Clinical Impact of Copy Number Variation on the Genetic Diagnosis of Syndromic Aortopathies

Impact of pathogenicFBN1variant types on the development of severe scoliosis in patients with Marfan syndrome

“…Among the 278 cases with pathogenic or likely pathogenic FBN1 variants, 7 were suspected or confirmed to have CNVs 22 ; 5 intragenic (multi-)exon deletions and 1 whole gene deletion were validated using chromosomal microarray analysis and multiplex ligation-dependent probe amplification analysis, respectively ( table 3 ). In one patient (patient 330) clinically diagnosed with Marfan syndrome, heterozygous deletion of exons 64–66 was strongly suspected via a simple CNV prediction method that visually reviews the coverage tracks from the Integrative Genomics Viewer browser 22 ( table 3 ). The distribution of pathogenic FBN1 variants of the remaining 271 cases is summarised in figure 2 .…”

“… 14 20–22 In this study, seven patients with or suspected of having CNVs of the FBN1 gene were also included. 22 Details of the genetic tests have been previously described. 14 22 The reference sequence used for FBN1 was RefSeq NM_000138.4.…”

“…Identification of the pathogenic FBN1 variants was performed using Sanger sequencing for the FBN1 gene or next generation sequencing (NGS)-based genetic tests 14. NGS-based genetic tests included exome sequencing conducted using Japan’s Initiative on Rare and Undiagnosed Diseases in Pediatrics research and hybridisation capture-based gene panel testing for aortopathies conducted at the Kazusa DNA Research Institute (Chiba, Japan) 14 20–22. In this study, seven patients with or suspected of having CNVs of the FBN1 gene were also included 22.…”

Nonsyndromic arteriopathy and aortopathy and vascular Ehlers–Danlos syndrome causing COL3A1 variants

“…In our Marfan syndrome center, genetic analysis for HTAAD had been performed using Sanger sequencing until March 2018 (Takeda et al, 2015; Takeda et al, 2018) and genetic testing for vEDS ( COL3A1 ) was performed limitedly for clinically suspected young patients. Since April 2018, hybridization capture‐based gene panel testing for HTAAD, which was provided by Kazusa DNA Research Institute (Chiba, Japan) and covered by Japanese health insurance, has been conducted for patients with highly suspected HTAAD and/or nonsyndromic unusual arteriopathies, and this gene panel includes the genes FBN1 , TGFBR1 , TGFBR2 , TGFB2 , TGFB3 , SMAD3 , ACTA2 , MYH11 , MYLK , and COL3A1 (Ouchi et al, 2019; Takeda et al, 2021). The pathogenicity of COL3A1 gene (NM_00090.3) was evaluated according to the American College of Medical Genetics and Genomics‐Association for Molecular Pathology classification guideline (Richards et al, 2015).…”

“…Recently, targeted multigene panel testing for HTAAD using next-generation sequencing (NGS) makes it possible to screen comprehensively multiple candidate genes in a clinical setting (Shendure et al, 2008). In our Marfan syndrome center, gene panel testing for HTAAD has been conducted for patients with highly suspected HTAAD and/or nonsyndromic unusual arteriopathies since April 2018 (Ouchi et al, 2019;Takeda et al, 2021), and we have unexpectedly experienced some patients harboring a pathogenic or likely pathogenic variant in COL3A1, who did not have typical extra-arterial features usually observed in vEDS patients. In this report, we summarize 12 Japanese vEDS patients in our hospital, among whom 7 patients were clinically diagnosed and/or suspected and 5 patients did not have any clinical features other than arteriopathy, and discuss the usefulness of NGS-based genetic testing for patients with nonsyndromic arteriopathies.…”