The Raphael Recanati Genetic Institute

Petah Tikva, Israel

The Raphael Recanati Genetic Institute

Petah Tikva, Israel

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Cohen L.,The Raphael Recanati Genetic Institute | Tzur S.,Emedgene Technologies | Goldenberg-Cohen N.,Schneider Childrens Medical Center | Bormans C.,Genomics Research Center | And 2 more authors.
Genetics research | Year: 2016

Inherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autosomal dominant optic atrophy and mitochondrial inherited Leber's hereditary optic neuropathy are the most common forms. Optic atrophy type 1, caused by mutations in the OPA1 gene is believed to be the most common hereditary optic neuropathy, and most patients inherit a mutation from an affected parent. In this study we used whole-exome sequencing to investigate the genetic aetiology in a patient affected with isolated optic atrophy. Since the proband was the only affected individual in his extended family, and was a product of consanguineous marriage, homozygosity mapping followed by whole-exome sequencing were pursued. Exome results identified a novel de novo OPA1 mutation in the proband. We conclude, that though de novo OPA1 mutations are uncommon, testing of common optic atrophy-associated genes such as mitochondrial mutations and OPA1 gene sequencing should be performed first in single individuals presenting with optic neuropathy, even when dominant inheritance is not apparent.


Reinstein E.,Medical Genetics Institute | Reinstein E.,Tel Aviv University | Smirin-Yosef P.,Ariel University | Smirin-Yosef P.,Felsenstein Medical Research Center | And 12 more authors.
Molecular Genetics and Metabolism | Year: 2016

The term isolated ectopia lentis (EL; subluxation or dislocation of the human crystalline lens) is applied to patients with EL, without skeletal features and in the absence of aortic root dilatation. To date, the only gene shown to cause autosomal-recessive isolated EL is ADAMTSL4. Here we report a novel founder mutation in ADAMTSL4 gene in children of Bukharian Jewish origin presenting with early-onset bilateral EL. A carrier frequency of 1:48 was determined among unrelated healthy Bukharian Jews. Given the complications associated with disease and the allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, pre-implantation or early postnatal diagnosis. © 2015 Elsevier Inc.


PubMed | Beilinson Hospital, Tel Aviv University, Statistical unit and The Raphael Recanati Genetic Institute
Type: | Journal: Hematological oncology | Year: 2016

Bone disease is a major cause for morbidity in multiple myeloma (MM), with the main focus concerning the manifestation as osteolytic lesions. Bone mineral loss is another reflection of myeloma bone involvement. Recently, osteoporosis has been omitted as a defining criterion for symptomatic disease in MM. We conducted a retrospective study to evaluate the use of bone mineral density (BMD) exams by dual-energy X-ray absorptiometry (DXA) among MM patients in a tertiary medical care centre. One-hundred seventy three patients were included. The T-scores of lumbar spine (LS), left femur neck (FN) and left total hip (TH) were obtained and analysed. The extent of osteolytic disease was categorized based on six bony areas. There was a strong correlation between spine and femurs T-scores (r=0.56-0.61, p<0.0001), although different sets of variables were correlated with LS and femurs T-scores. There was no correlation between BMD measurements and osteolytic disease extent. Patients with vertebral fracture(s) had significant lower T-scores of the spine in comparison to patients without vertebral fractures. Sixty-three patients (36.4% of the cohort) had follow-up DXA exam. In general, there was an increase in the LS T-scores, while femoral values decreased. However, in patients who achieved complete response (CR) and in those who retained CR during follow-up, femoral BMD increased as well. Because correlation between BMD and the extent of osteolytic lesions was not seen, our data support the recent exclusion of BMD assessment from the definition of symptomatic myeloma. Still, its use should be considered for evaluation of age- or therapy-related osteoporosis. Copyright 2016 John Wiley & Sons, Ltd.


PubMed | Felsenstein Medical Research Center, Ariel University, Tel Aviv University, Wolfson Medical Center and The Raphael Recanati Genetic Institute
Type: Case Reports | Journal: Molecular genetics and metabolism | Year: 2016

The term isolated ectopia lentis (EL; subluxation or dislocation of the human crystalline lens) is applied to patients with EL, without skeletal features and in the absence of aortic root dilatation. To date, the only gene shown to cause autosomal-recessive isolated EL is ADAMTSL4. Here we report a novel founder mutation in ADAMTSL4 gene in children of Bukharian Jewish origin presenting with early-onset bilateral EL. A carrier frequency of 1:48 was determined among unrelated healthy Bukharian Jews. Given the complications associated with disease and the allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, pre-implantation or early postnatal diagnosis.


COHEN L.,The Raphael Recanati Genetic Institute | COHEN L.,Schneider Childrens Medical Center | COHEN L.,Tel Aviv University | TZUR S.,Emedgene Technologies | And 6 more authors.
Genetics Research | Year: 2016

Inherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autosomal dominant optic atrophy and mitochondrial inherited Leber's hereditary optic neuropathy are the most common forms. Optic atrophy type 1, caused by mutations in the OPA1 gene is believed to be the most common hereditary optic neuropathy, and most patients inherit a mutation from an affected parent. In this study we used whole-exome sequencing to investigate the genetic aetiology in a patient affected with isolated optic atrophy. Since the proband was the only affected individual in his extended family, and was a product of consanguineous marriage, homozygosity mapping followed by whole-exome sequencing were pursued. Exome results identified a novel de novo OPA1 mutation in the proband. We conclude, that though de novo OPA1 mutations are uncommon, testing of common optic atrophy-associated genes such as mitochondrial mutations and OPA1 gene sequencing should be performed first in single individuals presenting with optic neuropathy, even when dominant inheritance is not apparent. Copyright © Cambridge University Press 2016


Muchtar E.,Beilinson Hospital | Muchtar E.,Tel Aviv University | Ram R.,Beilinson Hospital | Ram R.,Tel Aviv University | And 9 more authors.
Leukemia Research | Year: 2014

Total therapy 3 is an intensified protocol for multiple myeloma (MM). The "real life" outcomes of this protocol were seldom reported. Data was obtained for 81 patients (newly diagnosed, n=. 49; progressive MM, n=. 32), most of which had high-risk parameters. Overall response rate following (V)DT-PACE was 96% and 75% for the newly diagnosed and progressive groups, respectively. Median progression-free survival was 42.5 and 9 months, respectively. The 2-year overall survival was 88% and 40%, respectively. Treatment with (V)DT-PACE achieves high response rate among patients with high-risk disease, which can be translated into long-term remission only for newly diagnosed patients. © 2014 Elsevier Ltd.


Reinstein E.,The Raphael Recanati Genetic Institute | Reinstein E.,Tel Aviv University | Orvin K.,Rabin Medical Center | Tayeb-Fligelman E.,Technion - Israel Institute of Technology | And 15 more authors.
Human Mutation | Year: 2015

We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo-optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ domain containing protein implicated in regulation of the Wnt/β-catenin signaling pathway, as the causative mutation. The mutation affects a conserved residue located at the core of TAX1BP3 binding pocket and is predicted to impair the nature of a crucial hydrophobic patch, thereby interrupting the structure and stability of the protein, and its ability to interact with other proteins. TAX1BP3 is highly expressed in heart and brain and consistent with the clinical findings observed in our patients; a knockdown of TAX1BP3 causes elongation defects, enlarged pericard, and enlarged head structures in zebrafish embryos. Thus, we describe a new genetic disorder that expands the monogenic cardiomyopathy disease spectrum and suggests that TAX1BP3 is essential for heart and brain development. The term hereditary cardiomyopathy has been applied to heritable forms of heart failure with identifiable inheritance patterns. Although many cardiomyopathies have a genetic basis, only a limited number of genes have been identified as disease loci. We describe a novel cardiomyopathy syndrome caused by mutations in TAX1BP3; a gene previously not connected to monogenic disorders, thus expanding the spectrum of hereditary cardiomyopathies and suggests that TAX1BP3 is essential for heart development. © 2015 WILEY PERIODICALS, INC.


Cohen I.J.,The Raphael Recanati Genetic Institute | Cohen I.J.,Tel Aviv University | Wolff J.E.,The Floating Childrens Hospital for Children
Pediatric Blood and Cancer | Year: 2014

To determine the optimal time of folinic acid rescue after methotrexate (MTX) treatment in patients with ALL, we selected and evaluated relevant studies that included doses, rescue delay, and side effects. Rescue at 42-48 hours resulted in considerable toxicity, except when low doses of MTX were used (1 g/m2) or serum MTX levels remained consistently low at 24, 30, and 36 hours. Rescue started at 30-36 hours was safe. In the absence of evidence that later rescue improves prognosis, we suggest that folinic acid rescue (105 mg/m2) be started no later than 36 hours from the start of MTX (5-6 g/m2). Pediatr Blood Cancer 2014;61:7-10. © 2013 Wiley Periodicals, Inc.


PubMed | The Raphael Recanati Genetic Institute, Genomics Research Center, Tel Aviv University, Emedgene Technologies and Schneider Childrens Medical Center
Type: | Journal: Genetics research | Year: 2016

Inherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autosomal dominant optic atrophy and mitochondrial inherited Lebers hereditary optic neuropathy are the most common forms. Optic atrophy type 1, caused by mutations in the OPA1 gene is believed to be the most common hereditary optic neuropathy, and most patients inherit a mutation from an affected parent. In this study we used whole-exome sequencing to investigate the genetic aetiology in a patient affected with isolated optic atrophy. Since the proband was the only affected individual in his extended family, and was a product of consanguineous marriage, homozygosity mapping followed by whole-exome sequencing were pursued. Exome results identified a novel de novo OPA1 mutation in the proband. We conclude, that though de novo OPA1 mutations are uncommon, testing of common optic atrophy-associated genes such as mitochondrial mutations and OPA1 gene sequencing should be performed first in single individuals presenting with optic neuropathy, even when dominant inheritance is not apparent.


PubMed | The Raphael Recanati Genetic Institute
Type: | Journal: Genetics research | Year: 2015

Whole-genome and whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. The term newborn screening refers to public health programs designed to screen newborns for various treatable metabolic conditions, by measuring levels of circulating blood metabolites. The availability and significant decrease in sequencing costs has raised the question of whether metabolic newborn screening should be replaced by whole-genome or whole-exome sequencing. While newborn genome sequencing can potentially increase the number of disorders identified by newborn screening, the generalization of its practice raises a number of important ethical issues. This short article argues that there are medical, psychological, ethical and economic reasons why widespread dissemination of newborn screening is still premature.

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