Laboratory of Molecular Medicine

Laboratory of, Denmark

Laboratory of Molecular Medicine

Laboratory of, Denmark

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Reinstein E.,Medical Genetics Institute | Tzur S.,Laboratory of Molecular Medicine | Bormans C.,Genomics Research Center | Behar D.M.,Genomics Research Center
Genetics research | Year: 2016

Whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families.


Smirin-Yosef P.,Ariel University | Smirin-Yosef P.,Felsenstein Medical Research Center | Zuckerman-Levin N.,Clalit Health Services | Zuckerman-Levin N.,Rambam Medical Center | And 15 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2017

Context: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction, characterized by amenorrhea with elevated gonadotropin levels. The disorder presents as absence of normal progression of puberty. Objective: To elucidate the cause of ovarian dysfunction in a family with POI. Design: We performed whole-exome sequencing in 2 affected individuals. To evaluate whether DNA double-strand break (DSB) repair activities are altered in biallelic mutation carriers, we applied an enhanced green fluorescent protein-based assay for the detection of specific DSB repair pathways in blood-derived cells. Setting: Diagnoses were made at the Pediatric Endocrine Clinic, Clalit Health Services, Sharon-Shomron District, Israel. Genetic counseling and sample collection were performed at the Pediatric Genetics Unit, Schneider Children's Medical Center Israel, Petah Tikva, Israel. Patients and Intervention: Two sisters born to consanguineous parents of IsraeliMuslim Arab ancestry presented with a lack of normal progression of puberty, high gonadotropin levels, and hypoplastic or absent ovaries on ultrasound. Blood samples forDNAextractionwere obtained from all familymembers. Main Outcome Measure: Exome analysis to elucidate the cause of POI in 2 affected sisters. Results: Analysis revealed a stop-gain homozygous mutation in the SPIDR gene (KIAA0146) c.839G.A, p.W280∗. This mutation altered SPIDR activity in homologous recombination, resulting in the accumulation of 53BP1-labeled DSBs postionizing radiation and gH2AX-labeled damage during unperturbed growth. Conclusions: SPIDR is important for ovarian function in humans. A biallelic mutation in this gene may be associated with ovarian dysgenesis in cases of autosomal recessive inheritance. © 2017 by the Endocrine Society.


Melo M.R.,Laboratory of Molecular Medicine | Massarollo L.C.B.,Carlos Chagas Hospital and Guarulhos Oncology Institute
Revista do Colegio Brasileiro de Cirurgioes | Year: 2013

Objective: To evaluate the frequency of the BRAF V600E mutation in patients over 65 years of age undergoing thyroidectomy, correlating its presence or absence with the different histologic lesions, their variants and with prognostic factors of papillary carcinoma. Methods: We evaluated 85 patients over 65 years of age who underwent thyroidectomy, analyzing the BRAF V600E mutation by RT-PCR performed after DNA extraction from the paraffin blocks. Results: The study detected the presence or absence of BRAF V600E mutation in 47 patients (55.3%). Among the 17 papillary carcinomas studied, seven had the mutation (41.2%). There was a statistical association between the presence of this mutation and the classic variant of papillary carcinoma, and a trend of association with thyroid extravasation. Conclusion: BRAF mutation in the elderly is also exclusive of papillary carcinoma and is often significant. Furthermore, it is related to the classic variant and possibly to thyroid extravasation.


PubMed | Medical Genetics Institute, Laboratory of Molecular Medicine and Genomics Research Center
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016

Pathogenic variants in the NONO gene have been most recently implicated in X-linked intellectual disability syndrome. This observation has been supported by studies of NONO-deficient mice showing that NONO has an important role in regulating inhibitory synaptic activity. Thus far, the phenotypic spectrum of affected patients remains limited. We applied whole exome sequencing to members of a family in which the proband was presented with a complex phenotype consisting of developmental delay, dysmorphism, and non-compaction cardiomyopathy. Exome analysis identified a novel de novo splice-site variant c.1171+1G>T in exon 11 of NONO gene that is suspected to abolish the donor splicing site. Thus, we propose that the phenotypic spectrum of NONO-related disorder is much broader than described and that pathogenic variants in NONO cause a recognizable phenotype.


Mancini C.,University of Turin | Vaula G.,AOU San Giovanni Battista | Scalzitti L.,University of Turin | Cavalieri S.,University of Turin | And 6 more authors.
Neurogenetics | Year: 2012

Megalencephalic leukoencephalopathy with subcortical cysts is an autosomal recessive disease characterized by early onset macrocephaly; developmental delay; motor disability in the form of progressive spasticity and ataxia; seizures; cognitive decline; and characteristic magnetic resonance imaging findings. Mutations in two genes, MLC1 (22q13.33; 75 % of patients) or HEPACAM (11q24; 20 % of patients), are associated with the disease. We describe an adult MLC patient with moderate clinical symptoms. MLC1 cDNA analysis from lymphoblasts showed a strong transcript reduction and identified a 246-bp pseudoexon containing a premature stop codon between exons 10 and 11, due to a homozygous c.895-226 T>G deep-intronic mutation. This category of mutations is often overlooked, being outside of canonically sequenced genomic regions. The mutation c.895-226 T>G has a leaky effect on splicing leaving part of the full-length transcript. Its role on splicing was confirmed using a minigene assay and an antisense morpholinated oligonucleotide targeted to the aberrant splice site in vitro, which partially abrogated the mutation effect. © 2012 Springer-Verlag.


REINSTEIN E.,Medical Genetics Institute | REINSTEIN E.,Tel Aviv University | TZUR S.,Laboratory of Molecular Medicine | BORMANS C.,Genomics Research Center | BEHAR D.M.,Genomics Research Center
Genetics Research | Year: 2016

Whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families. Copyright © Cambridge University Press 2016


PubMed | Medical Genetics Institute, Laboratory of Molecular Medicine and Genomics Research Center
Type: | Journal: Genetics research | Year: 2016

Whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families.


Magen D.,Pediatric Nephrology Unit | Magen D.,Laboratory of Molecular Medicine | Magen D.,Technion - Israel Institute of Technology | Berger L.,Laboratory of Molecular Medicine | And 10 more authors.
New England Journal of Medicine | Year: 2010

We describe two siblings from a consanguineous family with autosomal recessive Fanconi's syndrome and hypophosphatemic rickets. Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, as the causative mutation. Functional studies in Xenopus laevis oocytes and in opossum kidney cells indicated complete loss of function of the mutant NaPi-IIa, resulting from failure of the transporter to reach the plasma membrane. These findings show that disruption of the human NaPi-IIa profoundly impairs overall renal phosphate reabsorption and proximal-tubule function and provide evidence of the critical role of NaPi-IIa in human renal phosphate handling. Copyright © 2010 Massachusetts Medical Society.


PubMed | University of Verona, Laboratory of Molecular Medicine, University of Helsinki and IRCCS Bambino Gesu Childrens Hospital
Type: | Journal: Cellular and molecular neurobiology | Year: 2016

Human SH-SY5Y neuroblastoma cells are widely utilized in in vitro studies to dissect out pathogenetic mechanisms of neurodegenerative disorders. These cells are considered as neuronal precursors and differentiate into more mature neuronal phenotypes under selected growth conditions. In this study, in order to decipher the pathways and cellular processes underlying neuroblastoma cell differentiation in vitro, we performed systematic transcriptomic (RNA-seq) and bioinformatic analysis of SH-SY5Y cells differentiated according to a two-step paradigm: retinoic acid treatment followed by enriched neurobasal medium. Categorization of 1989 differentially expressed genes (DEGs) identified in differentiated cells functionally linked them to changes in cell morphology including remodelling of plasma membrane and cytoskeleton, and neuritogenesis. Seventy-three DEGs were assigned to axonal guidance signalling pathway, and the expression of selected gene products such as neurotrophin receptors, the functionally related SLITRK6, and semaphorins, was validated by immunoblotting. Along with these findings, the differentiated cells exhibited an ability to elongate longer axonal process as assessed by the neuronal cytoskeletal markers biochemical characterization and morphometric evaluation. Recognition of molecular events occurring in differentiated SH-SY5Y cells is critical to accurately interpret the cellular responses to specific stimuli in studies on disease pathogenesis.


Troelsen L.N.,Copenhagen University | Garred P.,Laboratory of Molecular Medicine | Jacobsen S.,Copenhagen University
Journal of Rheumatology | Year: 2010

Objective. Patients with rheumatoid arthritis (RA) have increased overall and cardiovascular mortality. Mannose-binding lectin (MBL) may play differentiated roles in the pathogenesis of RA. We had observed that high serum levels of MBL increased the risk of ischemic heart disease in patients with RA. In this followup study we describe the mortality in a cohort of 229 Danish patients with RA.We examine if previously reported factors and MBL influence the risk of overall death and death due to cardiovascular disease. Methods. Known predictors of RA mortality were assessed. MBL extended genotypes (YA/YA, YA/XA, XA/XA, YA/YO, XA/YO, YO/YO) were determined; MBL serum concentrations were measured. The vital status and causes of death were assessed in a prospective study. Results. The median followup was 10.3 years. The overall risk of death was 4% per year. Comparing mortality in the RA cohort with mortality in an age- and sex-matched cohort based on the general Danish population, we found significantly increased overall mortality [standardized mortality ratio (SMR) 1.5, 95% CI 1.2-1.9, and cardiovascular mortality (SMR 1.7, 95% CI 1.3-2.6)]. In multivariate analysis, significant predictors of overall death were extraarticular manifestations, positive rheumatoid factor, increased C-reactive protein (CRP), poor nutritional state, and serum MBL. Predictors of cardiovascular death were Health Assessment Questionnaire score, increased CRP, poor nutritional state, and the high-producing MBL genotype YA/YA. Conclusion. Both overall and cardiovascular mortality were increased in Danish patients with RA. In our cohort, states of high MBL production and several previously reported factors contributed significantly to this increased risk of overall death and cardiovascular death. The Journal of Rheumatology © 2010. All rights reserved.

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