PO04 Precision genomics refines connective tissue disorder diagnosis from Marfan to Loeys-Dietz syndrome type 4 - end of a 30-year odyssey

Background In this paper, we describe the role of Copy Number Variation (CNV) detection applications in Genome Sequencing data in the diagnosis of Loeys-Dietz syndrome type 4 in a large family, bringing a 30-year diagnostic odyssey to an end. Initially, a 38-year-old man was referred for clinical assessment due to a family history of Marfan syndrome. He had several clinical features indicative of Marfan's syndome. Linkage analysis performed in the family in 1990s was considered informative within a 4.3Mb locus on chromosome 15 including FBN1, supporting the clinical suspicion of Marfan syndrome. Methods A range of genomic tests in the next two decades, initially DHPLC and later sequencing and MLPA of FBN1, failed to identify a pathogenic variant in the family. Genome sequencing (GS) through the UK 100,000 Genomes Project (100kGP) was performed in the patient and his affected maternal aunt using 150bp paired-end reads. Results Reanalysis of the GS data using the SVRare application (1) identified a heterozygous 19,256bp deletion encompassing the last exon of TGFB2 with TCC microhomology seen at breakpoints. This finding, one of the smallest deletions involving TGFB2 described to date (2,3,4), was consistent with a diagnosis of Loeys-Dietz syndrome in the patient and his affected aunt. There have been a range of clinical benefits from a precise molecular diagnosis in this family. The aortic phenotype in this family was significant, with history of aortic surgery or dissection in at least five relatives. Predictive genetic testing has resulted in Loeys-Dietz syndrome type 4 being diagnosed in five further patients in this family. Conclusions Heterozygous loss-of-function variants in TGFB2 cause Loeys-Dietz syndrome type 4 (2) and there are overlapping features between this condition and Marfan syndrome. Precise molecular diagnosis of connective tissue disorders is crucial in appropriate management and surveillance, with a range of clinical benefits seen within this family.