Basel-Vanagaite L.,Raphael Recanati Genetic Institute |
Basel-Vanagaite L.,Tel Aviv University |
Basel-Vanagaite L.,Felsenstein Medical Research Center |
Basel-Vanagaite L.,Pediatric Genetics Unit |
And 23 more authors.
American Journal of Human Genetics | Year: 2013
Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies. © 2013 The American Society of Human Genetics.
De Vries L.,Jesse Z And Sara Lea Shafer Institute For Endocrinology And Diabetes |
De Vries L.,Tel Aviv University |
Behar D.M.,Molecular Medicine Laboratory |
Behar D.M.,Raphael Recanati Genetic Institute |
And 7 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014
Context: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early menopause. Genes involved in essential steps in chromosome synapsis and recombination during meiosis, such as synaptonemal complex central element 1(SYCE1), have been shown to cause POI in animal models. We describe for the first time a homozygous mutation in SYCE1 in humans.Objective: To identify the genetic cause of POI in an Israeli Arab family with a consanguineous pedigree.Setting and Design: A family-based genetic study conducted at a tertiary medical center.Patients: Two daughters of consanguineous parents (first cousins) from a 13-member family were diagnosed with POI. Genotyping was performed in the index patients, their parents, and four unaffected siblings.Intervention: DNA from the affected sisters was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of the additional family members were determined by Sanger sequencing. Genotyping was also performed in 90 ethnically matched control individuals.Results: A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation. The mutation was not identified in the DNA samples from the 90 control subjects.Conclusions: Given the known function of the SYCE1 gene, wesuggestthatthe nonsense mutation identified accounts for the POI phenotype. These results highlight the importance of the synaptonemal complex and meiosis in ovarian function. Copyright © 2014 by the Endocrine Society.
Zarchi O.,Edmond and Lily Safra Childrens Hospital |
Zarchi O.,Institute for Clinical Neurophysiology and Audiology |
Attias J.,Institute for Clinical Neurophysiology and Audiology |
Attias J.,Haifa University |
And 6 more authors.
Journal of Pediatrics | Year: 2011
Objective: To comprehensively assess auditory impairments in velocardiofacial syndrome (VCFS) and Williams syndrome (WS). Study design: Audiologic measurements were conducted with 62 subjects with VCFS and 44 subjects with WS, as well as two control groups consisting of 22 subjects with idiopathic developmental disability and 23 typically developing controls. An association between severity of hearing loss in VCFS and the 158Val/Met polymorphism of the catechol-O-methyltransferase gene (COMT) was explored. Results: Hearing was significantly more impaired in the VCFS and WS groups compared with the developmental disability and typically developing groups. Audiologic abnormalities identified in both the VCFS and WS groups included high-tone hearing loss (predominantly sensorineural or mixed type), loss of acoustic reflex, and middle ear pathologies. In both the VCFS and WS groups, hearing loss severity was positively correlated with age. In the VCFS group, hearing loss was more severe in the subgroup carrying the COMT Val allele compared with the subgroup carrying the COMT Met allele. Conclusions: Hearing impairments, including sensorineural hearing loss and acoustic reflex dysfunction, are very common in both VCFS and WS. Hearing loss is less severe in subjects with the COMT Met allele, possibly due to the protective effect of dopamine on the hearing system. Copyright © 2011 Mosby Inc. All rights reserved.
PubMed | Pediatric Genetics Unit, CNR Institute of Neuroscience, Felsenstein Medical Research Center, Raphael Recanati Genetic Institute and 3 more.
Type: | Journal: Clinical genetics | Year: 2016
Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5 region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T-cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.
Masotti A.,Bambino Gesu Childrens Hospital |
Uva P.,CRS4 Bioinformatics Laboratory |
Davis-Keppen L.,University of South Dakota |
Basel-Vanagaite L.,Pediatric Genetics Unit |
And 12 more authors.
American Journal of Human Genetics | Year: 2015
Keppen-Lubinsky syndrome (KPLBS) is a rare disease mainly characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, a narrow nasal bridge, a tented upper lip, a high palate, an open mouth, tightly adherent skin, an aged appearance, and severe generalized lipodystrophy. We sequenced the exomes of three unrelated individuals affected by KPLBS and found de novo heterozygous mutations in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium channel and maps to the Down syndrome critical region between DIRK1A and DSCR4. In particular, two individuals shared an in-frame heterozygous deletion of three nucleotides (c.455-457del) leading to the loss of one amino acid (p.Thr152del). The third individual was heterozygous for a missense mutation (c.460G>A) which introduces an amino acid change from glycine to serine (p.Gly154Ser). In agreement with animal models, the present data suggest that these mutations severely impair the correct functioning of this potassium channel. Overall, these results establish KPLBS as a channelopathy and suggest that KCNJ6 (GIRK2) could also be a candidate gene for other lipodystrophies. We hope that these results will prompt investigations in this unexplored class of inwardly rectifying K+ channels. © 2015 The American Society of Human Genetics.
Michaelson-Cohen R.,Hebrew University of Jerusalem |
Gershoni-Baruch R.,Rambam Healthcare Campus |
Sharoni R.,Genetic Institute |
Shochat M.,Raphael Recanati Genetic Institute |
And 2 more authors.
Fetal Diagnosis and Therapy | Year: 2014
Non-invasive prenatal testing (NIPT) of cell-free fetal DNA in maternal plasma is a novel approach, designed for detecting common aneuploidies in the fetus. The Israeli Society of Medical Geneticists (ISMG) supports its use according to the guidelines stated herein. The clinical data collected thus far indicate that NIPT is highly sensitive in detecting trisomies 21 and 18, and fairly sensitive in detecting trisomy 13 and sex chromosome aneuploidies. Because false-positive results may occur, an abnormal result must be validated by invasive prenatal testing. At this juncture, NIPT does not replace existing prenatal screening tests for Down syndrome, as these are relatively inexpensive and cost-effective. Nonetheless, NIPT may be offered to women considered to be at high risk for fetal chromosomal abnormalities as early as 10 weeks of gestation. The ISMG states that NIPT should be an informed patient choice, and that pretest counseling regarding the limitations of NIPT is warranted. Women at high risk for genetic disorders not detected by NIPT should be referred for genetic counseling. A normal test result may be conveyed by a relevant healthcare provider, while an abnormal result should be discussed during a formal genetic consultation session. © 2014 S. Karger AG, Basel.
Sukenik-Halevy R.,Raphael Recanati Genetic Institute |
Pesso R.,Genetic Institute of Maccabi Health Insurance |
Garbian N.,Genetic Institute of Maccabi Health Insurance |
Magal N.,Raphael Recanati Genetic Institute |
Shohat M.,Raphael Recanati Genetic Institute
Genetic Testing and Molecular Biomarkers | Year: 2010
The carrier frequency of spinal muscular atrophy varies from 1:168 to 1:35. We analyzed the carrier rate in a large population in Israel, evaluated the false-negative rate based on the number of alleles with duplication of exon 7, and analyzed the ethnic differences in both parameters. Data were collected from two centers that conduct carrier screening using the multiplex ligation-dependent probe amplification kit. We studied the number of copies of exons 7 and 8 in our population, which we divided into six different ethnic groups. Statistical analysis was conducted using chi-square test. A total of 7308 healthy individuals were tested in an organized community health maintenance organization (HMO) program, and 1729 in a large hospital setup. The carrier rate was 1:62 and was not statistically different between the ethnic groups. Duplication was found in one in nine individuals (false-negative rate 5.5%) with a significant difference in frequency between the ethnic groups: 13.5% among Ashkenazim, 6% among North-African Jews (p<0.001). This difference was consistent in both centers and in exon 8 as well. There is, therefore, a higher prevalence of false negative results in some ethnic groups. The discrepancy between the rates of deletions versus duplications can be explained by the genetic disadvantage of deletions. © Copyright 2010, Mary Ann Liebert, Inc. 2010.
Peyrard-Janvid M.,Karolinska Institutet |
Leslie E.J.,University of Iowa |
Kousa Y.A.,Michigan State University |
Smith T.L.,University of Iowa |
And 20 more authors.
American Journal of Human Genetics | Year: 2014
Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6 +/-;Grhl3+/-) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS. © 2014 The American Society of Human Genetics.
Basel-Vanagaite L.,Schneider Childrens Medical Center |
Basel-Vanagaite L.,Raphael Recanati Genetic Institute |
Basel-Vanagaite L.,Tel Aviv University |
Pasmanik-Chor M.,Tel Aviv University |
And 3 more authors.
Molecular Syndromology | Year: 2011
Hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly and macular dystrophy (EEM) are both caused by mutations in the CDH3 gene. In this report, we describe a family with EEM syndrome caused by a novel CDH3 gene mutation and review the mutation spectrum and limb abnormalities in both EEM and HJMD. A protein structure model showing the localization of different mutations causing both syndromes is presented. The CDH3 gene was sequenced and investigation of the mutations performed using a protein structure model. The conservation score was calculated by ConSurf. We identified a novel CDH3 gene mutation, p.G277V, which resides in a conserved residue located on a β-strand in the second cadherin domain. Review of the data on previously published mutations showed intra-familial and inter-familial variations in the severity of the limb abnormalities. Syndactyly was the most consistent clinical finding present in all the patients regardless of mutation type. The results of our study point to a phenotypic continuum between HJMD and EEM. It is important for genetic counseling to keep in mind the possible clinical/phenotypic overlap between these 2 syndromes and to be aware of the possible risk of limb abnormalities in future pregnancies in families with HJMD syndrome. CDH3 gene mutation screening is recommended in patients with both these syndromes as part of the work-up in order to offer appropriate genetic counseling. Copyright © 2011 S. Karger AG, Basel.
PubMed | Raphael Recanati Genetic Institute and Tel Aviv University
Type: Journal Article | Journal: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | Year: 2015
Microdeletions of various sizes in the 2p16.1-p15 chromosomal region have been grouped together under the 2p16.1-p15 microdeletion syndrome. Children with this syndrome generally share certain features including microcephaly, developmental delay, facial dysmorphism, urogenital and skeletal abnormalities. We present a child with a de-novo interstitial 1665 kb duplication of 2p16.1-p15.Clinical features of this child are distinct from those of children with the 2p16.1-p15 microdeletion syndrome, specifically the head circumference which is within the normal range and mild intellectual disability with absence of autistic behaviors. Microduplications many times bear milder clinical phenotypes in comparison with corresponding microdeletion syndromes. Indeed, as compared to the microdeletion syndrome patients, the 2p16.1-p15 microduplication seems to have a milder cognitive effect and no effect on other body systems. Limited information available in genetic databases about cases with overlapping duplications indicates that they all have abnormal developmental phenotypes.The involvement of genes in this location including BCL11A, USP34 and PEX13, affecting fundamental developmental processes both within and outside the nervous system may explain the clinical features of the individual described in this report.