Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvem
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RESEARCH
Optimising the mutation screening strategy in Marfan syndrome and identifying genotypes with more severe aortic involvement Roland Stengl1,2,3* , András Bors3, Bence Ágg1,2,4 , Miklós Pólos1,2, Gabor Matyas5, Mária Judit Molnár6, Bálint Fekete6, Dóra Csabán6, Hajnalka Andrikovics3, Béla Merkely1, Tamás Radovits1, Zoltán Szabolcs1,2† and Kálmán Benke1,2†
Abstract Background: Marfan syndrome (MFS) is a systemic connective tissue disorder with life-threatening manifestations affecting the ascending aorta. MFS is caused by dominant negative (DN) and haploinsufficient (HI) mutations of the FBN1 gene. Our aim was to identify mutations of MFS patients with high detection rate and to investigate the use of a gene panel for patients with Marfanoid habitus. We also aimed to examine correlations between genotype and cardiovascular manifestations to predict “malignant” mutations. Methods: 136 individuals were enrolled. In the first phase, next-generation sequencing (NGS) and Sanger sequencing were performed for 57 patients to screen the FBN1 gene, followed by multiplex ligation-dependent probe amplification (MLPA) in negative cases. For repeated negative results, NGS gene panel involving 9 genes was used. In the second phase, 79 patients were tested primarily with the same gene panel, negative samples were tested by MLPA. Results: 84 pathogenic mutations were detected, out of which 78 affected FBN1, 6 non-FBN1 mutations (2 TGFB2, 1 TGFBR2, 2 TGFBR1, 1 SMAD3) are associated with Loeys-Dietz syndrome (LDS). LDS patients had lower systemic score and they were younger, but their aortic involvement did not differ. MLPA detected 4 multi-exon deletions of FBN1 gene, which could not be identified by our first-step screening method. Aortic involvement (aortic dissection and/or dilation) did not differ significantly among HI and DN mutations (p = 0.061). Combined group of HI and DN mutations eliminating a disulphide-bonding cysteine (DN Cys) had significantly higher aortic involvement rate than DN mutations not eliminating a disulphide-bonding cysteine (DN non-Cys) (p 50 bp) [9, 10]. CNVs are deletions and duplications affecting more than 50 bp and they account for around 10% of disease-causing genetic variants in Mendelian diseases [11]. FBN1 mutations can be classified into haploinsufficient (HI) and dominant negative (DN) groups based on their effect on the encoded protein. HI mutations result in the reduction of protein quantity, therefore in this case, only/mainly the normal protein can be found in the connective tissue [12, 13]. As opposed to that, DN mutations lead to abnormal protein structure, so the connective tissue contains both the normal and abnormal fibrillin-1 [14]. Genetic testing of the FBN1 gene has been receiving growing attention in the past few years and besides clinical features, it has become one of the key criteria of the diagnosis of MFS in the revised Ghent nosology [2].
To date, only a few well-established connections between genetic background and phenotype have been described
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