Combination Testing Using a Single MSH5 Variant alongside HLA Haplotypes Improves the Sensitivity of Predicting Coeliac Disease Risk in the Polish Population.

Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD) patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. DNA samples of 336 CD and 264 unrelated healthy controls were used to create DNA pools for a genome wide association study (GWAS). GWAS findings were validated with individual HLA tag single nucleotide polymorphism (SNP) typing of 473 patients and 714 healthy controls. Association analysis using four HLA-tagging SNPs showed that, as was found in other populations, positive predicting genotypes (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, and HLA-DQ2.5/DQ8) were found at higher frequencies in CD patients than in healthy control individuals in the Polish population. Both CD-associated SNPs discovered by GWAS were found in the CD susceptibility region, confirming the previously-determined association of the major histocompatibility (MHC) region with CD pathogenesis. The two most significant SNPs from the GWAS were rs9272346 (HLA-dependent; localized within 1 Kb of DQA1) and rs3130484 (HLA-independent; mapped to MSH5). Specificity of CD prediction using the four HLA-tagging SNPs achieved 92.9%, but sensitivity was only 45.5%. However, when a testing combination of the HLA-tagging SNPs and the MSH5 SNP was used, specificity decreased to 80%, and sensitivity increased to 74%. This study confirmed that improvement of CD risk prediction sensitivity could be achieved by including non-HLA SNPs alongside HLA SNPs in genetic testing

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

<div><p><i>TTN</i> gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in <i>TTN</i> in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the <i>TTN</i> gene. Truncating mutations were followed up by segregation study among family members. We identified 16 <i>TTN</i> truncating variants (<i>TTN</i> trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, <i>TTN</i> truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.</p></div

Comparison of clinical data on <i>TTN</i> trunc positive versus <i>TTN</i> trunc negative DCM probands.

<p>Comparison of clinical data on <i>TTN</i> trunc positive versus <i>TTN</i> trunc negative DCM probands.</p

List of <i>TTN</i> truncating variants identified in the study group annotated to transcript NM_001267550.2.

<p>List of <i>TTN</i> truncating variants identified in the study group annotated to transcript NM_001267550.2.</p

Clinical characteristics of affected and not affected <i>TTN</i> trunc positive relatives.

<p>Clinical characteristics of affected and not affected <i>TTN</i> trunc positive relatives.</p

Manhattan plot showing CD associations with the susceptibility region on chromosome 6.

<p>Manhattan plot showing CD associations with the susceptibility region on chromosome 6.</p

Kaplan-Meier cumulative survival curves for SAE (HF death, OHT or LVAD) in 46 carriers of <i>TTN</i> truncating variants, males and females, p = 0.018, log-rank test = -2.37.

<p>Kaplan-Meier cumulative survival curves for SAE (HF death, OHT or LVAD) in 46 carriers of <i>TTN</i> truncating variants, males and females, p = 0.018, log-rank test = -2.37.</p