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Introduction: The knowledge about clinical features of Polish patients with hereditary type of transthyretin cardiac amyloidosis (ATTR-CA) is scant., Objectives: We present rare transthyretin (TTR) gene variants and diagnostic difficulties among patients with hereditary ATTR-CA., Patients and Methods: In 2018-2024, 252 consecutive patients with suspected cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography, transthoracic echocardiography and [99mTc]Tc-DPD scintigraphy. TTR gene sequencing was performed, if mandatory., Results: Hereditary ATTR-CA was confirmed in 14 patients (including one female). Most of them had pathogenic or likely pathogenic TTR gene variants, which are very uncommon in the hereditary transthyretin amyloidosis population: p.Ala45Thr, p.Val91Ala, p.Phe53Cys, p.Ala101Val, p.Glu109Lys and p.Phe53Leu. Of note, patients with p.Ala101Val and p.Phe53Cys variants had inconclusive [99mTc]Tc-DPD scintigraphy results, which may be due to the low sensitivity of [99mTc]Tc-DPD bone scintigraphy for these variants. Cardiac biomarkers did not reflect the intensity of cardiac uptake on [99mTc]Tc-DPD bone scintigraphy - two patients with intense cardiac uptake of tracer had normal or borderline hs-cTnT and NT-proBNP levels. During follow-up, four patients died, two patients underwent combined heart and liver transplantation., Conclusions: This study enriches our knowledge regarding genotype-phenotype correlations of specific TTR variants, broadens the spectrum of identified TTR variants among Polish population, and shows limited value of [99mTc]Tc-DPD scintigraphy in some patients with hereditary ATTR-CA. In cases with strong suspicion of ATTR-CA and inconclusive [99mTc]Tc-DPD scintigraphy results, genetic testing should be considered.

Background: LMNA -related dilated cardiomyopathy ( LMNA -DCM) caused by mutations in the lamin A/C gene ( LMNA ) is one of the most common forms of hereditary DCM. Due to the high risk of mutation transmission to offspring and the high incidence of ventricular arrhythmia and sudden death even before the onset of heart failure symptoms, it is very important to identify LMNA -mutation carriers. However, many relatives of LMNA -DCM patients do not report to specialized centers for clinical or genetic screening. Therefore, an easily available tool to identify at-risk subjects is needed. Methods: We compared two cohorts of young, asymptomatic relatives of DCM patients who reported for screening: 29 LMNA mutation carriers and 43 individuals from the control group. Receiver operating characteristic (ROC) curves for potential indicators of mutation carriership status were analyzed. Results: PR interval, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hscTnT) serum levels were higher in the LMNA mutation carrier cohort. Neither group differed significantly with regard to creatinine concentration or left ventricular ejection fraction. The best mutation carriership discriminator was hscTnT level with an optimal cut-off value at 5.5 ng/L, for which sensitivity and specificity were 86% and 93%, respectively. The median hscTnT level was 11.0 ng/L in LMNA mutation carriers vs. <3.0 ng/L in the control group, p < 0.001. Conclusions: Wherever access to genetic testing is limited, LMNA mutation carriership status can be assessed reliably using the hscTnT assay. Among young symptomless relatives of LMNA -DCM patients, a hscTnT level >5.5 ng/L strongly suggests mutation carriers.

Background: In a population under 45 years of age, the predominant causes of sudden cardiac death (SCD) are inherited cardiac diseases. Determining the underlying cause may help identify relatives at risk and prevent further events but is more difficult if an autopsy has not been performed., Aims: We aimed to assess the diagnostic value of clinical and genetic screening in relatives of young non-autopsied sudden unexplained death (SUD) victims., Material and Methods: Eighty-seven relatives of 65 young non-autopsied SUD victims from 39 families were evaluated from 2016 to 2019. The relatives underwent extensive noninvasive cardiac workup. Genetic examinations were performed in 39 families., Results: The definite diagnoses were made in 17 of 39 (44%) families. Cardiomyopathies were identified in 10 families (5 hypertrophic, 4 dilated, and 1 arrhythmogenic), followed by long QT syndrome (5 families). In 3 families, probable diagnoses were made, whereas in 20 families no diagnosis was achieved. In total, definite and probable diagnoses were made in 18 and 5 patients, respectively. All affected relatives were offered medical management, one of them died of heart failure and one underwent transplantation during the median follow-up of 3 years. Disease-causing variants were found in 7 of 39 (18%) probands; all in families with a definite diagnosis. Variants of unknown significance were found in 2 probands., Conclusion: Screening of relatives of SUD victims is warranted and may save lives, even if it is not guided by autopsy results. Genetic testing in families without the disease phenotype has little effectiveness.

Endometriosis is a common gynecological disorder characterized by the ectopic growth of endometrial-like tissue outside the uterine cavity. Etiopathogenesis of endometriosis is poorly understood; it is plausible, however, that the disease may be associated with oxidative stress related to local heme and iron metabolism. Therefore, the aim of the study was to reveal a possible association of endometriosis with a stress-inducible heme oxygenase 1 (HMOX1). For this purpose, 228 patients with clinically confirmed endometriosis and 415 control parous women from general Polish population were examined for functional -413A>T (rs2071746) single-nucleotide polymorphism (SNP) and ( GT ) n dinucleotide repeat length polymorphism in the promoter of HMOX1 gene. In addition, -413A>T SNP was assessed by the specific TaqMan ® SNP Genotyping Assay, and ( GT ) n polymorphism was determined by PCR product size analysis. We found that endometriosis is associated with an increased frequency of - 413A ( GT ) 31,32 haplotype (OR (95%CI) = 1.27 (1.01-1.60), p = 0.0381) and - 413A ( GT ) 31,32 homozygous genotype [OR (95%CI) = 1.51 (1.06-2.17), p = 0.0238]. These data suggest that endometriosis is associated with functional polymorphism of HMOX1 gene, and this gene may play a part in the pathogenesis of this disorder.

We report on a 44-year-old woman with coincidence of two genetic disorders: Andersen-Tawil syndrome and Marfan syndrome. In both, life-threatening arrhythmias could occur. A 44-year-old woman presented acute ascending aortic dissection with aortic arch involvement and chronic thoracic descending and abdominal aortic dissection. Clinical and genetic examination confirmed Marfan syndrome (MFS) diagnosis. Due to repolarization disorder in ECG and premature ventricular contractions in Holter ECG, the sequencing data were analyzed again and mutation in KCNJ2 gene was identified. The case showed that coincidence of Andersen-Tawil syndrome (ATS) and MFS did not provoke life-threatening arrhythmias. Complication was rather caused by expression of FBN1 mutation., (© 2019 Wiley Periodicals, Inc.)

INTRODUCTION Unexplained sudden cardiac arrest (SCA), occurs in up to 10% of patients and is often attributed to an inherited arrhythmia syndrome. Family screening and genetic testing may help clarify the cause of unexplained SCA. OBJECTIVES We aimed to assess the usefulness of clinical evaluation and genetic testing in patients after unexplained SCA and in their families. PATIENTS AND METHODS In the years 2014-2017, we studied 44 unrelated patients after unexplained SCA and 96 of their relatives. All patients and relatives underwent comprehensive cardiac evaluation. In 31 patients with SCA, next generation sequencing (NGS) was performed. The Kaplan-Meier survival curve was constructed to compare the event-free survival depending on clinical diagnosis or genotype. An adverse event was defined as an adequate implantable cardioverter-defibrillator discharge. RESULTS Based on the clinical evaluation, diagnosis was established in 39% of probands (long QT syndrome 21%; short QT syndrome 7%; Brugada syndrome 7%; catecholaminergic polymorphic ventricular tachycardia, 2%; and early repolarization syndrome, 2%). Ventricular arrhythmia was identified in the relatives of 19% of probands. In 18 of the 31 probands (54.8%), 23 rare gene variants were identified, of which only 2 were classified as pathogenic. The event-free survival over a median of 4.5 years was similar in patients with or without clinical diagnosis and in carriers and noncarriers of a rare genetic variant. CONCLUSIONS This study shows the significance of an extensive clinical assessment in unexplained SCA victims and their relatives. Routine genetic testing by NGS has low diagnostic and prognostic value.

Background: Andersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS., Methods: This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0±17.3 years, female n=31). Additional genetic screening of 3 LQTS genes (KCNQ1, KCNH2, SCN5A) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats>2000/24h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated., Results: In KCNJ2 mutation carriers vs non-carriers (n=25 vs n=19) significant differences were observed in U-wave manifestations in V2-V4, T peak -T end duration, QTUc duration (p<0.0001), dysmorphic features, and neurological symptoms. Compared to asymptomatic carriers (n=9), in those with arrhythmias and/or syncope and/or CA (n=16) micrognathia (p=0.004), periodic paralysis (p=0.019), palpitation (p=0.005), U-wave n V2-V4 (p=0.049) were more frequent; QTU (p=0.045) and T peak -T end (p=0.014) were also longer (n=9). In the subgroup of carriers with syncope and/or cardiac arrest (n=10, 90% women), K897T-KCNH2 polymorphism (p=0.02), periodic paralysis (p=0.004), muscle weakness (p=0.04), palpitations (p=0.04), arrhythmias (biventricular VT, p=0.003; polymorphic VT, p=0.009) were observed more frequently. T peak -T end duration was longer (p=0.007) and the percentage of patients with premature ventricular contraction >2000/24h was higher (p=0.005)., Conclusion: A higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged T peak -T end time. Our findings suggest that K897T may contribute to the occurrence of syncope., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Andersen-Tawil Syndrome (ATS) is a channelopathy caused by mutations in KCNJ2 gene. It is characterized by symptoms of ventricular arrhythmias, periodic paralysis or muscle weakness, and dysmorphic features. ATS can present with the triad of symptoms, any combination or none of them. Risk factors for dangerous arrhythmias are unknown. The study assessed the impact of K897T polymorphism in hERG1 gene and H558R polymorphism in SCN5A gene coexisting with R218Q mutation in KCNJ2 in one family on clinical manifestation., Methods: Family members underwent clinical assessment, ECG and genotyping. Holter monitoring was performed in mutation carriers and additionally in one family member with no mutation, but with K897T polymorphism., Results: Proband with ATS mutation, K897T and H558R polymorphisms and proband's sister with ATS mutation and K897T polymorphism presented following symptoms: loss of consciousness, bidirectional and polymorphic ventricular tachycardia and about 5000 ventricular extrasystoles. Symptoms presented by the member with only the ATS mutation and by member with ATS mutation and H558R polymorphism were not as severe. U wave appeared in all examined family members regardless of the mutation presence. Studied individuals with ATS mutation had the T-peak-U-peak interval longer than 200 ms. In all ATS mutation carriers it was longer than in family members with no mutation. T-peak-T-end interval was the longest (>120 ms) in members with coexisting mutation and K897T polymorphism., Conclusion: ATS severity possibly depends on other genes' polymorphisms. In the presented family, it could depend on the presence of K897T polymorphism in hERG1., (© 2015 Wiley Periodicals, Inc.)

Background: In 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., Methods: We 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., Results: We detected three different heterozygous mutations in the PLN gene: a novel null c.9&#95;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., Conclusions: In Poland, similar to most populations, PLN mutations rarely cause cardiomyopathy. The 9(th) PLN residue is apparently a mutation hot spot whereas a single dose of c.9&#95;10insA, and likely other null PLN mutations, cause the disease only with low penetrance or are not pathogenic.

Atopic dermatitis (AD) is a common skin disease of complex etiology including affected humoral and cellular immune responses. The role of NK cells in development of this disease has been recently postulated, but is still poorly documented. The current study was undertaken to determine the impact of genes for the most polymorphic NK cell receptors, known as killer cell immunoglobulin-like receptors (KIRs), on the development of AD. We compared 240 patients suffering from AD with 570 healthy controls. Frequencies of the great majority of KIR genes did not differ between patients and controls, except for KIR2DS1, whose frequency was significantly (OR=0.629, CI95% (0.45; 0.87), pcorr=0.0454) lower in patients than in controls. These results were confirmed in a second cohort of 201 patients. When both patient groups were combined and compared to the control group, the result for KIR2DS1 achieved even higher significance (OR=0.658, CI95% (0.5; 0.86), pcorr=0.0158). To the best of our knowledge, this is the first report on KIR gene contribution to AD, and to allergy in general., (© 2013.)

Background: FLG null variants of which 2282del4 and R501X are the most frequent in Caucasians are established risk factors for atopic dermatitis (AD) with an effect probably mediated through impairment of epidermal barrier. Among subjects with AD FLG defects are also consistently associated with asthma and allergic rhinitis (AR) but it is less clear to what extent these associations are also present independently from skin disease. The aim of the present study was to evaluate the role of 2282del4 and R501X in predisposing to these allergic phenotypes in a Polish population., Methodology: 2282del4 and R501X were typed among 3,802 participants of the Epidemiology of Allergic Diseases in Poland (ECAP) survey, a cross-sectional population-based study using ECRHS II and ISAAC questionnaires, and ambulatory examination., Principal Findings: The FLG null variants were associated with AD (OR = 2.01, CI: 1.20-3.36, P = 0.007), allergic rhinitis (in particular persistent form, OR = 1.69, CI:1.12-2.54, P = 0.011), and asthma (in particular atopic asthma, OR = 2.22, CI:1.24-3.96, P = 0.006). Association with atopic asthma (but not persistent allergic rhinitis) was also present in the absence of AD, (OR = 2.02, CI: 1.07-3.81, P = 0.027) as well as in the absence of AD and history of broadly defined inflammatory skin disease (OR = 2.30, CI: 1.07-4.93, P = 0.03). Association to atopic asthma would have not been found if diagnosis was made by questionnaire only (OR = 1.15, CI: 0.58-2.32, P = 0.8). We did not observe an association between FLG variants and allergic sensitizations (P = 0.8) or total IgE. (P = 0.6)., Conclusions/significance: In a Polish population FLG 2282del4 and R501X carriage increases risk for development of AD and atopic asthma (also in the absence of AD or history thereof). This suggests that interventions aimed at restoring epidermal barrier may have a general role in asthma prophylaxis/treatment.

Background: Metachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Based on epidemiological surveys the incidence of MLD per 100,000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data., Methodology: We studied two independently ascertained cohorts from the Polish background population (N∼3000 each) and determined carrier rates of common ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1) and c.459+1G>A, p.I179S (cohort 2)., Principal Findings: Taking into account ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses) was estimated as 4.0/100,000 and 4.1/100,000, respectively for the 1(st) and the 2(nd) cohort with a pooled estimate of 4.1/100,000 (CI: 1.8-9.4) which was higher than the estimate of 0.38 per 100,000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients (OR = 3.6, P = 0.0082, for a comparison of p.I179S frequency relative to c.459+1G>A between controls vs. patients)., Conclusions/significance: The observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms.