Fetal magnetic resonance imaging in the confirmation of congenital anomalies found on routine mid-trimester ultrasound.

OBJECTIVE: To determine the added value of fetal magnetic resonance imaging (MRI) when clarifying a suspected anomaly detected by mid-trimester scan. METHODS: Women attending two centers of fetal medicine between January 2017 and December 2021 were identified. The centers carried out routine mid-trimester ultrasound scans to detect fetal anomalies. Those with a suspected anomaly which required further clarification were referred for fetal magnetic resonance imaging (MRI). The medical records of all referred women were examined to determine the anomalies found at scan, MRI and termination of pregnancy or delivery. A total of 9571 women had a routine mid-trimester scan and an anomaly was either diagnosed or suspected in 449 (4.7%); an MRI examination was made in 76 cases (0.79%). RESULTS: MRI confirmed the presence of an abnormality in 61 referrals (80%) and failed to yield a result in one case. Outcome information was available for 69 cases: the MRI confirmation rate was 89% (48/54) in those with abnormal outcome and 40% (6/15) if the outcome was normal, P<0.0001. Among defects in the most common anatomical systems identified at ultrasound, the highest confirmation rates were for urinary tract abnormalities (94%, 15/16) and facial abnormalities (100%, 8/8). Results in other systems varied according to the specific defect but the confirmation rate was high for ventriculomegaly (86%, 6/7) and neural tube defects (83%, 5/6). CONCLUSIONS: We have shown that in women with suspected anomaly scan results, requiring further clarification, MRI confirmed ultrasound at a high rate, particularly for urinary tract and facial anomalies.

New endemic familial parkinsonism in south Moravia, Czech Republic and its genetical background.

An increased prevalence of familial neurodegenerative parkinsonism or cognitive deterioration was recently found in a small region of southeastern Moravia.The aim of the study was to assess the genetic background of this familial disease.Variants in the ADH1C, EIF4G1, FBXO7, GBA + GBAP1, GIGYF2, HTRA2, LRRK2, MAPT, PRKN, DJ-1, PINK1, PLA2G6, SNCA, UCHL1, VPS35 genes were examined in 12 clinically positive probands of the pedigree in which familial atypical neurodegenerative parkinsonism was identified in previous epidemiological studies. Libraries were sequenced by massive parallel sequencing (MPS) on the Personal Genome Machine (PGM; Ion Torrent). Data were analyzed using Torrent Suite and IonReporter software. All variants were then verified and confirmed by Sanger sequencing.We identified 31 rare heterozygous variants: 11 missense variants, 3 synonymous variants, 8 variants in the UTR region, and 9 intronic variants. Six variants (rs1801334, rs33995883, rs35507033, rs781737269, rs779760087, and rs63750072) were evaluated as pathogenic by at least one in-silico predictor.No single "founder" pathogenic variant associated with parkinsonism has been found in any of the probands from researched pedigree. It may rather be assumed that the familial occurrence of this disease is caused by the combined influence of several "small-effect" genetic variants that accumulate in the population with long-lasting inbreeding behavior.

Single giant mediastinal rhabdomyoma as a sole manifestation of TSC in foetus.

BACKGROUND: Presence of multiple cardiac rhabdomyomas is one of the major features of Tuberous sclerosis (TSC), but isolated progressing single giant rhabdomyoma is very rare and not typical of TSC. CASE REPORT: This report presents family without obvious history of TSC with occurrence of giant mediastinal rhabdomyoma affecting the haemodynamics in male foetus, without other TSC symptoms. Girl from the next gravidity had prenatally detected multiple rhabdomyomas and small subcortical tuber of brain detected after birth. DNA analysis found novel c.4861A>T TSC2 variant and large deletion in TSC2 in tumour tissue from male foetus. The novel TSC2 variant was also present in the girl and her healthy father, in silico analysis suggested its functional effect on TSC2. Brain MRI of the father detected mild TSC specific abnormality. CONCLUSION: We suggest the novel TSC2 mutation is a cause of mild TSC in this family and has reduced expression. The clinical and molecular findings in this family also emphasize that TSC diagnosis should be also evaluated in case of single giant foetal cardiac rhabdomyoma.

Familial atypical parkinsonism with rare variant in VPS35 and FBXO7 genes: A case report.

BACKGROUND: A higher prevalence of parkinsonism was recently identified in southeastern Moravia (Czech Republic). Further research confirmed 3 large pedigrees with familial autosomal-dominant parkinsonism spanning 5 generations. METHODS: This case report concerns a patient belonging to one of these 3 pedigrees, in whom motor and oculomotor symptoms were accompanied by frontal-type dementia, who finally developed a clinical phenotype of progressive supranuclear palsy. Molecular genetic examinations were performed due to the positive family history. RESULTS: No previously described causal mutation was found. After filtering against common variants (minor allele frequency (MAF) < 0.01), 2 noncoding and 1 synonymous rare mutation potentially associable with parkinsonism were identified: GIGYF2-GRB10 Interacting GYF Protein 2, PARK11 (c.*2030G > A, rs115669549); VPS35 gene-vacuolar protein sorting 35, PARK17 (c.102 + 33G > A, rs192115886); and FBXO7-F-box only protein 7 gene, PARK15 (c.540A > G, rs41311141). CONCLUSION: As to the changes in the FBXO7 and VPS35 genes (despite phylogenetic conservation in primates), probably neither the FBXO7 nor the VPS35 variants will be direct causal mutations. Both described variants, and possibly the influence of their combination, could increase the risk of the disease.

Familial, autosomal-dominant neurodegenerative parkinsonism with cognitive deterioration spanning five generations in a genetically isolated population of south-eastern Moravia, Czech Republic.

BACKGROUND: An epidemiological study conducted over four years revealed increased prevalence of neurodegenerative parkinsonism in a small, isolated region (10 villages, with a combined population of 8664, with approx. 2927 over 50 years of age) of south-eastern Moravia, Czech Republic. The aim of this study was to obtain more detailed information on the medical history of the relatives of individuals with confirmed parkinsonism in an isolated rural population in south-eastern Moravia, Czech Republic. METHODS: We did detailed genealogical research on the families of all inhabitants with confirmed parkinsonism and compiled the pedigrees. These were modified on the basis of information from a consecutive door-to-door survey and local municipal and church registers. RESULTS: In the first stage, three large pedigrees with a familial occurrence of parkinsonism were found; two originated in one of the region's villages. In the second stage, these two pedigrees were combined into one large family tree. CONCLUSIONS: The high prevalence of parkinsonism in the researched area is caused by the familial aggregation of parkinsonism that was found in two large family trees. This is probably the result of the genetic isolation of the regional population due to the very low migration rate of its inhabitants to neighboring regions in the last two centuries.

STAT6 - polymorphisms, haplotypes and epistasis in relation to atopy and asthma.

BACKGROUND: STAT6 has an important role in the IL-4 / IL-13 signalling pathway. Genome - wide association studies have shown that particular polymorphism (SNP) or haplotype variants of STAT6 as well as epigenetic gene modifications are associated with IgE level and asthma in childhood. METHODS: A review of the available literature was performed to map out the function and signalling pathway of STAT6, studies of STAT6 SNPs association with susceptibility to asthma and atopy, covering the years 1997 - 2012 were summarized, and the value of epigenetic and epistatic influences on STAT6 and their relevance to the development of the studied phenotype (atopy or asthma) were determined. RESULTS: There are 2 SNPs (rs71802646 and rs320411) with clinical association and proven functional effect on STAT6 expression. The effect of STAT6 SNPs cumulates in haplotypes and more potently during interaction with SNPs in the genes from the signalling pathway (IL4, IL4Ra, and IL13). Expression of STAT6 is also influenced by DNA methylation. Atopy is traditionally believed to be maternally inherited but there is one report about paternally overtransmitted STAT6 haplotype (TCA haplotype, built from rs324011, rs3024974 and rs4559 SNPs). CONCLUSIONS: STAT6 polymorphisms and their combinations have an important influence on IgE level and development of asthma. However, the interaction between SNPs in the IL-4 / IL-13 signalling pathway is of greater impact. Hypermethylation of the STAT6 promoter is also significant in the regulation of STAT6 expression and this fact opens possibilities for targeting therapy in asthma.

Possible control of paternal imprinting of polymorphisms of the ADAM33 gene by epigenetic mechanisms and association with level of airway hyperresponsiveness in asthmatic children.

INTRODUCTION: ADAM33 is the candidate gene most commonly associated with asthma and airway hyperreactivity (AHR). AIM: The aim of this study was to determine whether level of AHR is associated with certain alleles or haplotypes of the ADAM33 gene in asthmatic children. METHODS: One hundred and nine asthmatic children and 46 controls from the general population were examined with spirometry before and after histamine and methacholine inhalation. All subjects were genotyped for single-nucleotide polymorphisms (SNPs) of the ADAM33 gene. Haplotypes were determined according to genotypes of the patient's parents. RESULTS: We found the three most frequent ADAM33 haplotypes (a1-3) were associated with the highest level of AHR to methacholine and histamine in 66% of asthmatic children. The paternally transmitted GGGCTTTCGCA haplotype was seen in 73.3% asthmatic children with serious AHR to methacholine challenge (paternal and maternal origin of haplotype 73.3% to 37.5, P=0.046) Significant differences in the relative frequency of paternal haplotypes with high levels of AHR to histamine were found (P=0.013). CONCLUSION: ADAM33 haplotypes (a1, a2, a3) are associated with severity of AHR and are significantly more often transmitted in the paternal line.

Association of STAT6 and ADAM33 single nucleotide polymorphisms with asthma bronchiale and IgE level and its possible epigenetic background.

BACKGROUND: ADAM33 and STAT6 belong to the candidate genes that have been commonly associated with asthma, bronchial hyperresponsiveness or IgE levels. Our objective was to assess the association of 11 SNPs of the ADAM33 and 6 of the STAT6 and their haplotypes with IgE levels and asthma. We also evaluated the possible role of parental origin of haplotypes on IgE levels. METHODS: We enrolled 109 children with asthma and 45 healthy controls. Genotyping was performed by TaqMan probes and confirmed by sequencing. Haplotype construction was based on the knowledge of parental genotypes and also inferred by using the EM algorithm and Bayes' theorem. RESULTS: None of the SNPs were associated with elevated IgE level or asthma. We found that the most frequent STAT6 haplotype ATTCAA (built from rs324012, rs324011, rs841718, rs3024974, rs3024974, rs4559 SNPs, respectively) was associated with elevated total IgE levels (P=0.01) and this haplotype was predominantly transmitted paternally (P<0.001). We compared our results with those of studies performed on German and Australian Caucasian populations and found that rs324011, rs3024974 and rs4559 SNPs in STAT6 should have a major effect on IgE levels. Therefore, we suggest the TCA haplotype alone (built from rs324011, rs3024974 and rs4559 SNPs, respectively) in STAT6 is associated with total IgE elevation. CONCLUSIONS: The influence of paternal origin of the STAT6 haplotype on IgE levels is surprising but the exact role of possible paternal imprinting in STAT6 regulation should be investigated and confirmed in future studies.

Sequence recombination in exon 1 of the TSPY gene in men with impaired fertility.

AIM: The aim of this study was to evaluate TSPY (testis specific protein on the Y chromosome) gene and 5'UTR (UnTranslated Region) polymorphisms in men with impaired fertility compared to fertile controls. METHODS: We analyzed 72 infertile men and 31 fertile controls usingconventional sequencing analysis to find crucial SNPs (single nucleotide polymorphism) and other changes. RESULTS: The most remarkable changes were found in the 1(st) exon only. In one half of the both infertile men and fertile controls, the most frequent finding was 26 SNPs with a similar pattern. In the other half we found highly relevant changes, generating a stop codon in the first third of exon 1. Early termination cut down the protein by 78.5%. This kind of change was not found in the fertile controls. No correlation was found between the spermiogram and the changes leading to the stop codon. The distribution of men with deletions, insertion and higher gene copy number was not statistically different. CONCLUSION: The changes found in exon 1 in infertile men could fundamentally affect the process of spermatogenesis. These findings could significantly enhance our understanding of the molecular-genetic causes of male infertility.