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Erythropoietic protoporphyria (EPP) is an autosomal recessive disorder of the heme biosynthesis pathway caused by pathogenic variants in FECH gene resulting in a decreased activity of ferrochelatase. Liver involvement is observed in 5%-20% of patients harbouring loss-of-function FECH variants and its manifestations are heterogeneous, ranging from mildly elevated liver transaminases, cholelithiasis to severe acute cholestatic hepatitis/liver failure. This paper presents the case of a Polish infant with EPP associated with two novel missense FECH variants accompanied by other congenital anomalies, namely atrial septal defect and renal hypodysplasia. Progressive cholestatic liver disease (with subsequent congestive heart failure) was observed in the course of EPP. Erytropoietic protoporphyria should be considered in patients with hepatosplenomegaly and cholestasis accompanied by skin damage. The natural history of liver disease in the course of EPP could be determined by other factors, like the co-existence of congenital anomalies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2025 Lipiński, Lipniacka, Klaudel-Dreszler, Ziółkowska, Kostrzewa, Odnoczko, Wasilewski, Płoski and Tylki-Szymańska.)

Background: Alport syndrome (AS) is a clinically and genetically heterogeneous glomerulopathy resulting from pathogenic variants in COL4A3, COL4A4, and COL4A5 . Genetic diagnosis is increasingly being conducted using next-generation sequencing (NGS). Methods: Within eight years, we examined a group of 247 Polish individuals and found in total 138 unrelated probands suspected with AS based on clinical course, laboratory findings, and/or family history, as well as the total of 109 family members. We applied a targeted NGS panel to identify the genetic spectrum of AS. Known and novel variants were revealed, and detailed evaluation was performed according to ACMG/AMP guidelines to classify them as pathogenic/likely pathogenic/VUS changes. Identified genotypes were compared with clinical manifestations: hematuria, proteinuria, chronic kidney disease, sensorineural hearing impairment, ocular abnormalities, and hypertension. Results: The molecular background was established in 109/138 probands. Overall, 79 different COL4A3-COL4A5 changes (56 known and 23 novel) were revealed. About 97% were SNVs, and only two COL4A5 CNVs were identified. In total, 11 recurrent COL4A3-COL4A5 variants were observed, including the most frequent COL4A5 :p.Gly624Asp, accounting for 31% of X-linked AS. Conclusions: The use of NGS panel has shown considerable promise in the field of AS, increasing diagnostic rate to 79% and reducing time to diagnosis. The phenotype-driven gene panel, specific for genetic diseases in the pediatric population, is an affordable alternative to WGS and WES, offering comparable diagnostic efficacy and supporting its implementation as a first-line genetic test in rare diseases, including AS. Based on the obtained genotype-phenotype correlation, we assessed that NGS allows us to avoid invasive renal biopsy in AS diagnosis. It provides AS confirmation/exclusion, atypical AS identification, symptomatic/asymptomatic monoallelic COL4A3-COL4A5 carrier (especially COL4A5 females) determination, and inheritance pattern establishment. AS diagnosis confirmation enables clinical course prediction and is crucial for the early introduction of renoprotective treatment with renin-angiotensin-aldosterone system blockade, aimed at slowing the disease progression and estimating the risk in family members, which is important for genetic counselling.

Aim: The study was designed to evaluate molecular alterations, relevant to the prognosis and personalized therapy of salivary gland cancers (SGCs)., Materials and Methods: DNA was extracted from archival tissue of 40 patients with various SGCs subtypes. A targeted next-generation sequencing (NGS) panel was used for the identification of small-scale mutations, focal and chromosomal arm-level copy number changes. The final analysis included selected genes with potential actionable aberrations for targeted therapies and outcome predictions in 37 tumours' samples., Results: The follow-up of the SGCs study cohort revealed disease recurrence or metastasis in 19 patients and indicated poor individual outcomes. The mean disease-free survival (DFS) within the poor outcome group was 2.4 years, and the overall survival (OS) was 5.4 years. The DFS and OS of the remaining 18 patients with favourable outcomes were 8.3 years. The genes most frequently affected with aberrations were NF1 (n = 9, 24%) and TP53 (n = 8, 22%), with increased occurrence observed in the poor outcome group: NF1 (n = 6, 32%) and TP53 (n = 6, 32%). CDKN2A biallelic deletion was the most common copy number variation (n = 5), and was detected in 4 cases with identified disease relapse. TERT promoter mutation and amplification were found in myoepithelial carcinoma. A p.Ile35Thr mutation was discovered in CTNNB1 in two cases of adenoid cystic carcinoma. ERBB2 alterations were remarkable for SDC ex PA. Furthermore, TP53 mutation was established as a relevant negative prognostic factor for overall survival (p = 0,04). The analysis revealed potentially actionable genes in detected alterations in: MECA 100% (1/1), SDC 100% (7/7), AD 92% (11/12), Ca ex PA 82% (18/22), MECA 65% (20/31), AdCC 64% (9/14) and AcCC 0% (0/1)., Conclusions: SGCs are a heterogeneous group of malignancies with distinct molecular landscape that characterized by poor prognosis and inadequate treatment options. Nonstandard strategies might be beneficial for patients who suffer from salivary gland cancers. Wider utilization of NGS analysis may increase the opportunity for patients with those rare cancers to receive more precise, personalized therapy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: Potassium ion channels play a crucial role in maintaining cellular electrical stability and are implicated in various epilepsies. Heterozygous pathogenic variants in KCNK4 cause a recognizable neurodevelopmental syndrome with facial dysmorphism, hypertrichosis, epilepsy, intellectual disability (ID), and gingival overgrowth (FHEIG). To date, no more than nine patients with FHEIG have been described worldwide and still little is known about epileptic phenotype in KCNK4-related disease., Methods: We identified a novel de novo p.(Gly139Arg) variant in KCNK4 in a patient with drug-resistant nocturnal seizures, mild ID, and dysmorphic features. In silico analyses of the variant strongly suggest a gain-of-function effect. We conducted a retrospective review of previously published cases, focusing on the epileptic features and response to various treatments., Results: To date, epilepsy has been reported in 8/10 patients with KCNK4-related disease. The mean age of seizure onset was 1.8 years, and the most common seizure type was focal to bilateral tonic-clonic (5/8). Sodium channel blockers and valproate were effective in the majority of patients, but in 3/8 the epilepsy was drug-resistant. Our patient showed improved seizure control after treatment with the carbonic anhydrase inhibitor sulthiame. Interestingly, the patient showed features of peripheral nerve hyperexcitability syndrome, a phenomenon not previously described in potassium channelopathies caused by increased K+ conductance., Conclusion: Gain-of-function variants in KCNK4 cause a spectrum of epilepsies, ranging from benign isolated epilepsy to epileptic encephalopathy, with focal to bilateral tonic-clonic seizures being the most commonly observed. Importantly, a subgroup of patients present with a mild extra-neurological phenotype without characteristic facial dysmorphism or generalized hypertrichosis. This report expands the phenotypic spectrum of KNCK4-associated disease and provides new insights into the clinical heterogeneity of this rare neurodevelopmental syndrome., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Genetic mosaicism caused by postzygotic mutations is of a great interest due to its role in human disease. Monozygotic twins arising from a single zygote are considered as genetically identical, and any differences likely to be caused by postzygotic events. Thus, phenotypically discordant monozygotic twins offer a unique opportunity to study genotype-phenotype correlation. Here, we present a three-generation family starting from a pair of monozygotic twins discordant for metachondromatosis due to postzygotic p.(Gln175His) variant in the PTPN11 gene. Both phenotypically discordant monozygotic twins harbor p.(Gln175His), however significant differences in mosaic ratio is observed not only between twins, but also within different tissue types within one individual. Phenotypic manifestation of p.(Gln175His) in examined family clearly depends on allele variant fraction (VAF). Individuals harboring constitutional mutation (VAF 50%) present typical metachondromatosis. Milder phenotype is observed in twin harboring high-level mosaicism in the tissue of ectodermal origin (VAF 45%), but not in a blood (VAF 5%). Finally, her twin sister harboring low-level mosaicism in blood (VAF 2%) and nonblood (VAF 12%) tissues is phenotypically normal. Our results provide insights into biological role of mosaicism in disease and further support the usefulness of nonblood tissues as an optimal source of DNA for the identification of postzygotic mutations in phenotypically discordant monozygotic twins., (© 2022 Wiley Periodicals LLC.)

Background: Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous cardiomyopathy in which myocardium consists of two, distinct compacted and noncompacted layers, and prominent ventricular trabeculations and deep intertrabecular recesses are present. LVNC is associated with an increased risk of heart failure, atrial and ventricular arrhythmias and thromboembolic events. Familial forms of primary sinus bradycardia have been attributed to alterations in HCN4 . There are very few reports about the association between HCN4 and LVNC. The aim of our study was to characterize the clinical phenotype of families with LVNC and sinus bradycardia caused by pathogenic variants of the HCN4 gene., Methods: From March 2008 to July 2021, we enrolled six patients from four families with diagnosed isolated LVNC based on the clinical presentation, family history and echocardiographic and cardiovascular magnetic resonance (CMR) evidence of LVNC. Next generation sequencing (NGS) analysis was undertaken for the evaluation of the molecular basis of the disease in each family., Results: A total of six children (median age 11 years) were recruited and followed prospectively for the median of 12 years. All six patients were diagnosed with LVNC by echocardiography, and five participants additionally by CMR. The presence of late gadolinium enhancement (LGE) was found in three children. Sinus bradycardia and dilation of the ascending aorta occurred in five studied patients. In four patients from three families, the molecular studies demonstrated the presence of rare heterozygous HCN4 variants., Conclusion: (1) The HCN4 molecular variants influence the presence of a complex LVNC phenotype, sinus bradycardia and dilation of the ascending aorta. (2) The HCN4 alteration may be associated with the early presentation of clinical symptoms and the severe course of the disease. (3) It is particularly important to assess myocardial fibrosis not only within the ventricles, but also in the atria in patients with LVNC and sinus bradycardia.

Developmental and epileptic encephalopathies (DEE) are a heterogenous group of conditions characterized by the co-occurrence of epilepsy and intellectual/developmental disability. Despite several known DEE-related genes, including these encoding ion channels, still many cases remain without molecular diagnosis. Here, we present a 2-year-old girl with severe DEE in whom whole exome sequencing revealed de novo p.(Val471Leu) variant in the KCNC2 encoding Kv3.2, a voltage-gated potassium channel. To the best of our knowledge, this is the third DEE case due to KCNC2 mutation. Our clinical and molecular findings, particularly the recurrence of p.(Val471Leu) in patient with similar clinical phenotype, further support KCNC2 as a novel DEE-associated gene., (© 2021 Wiley Periodicals LLC.)

Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of single-gene disorders in the prenatal period. Two patients with a prenatal diagnosis of polycystic kidney disease are presented in this article. TMEM67 mutations were identified in both fetuses using a whole-exome sequencing (WES) study. In one of them, the phenotypic syndrome diagnosed prenatally was different from that diagnosed in the postnatal period.

Background: Phenotypically discordant monozygotic twins (PDMZTs) offer a unique opportunity to study post-zygotic genetic variation and provide insights into the linkage between genotype and phenotype. We report a comprehensive analysis of a pair of PDMZTs., Methods: Dysmorphic features and delayed neuro-motor development were observed in the proband, whereas her twin sister was phenotypically normal. Four tissues (blood, skin, hair follicles, and buccal mucosa) from both twins were studied using four complementary methods, including whole-exome sequencing, karyotyping, array CGH, and SNP array., Results: In the proband, tetrasomy 18p affecting all studied tissues except for blood was identified. Karyotyping of fibroblasts revealed isochromosome 18p [i(18p)] in all metaphases. The corresponding analysis of the phenotypically normal sister surprisingly revealed low-level mosaicism (5.4%) for i(18p) in fibroblasts., Conclusion: We emphasize that when mosaicism is suspected, multiple tissues should be studied and we highlight the usefulness of non-invasive sampling of hair follicles and buccal mucosa as a convenient source of non-mesoderm-derived DNA, which complements the analysis of mesoderm using blood. Moreover, low-level mosaic tetrasomy 18p is well tolerated and such low-level mosaicism, readily detected by karyotyping, can be missed by other methods. Finally, mosaicism for low-level tetrasomy 18p might be more common in the general population than it is currently recognized, due to detection limitations., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: The insertion/deletion (I/D) polymorphism of the angiotensin‑converting enzyme (ACE) gene is associated with younger age at coronary artery disease (CAD) onset. Some data indicate the relationship between the DD genotype and the fibrinogen level. At the same time, the regulation of the renin-angiotensin system differs in women and men., Objectives: The objective of the study was to evaluate the sex‑dependentassociation of the ACE I/D polymorphism with the plasma fibrinogen level in patients with premature CAD., Patients and Methods: The study included 407 participants with premature CAD: 257 women not older than 55 years and 150 men not older than 45 years. Study participants had at least 1 stenosis ≥50% in a major epicardial coronary artery. The ACE I/D polymorphism (rs4343) was genotyped using polymerase chain reaction. Fibrinogen levels were measured with a modified Clauss method. We found a significant interaction indicating that sex modifies the influence of the I/D polymorphism of the ACE gene on fibrinogen levels (P = 0.02). The highest mean fibrinogen level, adjusted for age and smoking status, was observed in women with the DD genotype (575.7 mg/dl) and it was significantly higher than in men with the DD genotype (367.1 mg/dl; P <0.001) or in women with the ID genotype (491.7 mg/dl; P = 0.04). In men, there was no significant difference in mean adjusted fibrinogen levels across genotypes., Conclusions: The DD genotype of the ACE gene was associated with higher plasma fibrinogen levels in women with premature CAD yet not in men.

The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes ( TTN , DSP , SCN5A , TNNC1 , TPM1 , CRYAB , MYH7 ). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease ( TRIB3 , SLC2A6 ), a possible disease-causing biallelic genotype ( APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity ( UNC45A ). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript or in the decision to publish the results.

Objective: During the treatment of our patient we found that reports covering possible complications and their treatment are very scarce. Due to advancement in ultrasound diagnosis most of molar pregnancies are terminated in first trimester of pregnancy. There is the gap in knowledge concerning pregnancy complications in case of partial mole discovered in advanced pregnancy. This is why we incorporated extensive and up-to-date review of literature in our manuscript., Method: We described a case of previously healthy, 25 year old primigravida who delivered live daughter at 27 weeks of gestation, complicated with unusual ultrasound appearance of the placenta, severe hypotrophy, and subsequent post-partum eclampsia., Results: Healthy diploid female infant, now two years old and healthy mother taking care of her., Conclusions: In clinical practice early diagnosis of this complication usually lead to pregnancy termination. In modern medicine, decisions should be based on evidence and patient-doctor mutual understanding. Termination of pregnancy with suspicion of molar placenta can be specially difficult in gestation in older nulliparous women or after ART. We sincerely hope that this report will be useful for physicians across the world in counseling and treating their patients.

PPP3CA encodes calmodulin-binding catalytic subunit of calcineurin, a ubiquitously expressed calcium/calmodulin-regulated protein phosphatase. Recently de novo PPP3CA variants were reported as a cause of disease in 12 subjects presenting with epileptic encephalopathy and dysmorphic features. We describe a boy with similar phenotype and severe early onset epileptic encephalopathy in whom a novel de novo c.1324C>T (p.(Gln442Ter)) PPP3CA variant was found by whole exome sequencing. Western blot experiments in patient's cells (EBV transformed lymphocytes and neuronal cells derived through reprogramming) indicate that despite normal mRNA abundance the protein expression level is strongly reduced both for the mutated and wild-type protein. By in vitro studies with recombinant protein expressed in E. coli we show that c.1324C>T (p.(Gln442Ter)) results in constitutive activation of the enzyme. Our results confirm the role of PPP3CA defects in pathogenesis of a distinct neurodevelopmental disorder including severe epilepsy and dysmorphism and provide further functional clues regarding the pathogenic mechanism.

Overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features are the main symptoms of Weaver syndrome, a rare condition caused by mutations in EZH2 gene. Recently, in four patients with Weaver-like symptoms without mutations in EZH2 gene, pathogenic variants in EED were described. We present another patient clinically diagnosed with Weaver syndrome in whom WES revealed an EED de novo mutation affecting two neighboring aminoacids, NM&#95;003797.3:c.917&#95;919delinsCGG/p.(Arg306&#95;Asn307delinsThrAsp) located in one allele (in cis). Our observation, together with previous reports suggests that EED gene testing is warranted in patients with the overgrowth syndrome features and suspicion of Weaver syndrome with normal results of EZH2 gene sequencing.

Zellweger syndrome (ZS) is a consequence of a peroxisome biogenesis disorder (PBD) caused by the presence of a pathogenic mutation in one of the 13 genes from the PEX family. ZS is a severe multisystem condition characterized by neonatal appearance of symptoms and a shorter life. Here, we report a case of ZS with a mild phenotype, due to a novel PEX6 gene mutation. The patient presented subtle craniofacial dysmorphic features and slightly slower psychomotor development. At the age of 2 years, he was diagnosed with adrenal insufficiency, hypoacusis, and general deterioration. Magnetic resonance imaging showed a symmetrical hyperintense signal in the frontal and parietal white matter. Biochemical tests showed elevated liver transaminases, elevated serum very long chain fatty acids, and phytanic acid. After the death of the child at the age of 6 years, molecular diagnostics were continued in order to provide genetic counseling for his parents. Next generation sequencing (NGS) analysis with the TruSight One™ Sequencing Panel revealed a novel homozygous PEX6 p.Ala94Pro mutation. In silico prediction of variant severity suggested its possible benign effect. To conclude, in the milder phenotypes, adrenal insufficiency, hypoacusis, and leukodystrophy together seem to be pathognomonic for ZS.

The T allele of rs7927894 (at 11q13.5) was associated with atopic dermatitis and other allergic diseases. Our purpose was to replicate the association with allergic phenotypes and explore the role of rs7927894 in predisposing to persistent allergic rhinitis and atopic asthma. We also wanted to explore if other SNPs at 11q13.5 contributed to effect of rs7927894. We studied patients with atopic dermatitis (N = 270), atopic asthma (N = 486), persistent allergic rhinitis (N = 589) and controls matched for age, sex and region (N = 540, N = 372 and N = 1178, respectively). We found that rs7927894 T was associated with atopic dermatitis (OR = 1.39, CI: 1.12-1.73, P = 0.003) and independently with persistent allergic rhinitis (OR = 1.24, CI:1.07-1.43, P = 0.0043, Pcorrected = 0.013) but not atopic asthma. Analysis of additional tagging SNPs (rs7930763, rs2513517, rs7125552) showed that effect of rs7927894 T was limited to haplotypes encoding G at rs7125552. In conclusion, rs7927894 T is associated not only with atopic dermatitis but also persistent allergic rhinitis. Since these effects are haplotype dependent rs7927894 alone does not account for the association between 11q13.5 and atopic dermatitis/persistent allergic rhinitis.

In the light of contradictory results concerning OXTR polymorphism rs53576 and depression, we decided to verify the potential association between the two on 1) a large, ethnically homogenous sample of 1185 individuals who completed the Beck Depression Inventory (BDI), as well as on 2) a sample of 763 suicide victims. In the population sample, AA males showed significantly lower BDI scores (p=0.005, p cor =0.030). Exploratory analyses suggested that this effect was limited to a subgroup within 0-9 BDI score range (p=0.0007, U-Mann Whitney test), whereas no main effect on depressive symptoms (BDI>9) was found. In the suicide sample no association with rs53576 genotype was present. Exploratory analyses in suicides revealed higher blood alcohol concentration (BAC) among AA than GG/GA males (p=0.014, U-Mann Whitney test). Our results show that the OXTR rs53576 variant modulates the mood in male individuals and may positively correlate with alcohol intake among male suicides, but is not associated with suicide or depression. The study adds to the growing knowledge on rs53576 genotype characteristics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim of the study: We present the application of massively parallel sequencing (MPS) to extend the scope of analysis in a disputed paternity case. Material and methods: A standard paternity test comprising 16 autosomal STRs was performed by capillary electrophoresis (CE) using 3130xl Genetic Analyzer. Additionally, MPS was performed with ForenSeq DNA Signature Prep Kit and Illumina MiSeq FGx™ Forensic Genomics System. Paternity index (PI) was calculated using DNAStat v.2.1 software. Results>: CE revealed two mismatches, at D21S11 and VWA, between the putative father and the child. Based on MPS results, the mismatches were analyzed and a nonconsensus sequence of allele 14 at the VWA locus in the mother - child pair was identified. Different sequence variants were also detected in 16-16 homozygote alleles at the D3S1358 locus in the child. Conclusions: MPS helped to formulate a definite conclusion regarding the paternity of the defendant and provided full information on intra-allelic polymorphism.

Epileptic encephalopathies (EE) include a range of severe epilepsies in which intractable seizures or severe sub-clinical epileptiform activity are accompanied by impairment of motor and cognitive functions. Mutations in several genes including ion channels and other genes whose function is not completely understood have been associated to some EE. In this report, we provide a detailed clinical description of a sporadic male patient with early-onset epilepsy and epileptic encephalopathy in whom we performed complete exome sequencing (WES) and identified a GRIN2B mutation. The GRIN2B splicing mutation in intron 10 (c.2011-1G>A) was revealed in a WES study. The result was confirmed by Sanger sequencing. No mutation was found in both parents. Our finding confirms that early-onset EE may be caused not only by gain-of-function variants but also by splice site mutations-in particular those affecting the splice acceptor site of the 10th intron of the GRIN2B gene. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Endometriosis is defined as the presence of functional endometrial tissue outside the uterine cavity. Several hypotheses have attempted to explain the etiology and pathogenesis of endometriosis. Recently, it has been suggested that a defect of the natural killer (NK) activity in the recognition and lysis of endometrial cells is one of the crucial points in the development of this disease. Natural killer cells can express killer immunoglobulin-like receptors (KIR), which recognize class I human leukocyte antigens on target cells. We asked whether polymorphisms in KIR, HLA-C, and HLA-B genes are risk factors for endometriosis. We tested 153 women with endometriosis diagnosed on the basis of laparoscopic and histological examination, and 213 control healthy women, who gave birth to at least one child. The frequency of KIR genes in patients was similar to that in controls except for KIR2DS5, which exerted a protective effect only in HLA-C C2-positive individuals. Moreover, KIR2DS5-positive women with endometriosis had 13 times lower chance that the disease would occupy the peritoneum than KIR2DS5- and KIR2DS4del-negative ones (OR = 0.077, P = 0.0061). Similarly, KIR2DS4del-positive endometriotic persons had 11 times lower chance for peritoneal disease (OR = 0.094, P < 0.001). Negative linkage disequilibrium between KIR2DS5 and KIR2DS4del indicates that these genes are mutually exclusive. Our data suggest that KIR2DS5 may be associated with protection from endometriosis, whereas KIR2DS4del seems to be associated with higher disease stages, possibly by exclusion of protective KIR2DS5.

Genetic variants of Y chromosome predispose to hypertension in rodents, whereas in humans the evidence is conflicting. Our purpose was to study the distribution of a panel of Y chromosome markers in a cohort from a cross-sectional population-based study on the prevalence of cardiovascular risk factors in Poland (WOBASZ study). The HindIII, YAP Y chromosome variants, previously shown to influence blood pressure, lipid traits or height, as well as SNPs defining main Y chromosome haplogroups, were typed in 3026, 2783 and 2652 samples, respectively. In addition, 4 subgroups (N~100 each) representing extremes of LDL concentration or blood pressure (BP) were typed for a panel of 17 STRs. The HindIII and YAP polymorphism were not associated with any of the studied traits. Analysis of the haplogroup distribution showed an association between higher HDL level and hg I-M170 (P = 0.02), higher LDL level and hg F*(xI-M170, J2-M172, K-M9) (P = 0.03) and lower BMI and hg N3-Tat (P = 0.04). Analysis of STRs did not show statistically significant differences. Since all these associations lost statistical significance after Bonferroni correction, we conclude that a major role of Y chromosome genetic variation (defined by HindIII, YAP or main Y chromosome haplogroups) in determining cardiovascular risk in Poles is unlikely.

Background: We hypothesized that DNA variants affecting neurodevelopment such as rs4307059 (CDH10/CDH9), rs930752 (NRXN1), rs6265 (BDNF) or rs10868235 (NTRK2) may predispose to completed suicide., Methodology: We used a case-control two-stage approach based on a discovery cohort (557 cases and ∼550 controls) and replication cohort (159 cases and 186 controls). The suicides were ascertained as consecutive cases autopsied at the Department of Forensic Medicine, Medical University of Warsaw, Poland., Results: In the discovery cohort we found an association between suicide and the CC genotype in the rs4307059 polymorphism (OR 1.64, p = 0.012). The trend for an overrepresentation of the CC homozygotes among suicides was replicated in the second cohort (OR 1.97, p = 0.056). Analysis in the pooled cohorts showed that rs4307059 CC was associated with completed suicide (OR 1.71, p = 0.002) also after Bonferroni correction (p(cor.) = 0.024). In an exploratory search for genotype-phenotype correlation we found that males with the rs4307059 CC genotype committed suicide earlier than those with CT/TT genotypes (p = 0.049)., Conclusions: The CC genotype of rs4307059 located in the region between CDH9 and CDH10 is associated with completed suicide in a Polish cohort., (Copyright © 2012 S. Karger AG, Basel.)

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.

The association between suicide and a single nucleotide polymorphism (rs1386483) was examined in the recently identified tryptophan hydroxylase 2 (TPH2) gene. Blood samples of 143 suicide victims and 162 age- and sex-matched controls were examined. The frequency of the TT genotype in the TPH2 polymorphism was higher in suicide victims than in controls (17.5% vs. 8.6%; p = 0.02), particularly in those with a history of repeated suicide attempts (53.3% vs. 8.6%; p < 0.0001). The examined TPH2 polymorphism was found to be associated with suicide. This genetic marker may be particularly important in understanding risk of multiple suicide attempts. Further analyses are needed to confirm these results.

Objectives: To determine whether the 681 G>A (*2) polymorphism of cytochrome P450 (CYP2C19) is related to suboptimal reperfusion and mortality in patients with acute myocardial infarction (AMI) pretreated with clopidogrel., Methods: The study included 276 consecutive patients with AMI in whom percutaneous coronary intervention (PCI) with stenting was attempted. Four-year follow-up for all-cause mortality was obtained., Results: There were 15 failed procedures (5.4%). In the remaining 261 patients, suboptimal reperfusion (post-PCI TIMI flow <3) was observed in 12.6% of the cases. There were 56 carriers (50 heterozygous and 6 homozygous) of CYP2C19*2. The prevalence of carriers in patients with suboptimal flow was 39.4% in comparison to 18.9% in the other patients (p = 0.01). Independent predictors of suboptimal reperfusion were initial TIMI flow ≤1 (OR = 5.9, 95% CI 2.2-16.2, p = 0.001) and CYP2C19*2 (OR = 2.9, 95% CI 1.3-6.6, p = 0.01). Thirty patients died during follow-up (11.5%). Four-year mortality tended to be higher in carriers of CYP2C19*2 (17.9%) versus non-carriers (9.8%; p = 0.09), but the only independent predictors of death were age (HR = 2.0, 95% CI = 1.4-2.8, p = 0.0001) and suboptimal reperfusion (HR = 3.6, 95% CI 1.5-8.8, p = 0.004)., Conclusions: The CYP2C19*2 allele is an independent predictor of suboptimal reperfusion in patients with AMI undergoing PCI with stenting after pretreatment with clopidogrel and may increase the risk of all-cause mortality., (Copyright © 2010 S. Karger AG, Basel.)

Background: Genetic C3435T polymorphism of the multidrug resistance gene-1 (MDR-1) limits oral bioavailability of clopidogrel and influences prognosis in patients with myocardial infarction., Aim: To assess the effects of C3435T polymorphism on platelet reactivity and prognosis in patients with acute coronary syndromes treated with percutaneous coronary intervention with stenting., Methods: Ninety-eight patients were divided into subgroups according to closure time (CT) measured with the Platelet Function Analyzer-100 by means of collagen/adenosine diphosphate (CADP) and collagen/epinephrine (CEPI) cartridges. Patients with CADP-CT<130 s and patients with CEPI-CT

Endometriosis is a common gynaecological disorder due to ectopic implantation of endometrial tissue. It is manifested by pelvic inflammation and abrogation of cell-mediated immunity and may be also characterised by autoantibody production, thus suggesting that endometriosis might be an autoimmune disorder. Genetic factors also play a role in the aetiopathogenesis of this disease. Therefore, the present study was aimed at testing the association of endometriosis with the PTPN22/LYP 1858C> T gene polymorphism, which appears to be related to the development of a variety of autoimmune disorders. The study included 171 Polish patients of Caucasian origin with laparoscopically and histopathologically confirmed endometriosis and 310 unrelated, ethnically matched control individuals. DNA and serum were isolated from the peripheral blood. The PTPN22/LYP 1858C> T polymorphism was typed using a PCR-RFLP method. Anti-nuclear (ANA) and anti-cardiolipin (ACA) autoantibodies were detected by the Hep-2 indirect immunofluorescence test and a specific ELISA respectively. No statistically significant differences were found in distribution of C and T PTPN22/LYP alleles and genotypes in patients with endometriosis compared with the control population. However, on exploratory analyses we noted that the PTPN22/LYB T allele and the TT genotype may be associated with the prevalence of double positivity for ANA and ACA (p=0.003 by chi(2) test for trend and p=0.009 by Fisher's exact test respectively). The results of the present study show that endometriosis in a Polish population is not associated with the PTPN22/LYP 1858C> T gene polymorphism. The putative effect of the PTPN22/LYP genotype on the development of autoantibodies is potentially interesting, but it should be verified in further studies.

Background/aims: An association between the II genotype of the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and suicide was found among Japanese men. Our purpose was to replicate this finding in Caucasians and explore other putative genotypic associations among suicides., Methods: The ACE genotypes were studied by a 2-stage PCR method in 150 completed suicides and 165 age- and sex-matched controls., Results: We found an increase in the frequency of the ACEI allele among male victims of suicide compared to male controls (odds ratio, OR = 1.69, p < 0.006), female suicides (OR = 2.01, p = 0.006) and pooled controls (OR = 1.77, p = 0.001). Analysis of genotype distribution showed that the codominant model had the best fit (p = 0.7) whereas the recessive model could be rejected (p = 0.04). Among males we found an association between the number of the ACE I allele and the method of suicide: OR = 17.98, p(corrected) = 0.00003, for jumping from a height; OR = 0.36, p(corrected) = 0.048, for hanging. We also observed a trend for a negative effect of the number of copies of the ACE I allele on prevalence of depression (OR = 0.36, p = 0.013) and a trend for an effect on age at death (p = 0.021)., Conclusions: Our results suggest that low ACE activity associated with the I allele is a risk factor for suicide, especially in a subset of males. This may be of concern given the widespread use of drugs lowering ACE activity., (Copyright 2009 S. Karger AG, Basel.)

Background: Coexisting polymorphisms of the genes affecting clopiogrel resistance may influence platelet activation., Methods and Results: In 105 patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention, platelet function was measured and registered as closure time in the test with collagen and adenosine diphosphate (CADP-CT). Patients were followed for 12 months for death or recurrent myocardial infarction (MI). Genotyping revealed 7 carriers of both the C allele of P2Y12 and A allele of CYP2C19 (group 1), 14 carriers of the T allele of P2Y12 and A allele of CYP2C19 (group 2), 17 carriers of the C allele of P2Y12 and G allele of CYP2C19 (group 3) and 67 carriers of the T allele of P2Y12 and G allele of CYP2C19 (controls). The median CADP-CT value was significantly lower in group 1 than in group 2 or 3 (p<0.01) or controls (p<0.002), but did not differ between group 2 or 3 and controls. There were 2 cardiovascular deaths and 4 MI during follow-up, and the median CADP-CT value was lower in these patients (p=0.09)., Conclusions: Coexisting, rather then single, polymorphisms of different genes may be related to persistent platelet activation while on clopidogrel, which raises concern about harm in patients with ACS.

The purpose was to study the effect of PCSK9 46L on cholesterol concentration and cardiovascular morbidity. By comparing 176 carriers with 6618 non-carriers identified through a cross-sectional population study (WOBASZ) we confirmed the LDL lowering effect of PCSK9 46L and demonstrated that it increases with the concentration of LDL. We noted that PCSK9 46L was associated with tendency for protection from myocardial infarction but not stroke suggesting a difference in the effect on susceptibility to these disorders.

Objective: To investigate whether a polymorphism in the ESR2 gene (rs4986938, previously associated with endometriosis, ovulatory dysfunction and premature onset of coronary heart disease) increases the risk of Graves' disease (GD)., Subjects and Design: A cohort of 375 GD patients (300 females and 75 males) and 1001 individuals representative of the background population of Poland (502 males and 499 females) were genotyped for rs4986938 using allele-specific polymerase chain reaction (PCR)., Results: We found an increased frequency of the ESR2 A allele among the patients vs. controls (38.0%vs. 32.7%, OR = 1.26, P = 0.009) that was caused by a co-dominant (OR = 1.25, P = 0.01, P(for model fit) = 0.127) or a recessive (OR = 1.67, P = 0.003, P(for model fit) = 0.554) effect. The association was found in both sexes (OR = 1.21, P = 0.046 and OR = 1.53, P = 0.029, respectively, for co-dominant and recessive models in females, and OR = 1.44, P = 0.034 and OR = 2.29, P = 0.01, respectively, for the two models in males) and was more pronounced among the DRB1*03-negative (OR = 1.63, P = 0.0002) than DRB1*03-positive patients (OR = 1.04, P = 0.822). No other statistically significant associations between the ESR2 genotype and GD subsets were found (age of onset, smoking, clinically evident ophthalmopathy, family history of GD, and PTPN22 and CTLA4 (CT60) genotypes were analysed)., Conclusions: In a Polish population the ESR2 A allele is associated with GD with a strength comparable to polymorphisms of PTPN22 and CTLA4 CT60 loci (OR approximately 1.7). The association with ESR2 is found in both sexes and may be particularly strong among the DRB1*03-negative individuals.

Despite research the role of the M34T and V37I variants of GJB2 in causing hearing impairment (HI) remains controversial. Our purpose was to test a hypothesis that M34T and V37I are pathogenic but have distinct features resulting in a reduced penetrance. We screened for known GJB2/GJB6 mutations 233 Polish consecutive unrelated subjects with non-syndromic, sensorineural HI who were previously found to carry 35delG mutation on one chromosome. The most frequent mutations were also analyzed in approximately 1,000 controls. We found that M34T and V37I were significantly (P << 10(-6)) overrepresented among patients, but their penetrance was estimated as 1/10 relative to mutations of undisputed pathogenicity. This finding apparently could not be explained by low degree of HI associated with M34T and V37I since another mutation causing comparably mild HI (L90P) did not have reduced penetrance. Subsequent analyses showed that the patients with M34T/35delG and V37I/35delG had significantly later onset of HI than patients with other genotypes (P < 10(-6)) including the L90P/35delG (P = 0.006). Also, among these patients (but not others) a strong correlation between the degree of HI and its duration was found (r = 0.79, P < 10(-5)). We tentatively suggest that M34T and V37I might cause mild HI characterized by relatively late onset and progression., (Copyright 2007 Wiley-Liss, Inc.)