Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk.

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk.

Improved polygenic risk prediction in migraine-first patients.

BACKGROUND: Recent meta-analyses estimated 14.6% and 11.2% SNP-based heritability of migraine, compared to twin-heritability estimates of 30-60%. This study aimed to investigate heritability estimates in "migraine-first" individuals, patients for whom G43 (migraine with or without aura) was their first medical diagnosis in their lifetime. FINDINGS: Using data from the UK Biobank (N = 199,929), genome-wide association studies (GWAS) were conducted on 6,139 migraine-first patients and 193,790 healthy controls. SNP-based heritability was estimated using SumHer, yielding 19.37% (± 0.019) for all SNPs and 21.31% (± 0.019) for HapMap3 variants, substantially surpassing previous estimates. Key risk loci included PRDM16, FHL5, ASTN2, STAT6/LRP1, and SLC24A3, and pathway analyses highlighted retinol metabolism and steroid hormone biosynthesis as important pathways in these patients. CONCLUSIONS: The findings underscore that excluding comorbidities at onset time can enhance heritability estimates and genetic signal detection, significantly reducing the extent of "missing heritability" in migraine.

Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.

BACKGROUND: Evidence from rodents indicated that after recent stress, reduced expression of tight junction protein claudin-5 may weaken the blood-brain barrier and allow interleukin-6 to induce depressive symptoms. Our aims were to prove this pathomechanism in humans. METHODS: We used a large population genetic database (UK Biobank, n = 277 501) to test whether variation in the CLDN5 gene could modulate effects of the IL6 gene variant in stress-induced depression. Three-way interaction of functional polymorphisms, rs885985 of CLDN5, and rs1800795 of IL6 with recent stressful life events were tested on current depressive symptoms. Analyses were performed in male and female populations as well. RESULTS: The 3-way interaction including recent stress yielded highly significant results on current depressive symptoms in the UK Biobank sample, which was more pronounced in men and could be replicated on trend level in an independent cohort (NewMood, n = 1638). None of any other associations or interactions, including, for example, childhood stressors and lifetime depression as an outcome, yielded significance. CONCLUSIONS: These findings provide genetic evidence in humans for the interaction among interleukin-6, claudin-5, and recent stress, suggesting that inflammation is involved in the development of depression and that stress-connected brain entry of inflammatory molecules is a key factor in this pathomechanism. These genetic polymorphisms may help to identify people at higher risk for recent stress-induced depression.

Genetic Etiology of Nonsyndromic Hearing Loss in Hungarian Patients.

Hearing loss is the most prevalent sensory disorder worldwide. The majority of congenital nonsyndromic hearing loss (NSHL) cases are caused by hereditary factors. Previously, the majority of NSHL studies focused on the GJB2 gene; however, with the availability of next-generation sequencing (NGS) methods, the number of novel variants associated with NSHL has increased. The purpose of this study was to design effective genetic screening for a Hungarian population based on a pilot study with 139 NSHL patients. A stepwise, comprehensive genetic approach was developed, including bidirectional capillary sequencing, multiplex ligation-dependent probe amplification (MLPA), and an NGS panel of 108 hearing loss genes. With our results, a genetic diagnosis was possible for 92 patients. Sanger sequencing and MLPA identified the genetic background of 50% of these diagnosed cases, and the NGS panel identified another 16%. The vast majority (92%) of the diagnosed cases showed autosomal recessive inheritance and 76% were attributed to GJB2. The implementation of this stepwise analysis markedly increased our diagnostic yield and proved to be cost-effective as well.

Effect of pituitary adenylate cyclase-activating polypeptide supplementation, applied during or after vitrification on mouse embryo.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with widespread occurrence and diverse functions. It occurs in high levels in the gonads suggesting a potential central role in reproduction. The aim of our study was to assess the effect of PACAP treatment during embryo vitrification on the developmental rate and the expression of the heparin-binding EGF-like growth factor gene (Hbegf). Mouse embryos, obtained from superovulated females were allocated into the four treatment groups. In EM1 and EM2, the embryos were prepared for vitrification in an Equilibration Solution that was supplemented with 1 or 2 µM PACAP1-38, respectively. The embyos in groups CM1 and CM2 were not treated prior to vitrification but were cultured in a medium supplemented with 1 or 2 µM PACAP1-38 after thawing. The Vitrified Control group consisted of embryos vitrified and thawed then cultured without PACAP1-38 treatment. A non-vitrified, non-treated Fresh Control group was also used. After 24 h of culture, the developmental rate of the embryos, as well as the relative expression level of the Hbegf gene, as determined by qPCR, were compared among groups. Higher developmental rate and Hbegf gene expression level were found in the embryos treated with a higher concentration of PACAP. These results indicate that PACAP treatment has a beneficial effect on the survival and development of vitrified/thawed mouse embryos.

Genetic investigation confirmed the clinical phenotype of congenital chloride diarrhea in a Hungarian patient: a case report.

BACKGROUND: Congenital chloride diarrhea (CCD, OMIM 214700) is a rare autosomal recessively inherited condition characterized by watery diarrhea, hypochloremia and metabolic alkalosis. Mutations of the solute carrier family 26, member 3 (SLC26A3, OMIM 126650) gene are responsible for the disease. The gene encodes a transmembrane protein, which is essential for intestinal chloride absorption. CASE PRESENTATION: Here we report a Hungarian boy, presenting the clinical phenotype of CCD. The patient born at 32 weeks of gestation and underwent surgery for abdominal distension and intestinal obstruction related to malrotation. After recovery, electrolyte replacement therapy was necessary due to several periods of diarrhea. After exclusion of other possible causes, increased chloride concentration in the feces supported the diagnosis of CCD. The diagnosis was confirmed by molecular genetic testing. Direct sequencing revealed compound-heterozygosity for a frameshift mutation c.1295delT (p.Leu432Argfs*11) and the known Polish founder mutation c.2024_2026dupTCA (p.Ile675_Arg676insLeu). CONCLUSIONS: Here we present the clinical symptoms of the first patient in Hungary diagnosed with CCD. Based on the clinical symptoms, stool analysis and genetic testing, the diagnosis of CCD was established. Our study provides expansion for the mutation spectrum of the SLC26A3 gene and the genetic background of CCD.

[Steroid 21-hydroxylase deficiency, the most frequent cause of congenital adrenal hyperplasia]. / Szteroid-21-hidroxiláz-deficientia, a congenitalis adrenalis hyperplasia leggyakoribb oka.

Congenital adrenal hyperplasia is a group of genetic diseases due to the disablement of 7 genes; one of them is steroid 21-hydroxylase deficiency. The genes of congenital adrenal hyperplasia encode enzymes taking part in the steroidogenesis of adrenal gland. Steroid 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations of the steroid 21-hydroxylase gene. The mutations of steroid 21-hydroxylase gene cause 95% of the congenital adrenal hyperplasia cases. Although the non-classic steroid 21-hydroxylase deficiency with mild symptoms is seldom diagnosed, the classic steroid 21-hydroxylase deficiency may lead to life-threatening salt-wasting and adrenal crises due to the insufficient aldosterone and cortisol serum levels. The classic type requires life-long steroid replacement which may result in cushingoid side effects, and typical comorbidities may be also developed. The patients' quality of life is decreased, and their mortality is much higher than that of the population without steroid 21-hydroxylase deficiency. The diagnosis, consequences and the patients' life-long clinical care require a multidisciplinary approach: the specialists in pediatrics, internal medicine, endocrinology, laboratory medicine, genetic diagnostics, surgery, obstetrics-gynecology and psychology need to work together. Orv Hetil. 2018; 159(7): 269-277.

[Rapid first-tier genetic diagnosis in patients with Prader-Willi syndrome]. / Elsodleges genetikai vizsgálat Prader­Willi-szindróma igazolására.

INTRODUCTION: According to the international literature, DNA methylation analysis of the promoter region of SNRPN locus is the most efficient way to start genetic investigation in patients with suspected Prader-Willi syndrome. AIM: Our aim was to develop a simple, reliable first-tier diagnosis to confirm Prader-Willi syndrome, therefore to compare our self-designed simple, cost-efficient high-resolution melting analysis and the most commonly used methylation-specific multiplex ligation-dependent probe amplification to confirm Prader-Willi syndrome. METHOD: We studied 17 clinically suspected Prader-Willi syndrome children and their DNA samples. With self-designed primers, bisulfite-sensitive polymerase chain reaction, high-resolution melting analysis and, as a control, methylation-specific multiplex ligation-dependent probe amplification were performed. RESULTS: Prader-Willi syndrome was genetically confirmed in 6 out of 17 clinically suspected Prader-Willi syndrome patients. The results of high-resolution melting analysis and methylation-specific multiplex ligation-dependent probe amplification were equivalent in each case. CONCLUSION: Using our self-designed primers and altered bisulfite-specific PCR conditions, high-resolution melting analysis appears to be a simple, fast, reliable and effective method for primarily proving or excluding clinically suspected Prade-Willi syndrome cases. Orv Hetil. 2018; 159(2): 64-69.

[The prevalence of SHOX gene deletion in children with idiopathic short stature. A multicentric study]. / A SHOX géndeletio elofordulása idiopáthiás alacsonynövésben. Multicentrikus tanulmány.

INTRODUCTION: The isolated haploinsufficiency of the SHOX gene is one of the most common cause of short stature determined by monogenic mutations. The heterozygous deviation of the gene can be detected in 2-15% of patients with idiopathic short stature (ISS), in 50-90% of patients with Leri-Weill dyschondrosteosis syndrome (LWS), and in almost 100% of patients with Turner syndrome. AIM: The aim of our study was to evaluate the frequency of SHOX gene haploinsufficiency in children with ISS, LWS and in patients having Turner syndrome phenotype (TF), but normal karyotype, and to identify the dysmorphic signs characteristic for SHOX gene deficiency. METHOD: A total of 144 patients were included in the study. Multiplex Ligation-dependent Probe Amplification (MLPA) method was used to identify the SHOX gene haploinsufficiency. The relationships between clinical data (axiological parameters, skeletal disorders, dysmorphic signs) and genotype were analyzed by statistical methods. RESULTS: 11 (7.6%) of the 144 patients showed SHOX gene deficiency with female dominance (8/11, 81% female). The SHOX positive patients had a significantly higher BMI (in 5/11 vs. 20/133 cases, p<0.02) and presented more frequent dysmorphic signs (9/11vs 62/133, p = 0.02). Madelung deformity of the upper limbs was also significantly more frequent among the SHOX positive patients (4/11, i.e. 36%, vs. 14/133, i.e. 10%, p = 0.0066). There were no statistically significant differences between the mean age, mean height and auxological measurements (sitting height/height, arm span/height) between the two groups of patients. CONCLUSIONS: The occurrence of SHOX gene haploinsufficiency observed in our population corresponds to the literature data. In SHOX positive patients, in addition to short stature, the dysmorphic signs have a positive predictive value for SHOX gene alterations. However, the SHOX deletion detected in a patient with idiopathic short stature without dysmorphic signs suggest that SHOX deletion analysis can be recommended in patients with ISS. Orv Hetil. 2017; 158(34): 1351-1356.

Some GCR Polymorphisms (N363S, ER22/23EK, and Bcl-1) May Influence Steroid-induced Toxicities and Survival Rates in Children With ALL.

We investigated whether an altered individual glucocorticoid sensitivity due to particular glucocorticoid receptor single-nucleotide polymorphisms (SNPs) (N363S, ER22/23EK, and Bcl-1) influences the susceptibility to steroid-related toxicities, prognostic factors, and survival rates in children with acute lymphoblastic leukemia. In total, 346 pediatric patients with acute lymphoblastic leukemia were enrolled in our study. Their carrier status was investigated by allele-specific polymerase chain reaction analysis. Clinical and laboratory signs of glucocorticoid-related toxicities, day-8 prednisone response, 5-year event-free survival, and 5-year overall survival rates were analyzed and compared retrospectively. Hepatotoxicity occurred significantly more often in 363S carriers (P=0.004), and glucose metabolism abnormalities were more common in 363S carriers (P=0.001), but did not occur in patients with the ER22/23EK SNP. Hypertension and central nervous system/behavioral changes did not occur in patients with the ER22/23EK SNP. None of the patients with the N363S SNP, the ER22/23EK polymorphism, or the GG genotype for the Bcl-1 polymorphism had a poor prednisone response. The 363S carriers had significantly better 5-year event-free survival (P=0.012) and 5-year overall survival (P=0.013) rates compared with noncarriers. The Bcl-1 SNP was not associated with any of the toxicities investigated or survival. Children with the N363S polymorphism in the glucocorticoid receptor gene were more prone to steroid-related toxicities, whereas those with the ER22/23EK polymorphism were less susceptible. Children with the N363S polymorphism may have more favorable survival rates.