Updates on BpG Cardiovascular Panels

Published on May 6, 2014

Blueprint Genetics (BpG) is happy to launch new updated panels for cardiovascular diseases.

Our team at BpG is constantly evaluating the latest findings in genetics and updating our mutation and clinical information databases and sequencing panels. Our mission is to provide our customers the most current and up-to-date diagnostics that is available. During winter 2014 we have curated all of our mutation databases, enabling efficient and updated bioinformatic analysis of sequencing data. In total, eight carefully selected genes have been added to our current cardiovascular panels (see below for details). These genes represent recent findings in cardiovascular genetic research and we expect them to increase the diagnostic yield of our panels. This update enables Blueprint Genetics to provide even more comprehensive genetic analyses for hereditary cardiac diseases.

BpG cardiovascular mutation database – staying updated

From the beginning Blueprint Genetics has found it essential to have an own in-house-created mutation database that is incorporated into our bioinformatics pipeline. This is a critical tool in bringing efficacy and reliability into the analysis and also contributing to our fast turnaround times. New mutation data is coming out constantly, and in order to give our customers the best genetic statements possible, it is important to keep the database up-to-date. We have made a substantial update on the database and added over 1200 novel variants. We have gone through over 400 recent publications, evaluated existing online mutation databases and reviewed our own genetic findings in order to accomplish this. The BpG mutation database is considered as one of the most curated databases for hereditary cardiovascular and nephrotic syndrome diseases.

Cardiomyopathies – novel LVNC and HCM genes

Two genes, MIB1 and TRIM63, have been added to our Heart, Pan Cardiomyopathy and Core Cardiomyopathy Panels. MIB1 is recently identified as a novel causative gene for left ventricular non-compaction cardiomyopathy (LVNC). On February 2013 Luxan et al. published an article in Nature Medicine reporting that inactivating mutations in MIB1 lead to LVNC. In this article they identified two MIB1 mutations in two LVNC families and showed that inactivation of Mib1 in mouse myocardium results in a LVNC phenotype equivalent to human disease. In addition the human mutations were reported to disrupt MIB1 dimer formation in functional cell studies. Chen et al. identified TRIM63 as a possible novel hypertrophic cardiomyopathy (HCM) gene. They sequenced TRIM63 in 302 HCM patients and 339 control subjects and found several TRIM63 variants that were present only in HCM patients. These variants were also absent in an additional control group consisting of 751 individuals. A mouse model expressing mutated TRIM63 in its heart developed cardiac hypertrophy and cell studies showed that the identified TRIM63 mutations had loss-of-function effects.

Arrhythmias – the list of interesting genes grows

Three new genes, CALM2, DPP6 and SCN2B have been added to our Heart and Arrhythmia Panels. In addition, SCN2B has been added to our Brugada Panel, and CALM1 and CALM2 to LQTS Panel. Crotti et al. identified two CALM1 mutations and one CALM2 mutation in children suffering from severe early onset cardiac arrhythmias. Both of these genes encode calmodulin, a calcium-binding messenger protein. The mutations were shown to impair the calcium-binding ability of the protein, which was hypothesized to disrupt the calcium signaling of the heart. CALM1 has already been in our Heart, Arrhythmia and CPVT Panels because of its previous linkage to catecholaminergic polymorphic ventricular tachycardia (CPVT). The other calmodulin-encoding gene, CALM2, is a new addition to these panels. Alders et al. suggested a link between DPP6 and idiopathic ventricular fibrillation (IVF). They discovered a shared haplotype in three IVF families and independent IVF patients. The haplotype includes part of the DPP6 gene and harbors a variant in the 5’UTR region of DPP6 that was present in additional IVF patients and absent in 350 control subjects. The haplotype carriers were shown to have a 20-fold increase in DPP6 mRNA levels, which the authors hypothesize to be a consequence of the 5’UTR variant. Since the role of DPP6 expression in the pathogenesis of IVF seems promising, we have decided to add the whole DPP6 gene to our Heart and Arrhythmia Panels. Riuró et al identified SCN2B as a novel candidate gene for Brugada syndrome. SCN2B encodes one of the b2 subunits of voltage-gated sodium channels and has been previously associated with atrial fibrillation. The authors found a SCN2B missense mutation in a Brugada patient and discovered that the mutation causes a reduction in sodium current density. This is most likely a result of a decrease in the cell surface expression of sodium channels.

Aortic diseases – novel syndromic and non-syndromic genes

Two new genes, PRKG1 and SKI have been added to our Aorta Panel. SKI is also included in our Marfan Panel. A missense mutation in PRKG1 was reported as being causative for thoracic aortic aneurysms and acute aortic dissections. In the article, published by Guo et al., the mutation was identified in four affected families and was seen segregating with aortic disease. The mutation was shown to have a gain-of-function effect on the protein, which was hypothesized to cause decreased contraction of vascular smooth muscle cells. Another new aortic disease gene SKI was reported causative for Shprintzen-Goldberg syndrome (SGS) by Doyle et al. SGS is a syndrome with very similar presentation as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). The main difference is that SGS is more likely to present with mental retardation and often comes with a milder aneurysm phenotype. The reported mutations were shown to increase TGF-β signaling, an event that is considered important in the pathogenesis of syndromic forms of aortic aneurysms.

Pulmonary arterial hypertension – KCNK3 channel dysfunction

Our PAH (pulmonary arterial hypertension) Panel has been complemented with the KCNK3 gene. Ma et al. published recently an article in New England Journal of Medicine, where they identified several mutations in KCNK3 in both familiar and idiopathic PAH patients. KCNK3 encodes a type of pH-sensitive potassium channel expressed in multiple tissues. The channel is thought to have a role in the regulation of pulmonary vascular tone. The authors performed electrophysiological studies on mutated KCNK3 channels and noticed that the identified mutations resulted in a loss of KCNK3 channel function in physiological pH. They hypothesized that the loss of function could lead to pulmonary-artery vasoconstriction and thus cause the PAH phenotype.

All these updates are valid from today the 6th of May.

With kind regards,

The Blueprint Genetics Team

 

 

References

Alders, M. et al. Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation. Am J Hum Genet 2009, 84(4), 468-476. PubMed:19285295

Chen, S.N. et al. Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy. Circ Res 2012, 111(7), 907-919. PubMed:22821932

Crotti, L. et al. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation 2013, 127(9), 1009-1017. PubMed:23388215

Doyle, A.J. et al. Mutations in the TGF- repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet 2012, 44(11), 1249-1254. PubMed:23023332

Guo, D.C. et al. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 2013, 93(2), 398-404. PubMed:23910461

Luxán, G. et al. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat Med 2013, 19(2), 193-201. PubMed:23314057

Ma, L. et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013, 369(4), 351-361. PubMed:23883380

Riuró, H. et al. A missense mutation in the sodium channel b2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Hum Mutat 2013 34(7), 961-966. PubMed:23559163

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