A study in Polish patients with cardiomyopathy emphasizes pathogenicity of phospholamban (PLN) mutations at amino acid position 9 and low penetrance of heterozygous null PLN mutations

Abstract

BackgroundIn humans mutations in the PLN gene, encoding phospholamban - a regulator of sarcoplasmic reticulum calcium ATPase (SERCA), cause cardiomyopathy with prevalence depending on the population. Our purpose was to identify PLN mutations in Polish cardiomyopathy patients.MethodsWe studied 161 unrelated subjects referred for genetic testing for cardiomyopathies: 135 with dilated cardiomyopathy, 22 with hypertrophic cardiomyopathy and 4 with other cardiomyopathies. In 23 subjects multiple genes were sequenced by next generation sequencing and in all subjects PLN exons were analyzed by Sanger sequencing. Control group included 200 healthy subjects matched with patients for ethnicity, sex and age. Large deletions/insertions were screened by real time polymerase chain reaction.ResultsWe detected three different heterozygous mutations in the PLN gene: a novel null c.9_10insA:(p.Val4Serfs*15) variant and two missense variants: c.25C > T:(p.Arg9Cys) and c.26G > T:(p.Arg9Leu). The (p.Val4Serfs*15) variant occurred in the patient with Wolff-Parkinson-White syndrome in whom the diagnosis of cardiomyopathy was not confirmed and his mother who had concentric left ventricular remodeling but normal left ventricular mass and function. We did not detect large deletions/insertions in PLN in cohort studied.ConclusionsIn Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9thPLN residue is apparently a mutation hot spot whereas a single dose of c.9_10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0167-0) contains supplementary material, which is available to authorized users.

Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice

“…Several studies have identified CNVs as causative of cardiac diseases associated with SCD [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. However, exhaustive analysis of multiple genes in large cohorts of patients has never been performed for most SCD-related diseases.…”

“…In the last years, several authors consider a CNV any imbalance larger than 50 base pairs [3] (bp) (this latter criterion is the one followed in the present work). Evidence supporting a role of CNVs in SCD-related pathologies has been reported, but robust studies with large cohorts of patients and multiple genes being screened have only been performed for specific SCD-related diseases [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish cases affected by hypertrophic cardiomyopathy

“…Until now, only single reports describing genetic causes of HCM in Polish patients have been reported. [13][14][15] Therefore, the aim of the current study was to assess the genetic background of HCM in a cohort of patients from the south--eastern part of Poland, analyzed by an NGS panel including 404 genes known to harbor alterations affecting cardiovascular system function. Thanks to this approach, we could identify a MYB-PC3 truncating alteration that could represent a novel Polish founder MYBPC3 pathogenic variant.…”

Dilated Cardiomyopathy

“…Similarly, individuals from the Netherlands with the R14del founder mutation have a severe phenotype 100 . However, other reports suggest a milder phenotype 101, 102 . Identifying the same primary mutation(s) with a range of phenotype dependent on genetic background supports that other factors, including genetic factors, may modify the outcome of DCM due to PLN mutations.…”