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22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome.

The most common form of inherited lipid disorders is familial hypercholesterolemia (FH). It is characterized primarily by high concentrations of the clinical triad of low-density lipoprotein cholesterol, tendon xanthomas and premature CVD. The well-known genetic background are mutations in LDLR, APOB and PCSK9 gene. Causative mutations can be found in 60–80% of definite FH patients and 20–30% of those with possible FH. Their occurrence could be attributed to the activity of minor candidate genes, whose causal mechanism has not been fully discovered. The aim of the conducted study was to identify disease-causing mutations in FH-related and candidate genes in pediatric patients from Poland using next generation sequencing (NGS). An NGS custom panel was designed to cover 21 causative and candidate genes linked to primary dyslipidemia. Recruitment was performed using Simon Broome diagnostic criteria. Targeted next generation sequencing was performed on a MiniSeq sequencer (Illumina, San Diego, CA, USA) using a 2 × 150 bp paired-end read module. Sequencing data analysis revealed pathogenic and possibly pathogenic variants in 33 out of 57 studied children. The affected genes were LDLR, APOB, ABCG5 and LPL. A novel pathogenic 7bp frameshift deletion c.373_379delCAGTTCG in the exon 4 of the LDLR gene was found. Our findings are the first to identify the c.373_379delCAGTTCG mutation in the LDLR gene. Furthermore, the double heterozygous carrier of frameshift insertion c.2416dupG in the LDLR gene and missense variant c.10708C>T in the APOB gene was identified. The c.2416dupG variant was defined as pathogenic, as confirmed by its cosegregation with hypercholesterolemia in the proband’s family. Although the APOB c.10708C>T variant was previously detected in hypercholesterolemic patients, our data seem to demonstrate no clinical impact. Two missense variants in the LPL gene associated with elevated triglyceride plasma level (c.106G>A and c.953A>G) were also identified. The custom NGS panel proved to be an effective research tool for identifying new causative aberrations in a genetically heterogeneous disease as familial hypercholesterolemia (FH). Our findings expand the spectrum of variants associated with the FH loci and will be of value in genetic counseling among patients with the disease.

Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1-related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson–Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1. Here, we report three patients with Hartsfield syndrome from two unrelated families. Exome sequencing revealed two siblings harboring a novel de novo heterozygous synonymous variant c.1029G>A, p.Ala343Ala causing a cryptic splice donor site in exon 8 of FGFR1 likely due to gonadal mosaicism in one parent. The third case was a sporadic patient with a novel de novo heterozygous missense variant c.1868A>G, p.(Asp623Gly).

Introduction Deletion of chromosome 22q11.2, which causes DiGeorge syndrome, is one of the most frequently diagnosed microdeletion syndromes in the human. It is characterised by a wide variety of symptoms. The main symptoms consist of congenital heart diseases, particularly conotruncal malformations, characteristic facial dysmorphism, palatal abnormalities, an immune deficiency and hypocalcemia. We present phenotypical analysis of 15 patients with DiGeorge syndrome without structural heart disease. A diagnosis of DiGeorge syndrome was confirmed by Multiplex Ligation-dependent Probe Amplification (MLPA) and Fluorescent in situ Hybridization (FISH) with a specific probe. Results FISH method was used in 10 patients in genetic diagnosis of microdeletion 22q11.2 syndrome, and MLPA method confirmed that FISH analysis was used in 5 patients. None of the patient exhibited heart disease in an ultrasound examination. Developmental delay (13/15), delay in emergence of language (8/15), palatal abnormalities (10/15) and frequent infections (11/15) were observed. All the patients presented characteristic facial features. Conclusions It is difficult to diagnose DiGeorge syndrome in patients who do not present heart disease. In such cases careful phenotypical analysis and microdeletions screening with MLPA method may be helpful to make a diagnosis. To establish appropriate therapy and further clinical evaluation exact and early diagnosis is crucial. There lacks diagnostic guidelines for patients with unexplained developmental delay and/or developmental malformations.

In EN 13670:2009 standard: Execution of concrete structures there are general rules of moisture curing of concrete in structures. In the standard 4 classes of concrete curing are described. Determination of curing class depends on required level of compressive strength immediately after curing (percentage of required characteristic strength after 28 days). Time of curing depends on rate of strength development and concrete surface temperature. In the standard there is a lack of information about influence of curing class on concrete durability characteristics. The main condition to obtain durable concrete is proper curing regime. Not cured on improperly cured concrete has weakened surface layer. Extremely faults in curing process could lead to defects visible on the concrete surface. More often defects are latent inside the concrete and could be revealed during exploitation, leading to durability reduction. The main effect is increase of surface layer porosity (reinforcement cover) and decrease of its protective properties and tightness. Consequently worsening of mechanical properties could be observed as well as water-tightness, frost resistance, chemical aggression resistance, carbonation resistance and diffusivity of chloride. The analysis shown in the paper are the result of 3-yers long investigation conducted by authors, which main goal was to determine appropriateness and way to include durability requirements in designing of curing class according to EN 13670:2009. Thawing-freezing resistance, scaling with salts resistance, depth of water penetration under pressure and absorptivity were adopted as the basic durability factors. Concretes with different cement types, different rate of compressive strength development, air-entrained and non-air-entrained were tested. Time of curing was differentiated in the range of classes 1,3,4 following standard EN 13670:2009 requirements. Practical conclusions were formulated which allows to consider durability presumptions in technological requirements contained in concrete works specifications.

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

Noonan syndrome (NS) is a common developmental disorder presenting with dysmorphic craniofacial features, heart defects, and short stature. It belongs to the group of RASopathies caused by germline mutations in genes encoding proteins involved in the RAS/MAPK signaling pathway. Although mutations in nine genes are known to cause NS, approximately 30% of the cases still have unexplained etiology. To identify the new causative genes, 42 patients with a clinical diagnosis of NS, who had negative results on Sanger sequencing of PTPN11, SOS1, and RAF1 (the most common NS genes), were selected for whole exome sequencing. In two patients, mutations in recently described new NS gene—RIT1 were found (c.244T>G [p.Phe82Val] and c.270G>C [p.Met90Ile]). Further analysis of a larger cohort (n = 64) of NS patients with classic Sanger sequencing revealed the presence of RIT1 mutation c.284G>C (p.Gly95Ala) in two additional patients. All the detected mutations were localized in switch II domain responsible for GTPase activity. The modeling of RIT1 protein structure revealed that the mutated amino acids and their interacting residues are evolutionary conserved and any residue replacement might change the structural stability and/or protein internal dynamics influencing catalytic activity of the protein. It seems that the identified mutations might alter protein function and therefore, the activity of ERK and P38 MAPK pathways, thus underlying the specific phenotype observed in NS patients. Our study independently confirms the role of RIT1 in the pathogenesis of Noonan syndrome. © 2014 Wiley Periodicals, Inc.

© 2016, Springer-Verlag Berlin Heidelberg. The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS; MIM #192430; 188400) is the most common microdeletion syndrome. The phenotypic presentation of 22q11DS is highly variable; approximately 60–75 % of 22q11DS patients have been reported to have a congenital heart defect (CHD), mostly of the conotruncal type, and/or aortic arch defect. The etiology of the cardiac phenotypic variability is not currently known for the majority of patients. We hypothesized that rare copy number variants (CNVs) outside the 22q11.2 deleted region may modify the risk of being born with a CHD in this sensitized population. Rare CNV analysis was performed using Affymetrix SNP Array 6.0 data from 946 22q11DS subjects with CHDs (n = 607) or with normal cardiac anatomy (n = 339). Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q11DS individuals with CHDs. When the rare CNVs were examined with regard to gene interactions, specific cardiac networks, such as Wnt signaling, appear to be overrepresented in 22q11DS CHD cases but not 22q11DS controls with a normal heart. Collectively, these data suggest that CNVs outside the 22q11.2 region may contain genes that modify risk for CHDs in some 22q11DS patients.

Wstep Czestośc wad u zywo urodzonych noworodkow wynosi od 0,94 do 4%, u martwo urodzonych jest kilkakrotnie wieksza i wynosi od ok. 9 do 20%. Spośrod wad o znanej etiologii ok. 35% jest spowodowanych przez czynniki wylącznie genetyczne. Cel pracy Celem pracy byla analiza genetycznych przyczyn niepowodzen ciązowych u par z poronieniami i urodzeniem dziecka martwego lub zywego z wadami wrodzonymi, z uwzglednieniem rodzaju wad plodow i noworodkow oraz kariotypow rodzicow. Material i metody Analize kariotypu rodzicow przeprowadzono na podstawie uzyskiwanych z 72 godzinnych hodowli limfocytow krwi obwodowej chromosomow metafazowych wybarwionych w technice GTG oraz, w pojedynczych przypadkach, w technice FISH. Wyniki Wśrod 59 par u 7 (11,85%) rozpoznano aberracje strukturalne. U 1 kobiety stwierdzono t(3;10)(p21;q21). Pozostale translokacje zrownowazone rozpoznano u mezczyzn: t(4;13)(q34;q31), t(10;22)(p11.2;q13), t(3;14)(p25;q24), t(13;18)(q14;q21.1). Ponadto u 1 kobiety rozpoznano translokacje robertsonowską; t(14;21)(q10;q10), a u innej niezidentyfikowaną aberracje chromosomu 16. Poznanie etiologii niepowodzen ciązowych pozwala na zwiekszenie efektywności zarowno poradnictwa genetycznego, jak i zapobiegania kolejnym niepowodzeniom.

© 2015 by The American Society of Human Genetics. All rights reserved. The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10-3, two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10-2, two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10-4, two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.

Supplemental Digital Content is available in the text., Background— The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort. Methods and Results— To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P=2.98×10−8) in an intron of the adhesion GPR98 (G-protein–coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98, including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. Conclusions— In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.

Although congenital talipes equinovarus (CTEV) is one of the most frequently occurring congenital defects of locomotor organs, its ethiopathogenesis is still not fully known. Amongst the others, the inheritance patterns of that defect are not fully known, and that restricts genetic therapeutics and development of new treatment technologies. The aim of this study was analysis of family lineages of 205 children with CTEV (298 feet) treated at our centre in the years 1998-2008. The family occurrence of CTEV was found in 16 cases (8% of analysed group). 6 lineages, in which CTEV occurred in successive generations, were analysed in detail. Particularly interesting is the lineage of the family 1, in which the defect occurred in three successive generations. In case of that family, an autosomal dominant inheritance pattern is possible. Previously that pattern of CTEV inheritance was described only for isolated populations of Polynesians. In own material the family occurrence of CTEV was found to be less frequent than in bibliographic references. The defect occurred twice as often in boys, while the severe form was more frequently observed in girls, and that is consisted with data in the available bibliography. The analysis of presented lineages of families with CTEV did not allow unambiguous defining of the inheritance pattern for that defect. To confirm the autosomal dominant pattern of CTEV inheritance in the family in which the defect occurred in three successive generations, genetic tests would be necessary.

The aim of the study was to present rarely reported neurologic complications in Nijmegen breakage syndrome. A 13-year-old female was referred because of chronic progressive headaches. There were dysmorphic features on physical examination, which suggested a diagnosis of chromosomal instability syndrome. The results of genetic and immunologic examinations confirmed the diagnosis. Cerebral magnetic resonance imaging revealed an 8 mm thickening of the meninges over the left hemisphere, corresponding with a chronic inflammatory condition, and symptoms of left cavernous thrombophlebitis were detected. Cerebrospinal fluid examination and an infusion test demonstrated disorders in its absorption. Antibiotic, anticoagulant and cerebral edema treatment was given and after 1 week improvement was observed. Regression of symptoms occurred after 14 days.

Peutz-Jeghers syndrome is an autosomal dominant inherited disorder which is characterized by mucocutaneus melanocytic macules and intestinal hamartomatous polypus. The aim of our work is to underline the role of pigmented changes in the diagnostic process. Numerous lentigines should always lead to multiorgan investigations.

The aim of our study is to introduce a larger number of doctors to the subject of lentigines. They may be a first syndrome coexistent with very rare multiple organ defects as syndrome Peutz-Jeghers, LEOPARD, LAMB and Carney syndrome.

The 22q11.2 deletion syndrome occurs in approximately 1 of 3000-5000 children. This is a congenital disorder characterized by facial dysmorphic features, cardiac defects, thymic hypoplasia, cleft palate, hypoparathyroidism, and psychiatric disorders. Patients generally exhibit a mild to moderate decrement in T-cell numbers with preservation of T-cell function. We describe advances in understanding the genetic basis of this syndrome, its clinical manifestations, and new information on immunodeficiences in this syndrome.

The coexistence of atopic dermatitis and psoriasis is especially rare diagnosed disease in small children. Authors present a 12 months-old girl with both of these diseases. It is important to underline that early diagnosis can apply proper coexistence therapy.

To determine whether it is fetal blood and not with mother blood in question.We discuss the "Apt test" results which examines the fetal hemoglobin in blood samples obtained by genetic cordocentesis. This material was used to elaborate the fetal cariotypes.106 samples of blood samples obtained by genetic cordocentesis were examined. Examination of each cordocentesis blood sample intended for genetic tests by means of a test estimating fetal hemoglobin (HbF). In each case the estimation was independently done by means of the Kleihauer-Betke method.The obtained results have evidenced the full usefulness of the "APT test" in genetic cordocentesis.The ATP test allows to estimate the HbF in the analysed sample of fetal blood in a course of few seconds.

Assessment of usefulness of the fetal echocardiography and genetic sonography in prenatal diagnosis trisomy 13 (retrospective analysis).Between 1994-1999 at the Department for Diagnosis of Congenital Malformation at the Institute of PPMH in 11 fetuses with Patau Syndrome ultrasound and echocardiography examination were performed. In our study the most of cases come from low risk of pregnant women.Fetal heart defect was the most common anomaly diagnosed prenatally in fetuses with Patau Syndrome (7/11), the second one were central nervous system anomalies (6/11) and genitourinary system anomalies (6/11).

Between 1994-1999 at the Department for Diagnosis of Congenital Malformations at the PPMH Institute there were ultrasound and echocardiography examinations performed in 40 fetuses with Down Syndrome. In our study most of the cases come from low risk groups of pregnant women. Congenital heart defects (AV-canal in 13/18 cases) were the most common anomalies diagnosed prenatally in fetuses with Down Syndrome. In fetuses with DS, functional cardiac anomalies with normal heart anatomy were recorded: disproportion and hypertrophy in 4/12 cases, tricuspid valve regurgitation, bright spot and pericardial effusion in 3/12 cases. The aim of our study was a retrospective analysis of fetuses with DS, which were diagnosed at the Department for Diagnosis of Congenital at the Institute of "PMMH" in 1994-1999 years.

Background The aim of our study was retrospective analysis of 40 cases fetuses with down syndrome (T21) who had detailed sonography and echocardiography. Method Video tape analysis of 40 fetuses with T21 who had completed ultrasound and echocardiography examinations and completed neonatal follow-up in the same center. Results In our study the majority of cases 26 (65%) were low risk pregnancies. High risk pregnancies were in 14 (35%) cases. Congenital heart defect (72%) (AV-canal in 13/18 cases) was the most common anomaly diagnosed prenataly in fetuses with T21. Functional cardiac anomalies with normal heart anatomy were recorded also such as: dyspoportion and hypertrophy in 4/12 cases, tricuspid valve regurgitation, bright spot and pericardial effusion in 3/12 cases. Extracardiac malformations (25%) were diagnosed in fetuses with T21 such as: dudenal atresia, femur length shortening, pyelectasis bilateralis, face anomalies, sceletal malformations, hydrops fetalis. Conclusions 1. Congenital heart defect (72%) (AV-canal in 13/18 cases) was the most common anomaly diagnosed in fetuses with T21. 2. The most common extracardiac malformation was duodenal atresia 13/40 = 32.5% cases. 3. Fetal echocardiography can be usefull to identify in the group of low risk pregnancies, the potential patients for cytogenetic examinations of trisomy 21.