the final exon of TGFB2, revealing Loeys-Dietz syndrome type 4 as the actual diagnosis. This allowed predictive testing of at-risk relatives and appropriate screening of affected patients. Small genomic deletions are difficult to detect on microarray and standard sequencing platforms, and the report highlights the role of high-resolution CNV detection in molecular diagnostics.