Search

CTCF germline mutations have been related to MRD21. We report the first bilateral Wilms tumor suffered by a MRD21 patient carrying an unreported CTCF missense variant in a zinc finger domain of CTCF protein. We found that germline heterozygous variant I446K became homozygous in the tumor due to a loss of heterozygosity rearrangement affecting the whole q arm on chromosome 16. Our findings propose CTCF I446K variant as a link between MRD21 and Wilms tumor predisposition.

Background Patients with 13q-syndrome are at risk of retinoblastoma when the RB1 gene, located in the chromosomal band 13q14.2, is deleted. This syndrome is frequently associated with congenital malformations and developmental delay, although these signs could be mild. Mosaic 13q-deletion patients have been previously reported in the literature; their phenotype is variable, and they may not be recognized. Case presentation Retinoblastoma diagnosed in a child with 13q-mosaicism confirmed in blood, oral mucosa, healthy retina and retinoblastoma. A second RB1 hit is present exclusively in the retinoblastoma sample (RB1 c.958C>T p.Arg320Ter). Other detected molecular events in retinoblastoma are 6p12.3pter gain and 6q25.3qter loss. Clinical examination is unremarkable except for clinodactyly of the right fifth finger. Discussion and conclusions We describe a case of mosaic 13q deletion syndrome affected by retinoblastoma. Molecular data obtained from the tumor analysis are similar to previous data available about this malignancy. High clinical suspicion is essential for an adequate diagnosis of mosaic cases.

Simple Summary: The idea that motivated the design of the project is to offer a genetic germline analysis to all pediatric patients diagnosed in our pediatric oncology unit. The main objective is to determine the incidence of predisposing genetic variants when studying a cohort of pediatric cancer patients using an NGS gene panel. The custom panel employed is designed to detect variants in a large number of genes involved in pediatric cancer in order to be able to identify new genotype-phenotype relationships. The data obtained are valuable for estimating the incidence of predisposing genetic alterations, due to the large number of pediatric patients included in the study. Furthermore, the novel results collected in the main document, which suggest the involvement of new genes in the predisposition to different oncological diseases, are worthwhile.Knowledge about genetic predisposition to pediatric cancer is constantly expanding. The categorization and clinical management of the best-known syndromes has been refined over the years. Meanwhile, new genes for pediatric cancer susceptibility are discovered every year. Our current work shares the results of genetically studying the germline of 170 pediatric patients diagnosed with cancer. Patients were prospectively recruited and studied using a custom panel, OncoNano V2. The well-categorized predisposing syndromes incidence was 9.4%. Likely pathogenic variants for predisposition to the patient's tumor were identified in an additional 5.9% of cases. Additionally, a high number of pathogenic variants associated with recessive diseases was detected, which required family genetic counseling as well. The clinical utility of the Jongmans MC tool was evaluated, showing a high sensitivity for detecting the best-known predisposing syndromes. Our study confirms that the Jongmans MC tool is appropriate for a rapid assessment of patients; however, the updated version of Ripperger T criteria would be more accurate. Meaningfully, based on our findings, up to 9.4% of patients would present genetic alterations predisposing to cancer. Notably, up to 20% of all patients carry germline pathogenic or likely pathogenic variants in genes related to cancer and, thereby, they also require expert genetic counseling. The most important consideration is that the detection rate of genetic causality outside Jongmans MC et al. criteria was very low.

Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent research studies focused on genetic diagnosis in patients with CP of unknown etiology. The present study was carried out in 20 families with one family member affected with idiopathic CP. Chromosomal microarray and exome sequencing techniques were performed in all patients. Chromosomal microarray analysis did not show any pathological or probable pathological structural variant. However, the next-generation sequencing study showed a high diagnostic yield. We report 11/20 patients (55%) with different pathogenic or potentially pathogenic variants detected by exome sequencing analysis: five patients with mutations in genes related to hereditary spastic paraplegia, two with mutations in genes related to Aicardi-Goutières syndrome, three with mutations in genes related to developmental/epileptic encephalopathies, and one with a mutation in the PGK1 gene. The accurate and precise patients' selection, the use of a high-throughput genetic platform, the selection of adequate target genes, and the application of rigorous criteria for the clinical interpretation are the most important elements for a good diagnostic performance. Based on our findings, next-generation sequencing should be considered in patients with cryptogenic CP as the first line of genetic workup. IMPACT: Sequencing techniques in CP of uncertain etiology provides a diagnostic yield of 55%. The appropriate selection of cases optimizes the diagnostic yield. NGS facilitate better understanding of new phenotypes of certain genetic diseases.

Background A study is made of the association between maxillary sinus pathology and odontogenic lesions in patients evaluated with cone beam computed tomography. Material and Methods A literature search was made in five databases and OpenGrey. Methodological assessment was carried out using the Newcastle-Ottawa tool for observational studies. The random-effects model was used for the meta-analysis. Results Twenty-one studies were included in the qualitative review and 6 in the meta-analysis. Most presented moderate or low risk of bias. The periodontal disease showed to be associated with the thickening of the sinus membrane (TSM). Mucous retention cysts and opacities were reported in few studies. The presence of periapical lesions (PALs) was significantly associated to TSM (OR=2.43 (95%CI:1.71-3.46); I2=34.5%) and to odontogenic maxillary sinusitis (OMS) (OR=1.77 (95%CI: 1.20-2.61); I2=35.5%). Conclusions The presence of PALs increases the probability of TSM and OMS up to 2.4-fold and 1.7-fold respectively. The risk differences suggests that about 58 and 37 of out every 100 maxillary sinuses having antral teeth with PALs are associated with an increased risk TSM and OMS respectively. The meta-evidence obtained in this study was of moderate certainty, and although the magnitude of the observed associations may vary, their direction in favor sinus disorders appearance, would not change as a result. Key words:Sinus pathology, Odontogenic Sinusitis, Sinus membrane thickening, CBCT, Periapical lesions, Periodontal disease

PURPOSE: The study of breast cancer nearly always involves patients close to menopause or older. Therefore, young patients are mostly underrepresented. Our aim in this study was to demonstrate biological differences in breast cancer of young people using as a model available cell lines derived from people with breast cancer younger than 35years. METHODS: Global miRNA expression was analyzed in breast cancer cells from young (HCC1500, HCC1937) and old patients (MCF-7, MDA-MB-231, HCC1806, and MDA-MB-468). In addition, it was compared with same type of results from patients. RESULTS: We observed a differential profile for 155 miRNAs between young and older cell lines. We identified a set of 24 miRNA associated with aggressiveness that were regulating pluripotency of stem cell-related pathways. Combining the miRNA expression data from cell lines and breast cancer patients, 132 miRNAs were differently expressed between young and old samples, most of them previously found in cell lines. MiR-23a-downregulation was also associated with poor survival in young patients. CONCLUSIONS: Our results suggest that HCC1500 and HCC1937 cell lines could be suitable cellular models for breast cancer affecting young women. The miR-23a-downregulation could have a potential role as a poor prognosis biomarker in this age group.

We present some tentative conclusions of our ongoing research, whose main objective is to contribute to understand how genomic disorders (and presumably, mutations in specific genes) may produce language disorders. A rare genetic anomaly which impairs speech and language production and reception (to different degrees) has been reported to one of the authors. This is a case of a girl (A) who has a balanced translocation between chromosomes 7 and 11 (t[7;11] [p13;p13]); remarkably, the affected chromosome 7 also exhibits a pericentromeric inversion with a rupture in 7p13 and 7q31. We discuss the significance of this genetic case in view of what is known so far on 7q31, a chromosomal region which encompasses some relevant loci for specific language impairment (SLI) (including the locus for FOXP2, a well-characterised “gene for language”) and autism (locus AUTS1), but which is also deleted in a rare clinical case in which language is moderately impaired. In order to explore the level of speech and language impairment of A, we have compared A's Castilian speech to that of a girl matched for age for some general tasks. We argue that this particular case can shed some light on how linguistic tasks are disabled by the malfunctioning of specific genes.

To evaluate the impact of common Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations, 5T polymorphism and presence of severe Cystic Fibrosis (CF) on fertility outcomes with Assisted Reproductive Techniques (ART) in patients presenting Congenital Bilateral Absence of Vas Deferens (CBAVD).

Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically including EWS and FLI1 genes. Little is known about Ewing sarcoma predisposition, although the role of environmental factors, ethnicity and certain polymorphisms on Ewing sarcoma susceptibility has been studied during the last few years. Its prevalence among cancer predisposition syndromes has also been thoroughly examined. This review summarizes the available evidence on predisposing factors involved in Ewing sarcoma susceptibility. On the basis of these data, an integrated approach of the most influential factors on Ewing sarcoma predisposition is proposed.

PURPOSE: Breast cancer (BC) in very young women (BCVY) is more aggressive than in older women. The purpose of this study was to evaluate the relevance of a range of clinico-pathological factors in the prognosis of BCVY patients. METHODS: We retrospectively analyzed 258 patients diagnosed with BCVY at our hospital from 1998 to 2014; the control group comprised 101 older patients with BC. We correlated clinicopathological factors, treatments, relapse and exitus with age and with previously published miRNA expression data. RESULTS: We identified some significant differences in risk factors between BCVY and older patients. The age at menarche, number of pregnancies, and age at first pregnancy were lower in the BCVY group and had a greater probability of recurrence and death in all cases. Lymph node-positive patients in the BCVY group are associated with a worse prognosis (P = .02), an immunohistochemical HER2+ subtype, and disease relapse (P =.03). Moreover, there was a shorter time between diagnosis and first relapse in BCVY patients compared with controls, and they were more likely to die from the disease (P = .002). Finally, from our panel of miRNAs deregulated in BC, reduced miR-30c expression was associated with more aggressive BC in very young patients, lower overall survival, and with axillary lymph node metastases. CONCLUSIONS: Patient age and axillary lymph node status post-surgery are independent and significant predictors of distant disease-free survival, local recurrence-free survival, and overall survival. The HER2+ subtype and lower miR-30c expression are related to poor prognosis in lymph node-positive young BC patients.

Two new photoactive compounds (1 and 2) derived from the 9-amidoacridine chromophore have been synthesized and fully characterized. Their abilities to produce singlet oxygen upon irradiation have been compared. The synthesized compounds show very different self-aggregating properties since only 1 present a strong tendency to aggregate in water. Biological assays were conducted with two cell types: hepatoma cells (Hep3B) and human umbilical vein endothelial cells (HUVEC). Photodynamic therapy (PDT) studies carried out with Hep3B cells showed that non-aggregating compound 2 showed photoxicity, ascribed to the production of singlet oxygen, being aggregating compound 1 photochemically inactive. On the other hand suspensions of 1, characterized as nano-sized aggregates, have notable antiproliferative activity towards this cell line in the dark. (C) 2018 Elsevier Ltd. All rights reserved.

The incidence of SF3B1 mutations in patients with RARS is high. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected, although it is not clear how this could affect the disease. We studied SF3B1 and DNMT3A in 123 RARS patients: 101 out of 123 samples (82%) had somatic mutations in SF3B1, and 13 of them (13%) showed a co-mutation (SF3B1mutDNMT3Amut). All co-mutated patients had a normal karyotype, and 12 of them (92%) were lower-risk patients (IPSS and IPSS-R). Despite their favorable profile, SF3B1mutDNMT3Amut patients showed a higher RBC transfusion dependency (92% versus 48%, p =.007), a shorter overall survival (OS) (median, 30 versus 97 months, p =.034), and a higher risk of progression to acute myeloid leukemia (AML) at 5 years (25% versus 2%, p =.023) than SF3B1mutDNMT3Awt patients. In conclusion, DNMT3A mutations are present in a significant proportion of SF3B1mut patients with a negative clinical impact. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

Clinical and molecular studies are reported on a Basque family (MRX82) with nonsyndromic X-linked mental retardation (XLMR) in five affected males. A total of 38 microsatellite markers were typed. The XLMR locus has been linked to DXS8067, DXS1001, DXS425, DXS7877, and DXS1183 with a maximum LOD score of 2.4. The haplotype studies and multipoint linkage analysis suggest a localization of the MRX82 locus to an interval of 7.6 Mb defined by markers DXS6805 and DXS7346, in Xq24 and Xq25, respectively. No gene contained in this interval has been so far associated with nonsyndromic mental retardation, except for GRIA3, disrupted by a balanced translocation in a female patient with bipolar affective disorder and mental retardation. However, the search for mutations of this gene did not showed a pathogenic mutation in the present family. Given that there are other eight MRX families overlapping this interval, none of them with known mutation, we conclude that at least one new gene responsible for nonsyndromic mental retardation is located in this region.

BACKGROUND AND OBJECTIVE: Subtelomeric chromosome imbalances are increasingly known as a cause for mental retardation. New phenotypes associated with specific rearrangements are also being delineated, such as 9q microdeletion syndrome. Here we define the major phenotypic features and the parental origin of 9q deletion. PATIENTS AND METHOD: We present 2 children with a phenotype that is characterized by mental retardation, distinctive facial features and congenital anomalies. Both patients showed a chromosome 9q subtelomeric deletion detected by MLPA (multiplex ligation-dependent probe amplification), and confirmed by FISH (fluorescent in situ hybridization). In order to delimit the size and the parental origin of 9q deletion, we performed microsatellite segregation analyses. RESULTS: We identified 2 patients with a de novo terminal deletion of the chromosome region 9q34. The deleted region spanned less than 0.8 and 1.5 Mb, respectively, affecting in both cases the paternal chromosome. CONCLUSIONS: 9q34 deletion syndrome appears as a clinically recognizable phenotype characterised by moderate-severe mental retardation, hypotonia, flat face with hyperthelorism, synophrys, anteverted nares, carp-shaped mouth with protruding tongue and conotruncal heart defects. Most de novo deletions arise in the chromosomes of paternal origin.

BACKGROUND: Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. METHODS: Genotyping of 1,256 genes related with neuro-development was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. RESULTS: Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. CONCLUSION:The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.

Background: Human pigmentation is a polygenic quantitative trait with high heritability. In addition to genetic factors, it has been shown that pigmentation can be modulated by oestrogens and androgens via up-or down-regulation of melanin synthesis. Our aim was to identify possible sex differences in pigmentation phenotype as well as in melanoma association in a melanoma case-control population of Spanish origin. Methods: Five hundred and ninety-nine females (316 melanoma cases and 283 controls) and 458 males (234 melanoma cases and 224 controls) were analysed. We genotyped 363 polymorphisms (single nucleotide polymorphisms (SNPs)) from 65 pigmentation gene regions. Results: When samples were stratified by sex, we observed more SNPs associated with dark pigmentation and good sun tolerance in females than in males (107 versus 75; P = 2.32 x 10(-6)), who were instead associated with light pigmentation and poor sun tolerance. Furthermore, six SNPs in TYR, SILV/CDK2, GPR143, and F2RL1 showed strong differences in melanoma risk by sex (P < 0.01). Conclusions: We demonstrate that these genetic variants are important for pigmentation as well as for melanoma risk, and also provide suggestive evidence for potential differences in genetic effects by sex.

Purpose In metastatic neuroblastoma (NB) patients, accurate risk stratification and disease monitoring would reduce relapse probabilities. This study aims to evaluate the independent prognostic significance of detecting tyrosine hydroxylase (TH) and doublecortin (DCX) mRNAs by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral blood (PB) and bone marrow (BM) samples from metastatic NB patients. Procedures RT-qPCR was performed on PB and BM samples from metastatic NB patients at diagnosis, post-induction therapy and at the end of treatment for TH and DCX mRNAs detection. Results High levels of TH and DCX mRNAs when detected in PB and BM at diagnosis independently predicted worse outcome in a cohort of 162 metastatic NB. In the subgroup of high-risk metastatic NB, TH mRNA detected in PB remained as independent predictor of EFS and OS at diagnosis. After the induction therapy, high levels of TH mRNA in PB and DCX mRNA in BM independently predicted poor EFS and OS. Furthermore TH mRNA when detected in BM predicted worse EFS. TH mRNA in PB samples at the end of treatment is an independent predictor of worse outcome. Conclusion TH and DCX mRNAs levels in PB and BM assessed by RT-qPCR should be considered in new pre-treatment risk stratification strategies to reliable estimate outcome differences in metastatic NB patients. In those high-risk metastatic NB, TH and DCX mRNA quantification could be used for the assessment of response to treatment and for early detection of progressive disease or relapses.

Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders.

This paper describes the presence of an interstitial pure duplication of 19p13.3 (4.95Mb) in a patient with intellectual disability studied by array-CGH which was initially considered as a de novo alteration. The discovery of the same chromosomal alteration in a first-degree cousin of this patient led us to investigate the presence of insertional translocations, which were consequently found in three family generations. The same duplication was found in three intellectually disabled patients and among the translocation carrier family members a very high incidence of miscarriages are reported. A review of other published cases has allowed us to find three other patients with a similar pure duplication, all of them sharing some common clinical findings such as intrauterine growth retardation, microcephaly, motor and speech delay, moderate to severe intellectual disability, and dysmorphic features. These findings allow us to suggest the presence of a new microduplication syndrome in chromosomal region 19p13.3. (C) 2015 Wiley Periodicals, Inc.

The NSDHL gene encodes 3-hydroxysteroid dehydrogenase involved in one of the later steps of the cholesterol biosynthetic pathway. Mutations in this gene can cause CHILD syndrome (OMIM 308050) and CK syndrome (OMIM 300831). CHILD syndrome is an X-linked dominant, male lethal disorder caused by mutations in the NSDHL gene that result in the loss of the function of the NSDHL protein. CK syndrome is an allelic X-linked recessive disorder. So far, 13 patients with CK syndrome from two families have been reported on. We present a new five-generation family with affected males manifesting clinical features of CK syndrome. Next generation sequencing was targeted to a custom panel of 542 genes with known or putative implication on intellectual disability. Missense mutation p.Gly152Asp was identified in the NSDHL gene in the DNA sample of the affected male. Mutation carrier status was confirmed for all the obligate carriers in the family. The clinical features of the affected males in the family manifested as weak fetal movements, severe intellectual disability, seizures, spasticity, atrophy of optic discs, microcephaly, plagiocephaly, skeletal abnormalities, and minor facial anomalies, including a high nasal bridge, strabismus, and micrognathia. A highly significant preferential transmission of the mutation was observed in this and previous families segregating CK syndrome. Our report expands the clinical spectrum of this syndrome to include weak fetal movements, spasticity, and plagiocephaly, and transmission ratio distortion. The various findings in these patients increase our understanding of the diversity of the clinical presentation of cholesterol biosynthesis disorders. (c) 2015 Wiley Periodicals, Inc.

Introduction. Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. Case reports. Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-year-old female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. Conclusions. Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway.