Publications by authors named "Lior Cohen"

58 Publications

Efficient Simulation of Loop Quantum Gravity: A Scalable Linear-Optical Approach.

Phys Rev Lett 2021 Jan;126(2):020501

Department of Physics, Florida Atlantic University, 777 Glades Road, Boca Raton, Florida 33431, USA.

The problem of simulating complex quantum processes on classical computers gave rise to the field of quantum simulations. Quantum simulators solve problems, such as boson sampling, where classical counterparts fail. In another field of physics, the unification of general relativity and quantum theory is one of the greatest challenges of our time. One leading approach is loop quantum gravity (LQG). Here, we connect these two fields and design a linear-optical simulator such that the evolution of the optical quantum gates simulates the spin-foam amplitudes of LQG. It has been shown that computing transition amplitudes in simple quantum field theories falls into the bounded-error quantum polynomial time class, which strongly suggests that computing transition amplitudes of LQG are classically intractable. Therefore, these amplitudes are efficiently computable with universal quantum computers, which are, alas, possibly decades away. We propose here an alternative special-purpose linear-optical quantum computer that can be implemented using current technologies. This machine is capable of efficiently computing these quantities. This work opens a new way to relate quantum gravity to quantum information and will expand our understanding of the theory.
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http://dx.doi.org/10.1103/PhysRevLett.126.020501DOI Listing
January 2021

The alliance mediates outcome in cognitive-behavioral therapy for social anxiety disorder, but not in attention bias modification.

Psychother Res 2020 Oct 28:1-15. Epub 2020 Oct 28.

Department of Psychology, The Hebrew University of Jerusalem, Israel.

The aim of the current study was to examine changes in the therapeutic alliance and its role as a mediator of treatment outcome in cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) compared to attention bias modification (ABM). Patients were randomized to 16-20 sessions of CBT (n = 33) or 8 sessions of ABM (n = 17). Patient-rated alliance and self-reported social anxiety were measured weekly and evaluator-rated social anxiety was measured monthly. Early alliance predicted greater subsequent anxiety reduction in CBT but not in ABM. The alliance increased and weekly improvements in alliance predicted weekly contemporaneous and subsequent decreases in anxiety only in CBT. Decreases in anxiety did not predict subsequent improvements in alliance. Both treatments were effective in reducing anxiety, but treatment effects were mediated by stronger early alliance and stronger cross-lagged effects of alliance on outcome in CBT compared to ABM. The results highlight the importance of the alliance in CBT for SAD. Further studies should examine the role of alliance alongside additional mediators to better understand differential mechanisms in CBT and ABM.
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http://dx.doi.org/10.1080/10503307.2020.1836423DOI Listing
October 2020

The role of expressive suppression and cognitive reappraisal in cognitive behavioral therapy for social anxiety disorder: A study of self-report, subjective, and electrocortical measures.

J Affect Disord 2021 Jan 14;279:334-342. Epub 2020 Oct 14.

Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.

Background: Contemporary models of cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) emphasize emotion dysregulation as a core impairment whose reduction may play a causal role in psychotherapy. The current study examined changes in use of emotion regulation strategies as possible mechanisms of change in CBT for SAD. Specifically, we examined changes in expressive suppression and cognitive reappraisal during CBT and whether these changes predict treatment outcome.

Methods: Patients (n = 34; 13 females; Mean age = 28.36 (6.97)) were allocated to 16-20 sessions of CBT. An electrocortical measure of emotion regulation and a clinician-rated measure of SAD were administered monthly. Self-report measures of emotion regulation and social anxiety were administered weekly. Multilevel models were used to examine changes in emotion regulation during treatment and cross-lagged associations between emotion regulation and anxiety.

Results: CBT led to decreased suppression frequency, increased reappraisal self-efficacy, and decreased unpleasantness for SAD-related pictures (ps < .05). At post-treatment, patients were equivalent to healthy controls in terms of suppression frequency and subjective reactivity to SAD-related stimuli. Gains were maintained at 3-months follow-up. Decreases in suppression frequency and electrocortical reactivity to SAD-related pictures predicted lower subsequent anxiety but not the other way around (ps < .05). Lower anxiety predicted greater subsequent increases in reappraisal self-efficacy.

Limitations: The lack of a control group precludes conclusions regarding mechanisms specificity.

Conclusions: Decreased frequency of suppression is a potential mechanism of change in CBT for SAD.
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http://dx.doi.org/10.1016/j.jad.2020.10.021DOI Listing
January 2021

Quantum-Limited Squeezed Light Detection with a Camera.

Phys Rev Lett 2020 Sep;125(11):113602

Hearne Institute for Theoretical Physics, and Department of Physics and Astronomy, Louisiana State University, Baton Rouge, Louisiana 70803, USA.

We present a technique for squeezed light detection based on direct imaging of the displaced-squeezed-vacuum state using a CCD camera. We show that the squeezing parameter can be accurately estimated using only the first two moments of the recorded pixel-to-pixel photon fluctuation statistics, with accuracy that rivals that of the standard squeezing detection methods such as a balanced homodyne detection. Finally, we numerically simulate the camera operation, reproducing the noisy experimental results with low signal samplings and confirming the theory with high signal samplings.
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http://dx.doi.org/10.1103/PhysRevLett.125.113602DOI Listing
September 2020

Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.

Front Neurol 2020 24;11:631. Epub 2020 Jul 24.

Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.

Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to gene mutations, falls into this group of disorders. KBG syndrome, caused by gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A deletion of 116 kb partially involving and two frameshift variants in were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS.
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http://dx.doi.org/10.3389/fneur.2020.00631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393934PMC
July 2020

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.

Am J Hum Genet 2020 04 26;106(4):467-483. Epub 2020 Mar 26.

Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic. Electronic address:

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118584PMC
April 2020

Thresholded Quantum LIDAR: Exploiting Photon-Number-Resolving Detection.

Phys Rev Lett 2019 Nov;123(20):203601

Hearne Institute for Theoretical Physics, and Department of Physics and Astronomy, Louisiana State University, Baton Rouge, Louisiana 70803, USA.

We present a technique that improves the signal-to-noise-ratio (SNR) of range-finding, sensing, and other light-detection applications. The technique filters out low photon numbers using photon-number-resolving detectors. This technique has no classical analog and cannot be done with classical detectors. We investigate the properties of our technique and show under what conditions the scheme surpasses the classical SNR. Finally, we simulate the operation of a rangefinder, showing improvement with a low number of signal samplings and confirming the theory with a high number of signal samplings.
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http://dx.doi.org/10.1103/PhysRevLett.123.203601DOI Listing
November 2019

Single Admission C-reactive protein Levels as a Sole Predictor of Patient Flow and Clinical Course in a General Internal Medicine Department.

Isr Med Assoc J 2019 Oct;21(10):686-691

Department of internal medicine "C", Assaf Harofeh Medical Center, Zerifin, affiliated with Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel.

Background: C-reactive protein (CRP) blood level is associated with clinical outcomes of several diseases. However, the independent predictive role of CRP in the heterogeneous population of patients admitted to internal medicine wards is not known.

Objectives: To determine whether single CRP levels at admission independently predicts clinical outcome and flow of patients in general medicine wards.

Methods: This study comprised 275 patients (50.5% female) with a mean age of 68.25 ± 17.0 years, hospitalized with acute disease in a general internal medicine ward. The association between admission CRP levels and clinical outcomes including mortality, the need for mechanical ventilation, duration of hospitalization, and re-admission within 6 months was determined.

Results: A significant association was found between CRP increments of 80 mg/L and risk for the major clinical outcomes measured. The mortality odds ratio (OR) was 1.89 (95% confidence interval (95%CI, 1.37-2.61, P < 0.001), mechanical ventilation OR 1.67 (95%CI, 1.10-2.34, P = 0.006), re-admission within 6 months OR 2.29 (95%CI, 1.66-3.15 P < 0.001), and prolonged hospitalization >7 days OR 2.09 (95%CI, 1.59-2.74, P < 0.001). Lower increments of10 mg/L in CRP levels were associated with these outcomes although with lower ORs. Using a stepwise regression model for admission CRP levels resulted in area under the receiver operating characteristics curves between 0.70 and 0.76 for these outcomes.

Conclusions: A single admission CRP blood level is independently associated with major parameters of clinical outcomes in acute care patients hospitalized in internal medicine wards.
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October 2019

De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures.

Brain 2019 11;142(11):3351-3359

Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.

Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer. Upon GTPase binding via CDC42 or RAC1, the PAK1 dimers dissociate and become activated. All identified variants are located within or close to the autoinhibitory switch domain that is necessary for trans-inhibition of resting PAK1 dimers. Protein modelling supports a model of reduced ability of regular autoinhibition, suggesting a gain of function mechanism for the identified missense variants. Alleviated dissociation into monomers, autophosphorylation and activation of PAK1 influences the actin dynamics of neurite outgrowth. Based on our clinical and genetic data, as well as the role of PAK1 in brain development, we suggest that gain of function pathogenic de novo missense variants in PAK1 lead to moderate-to-severe intellectual disability, macrocephaly caused by the presence of megalencephaly and ventriculomegaly, (febrile) seizures and autism-like behaviour.
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http://dx.doi.org/10.1093/brain/awz264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821231PMC
November 2019

Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities.

Eur J Hum Genet 2020 01 8;28(1):76-87. Epub 2019 Aug 8.

Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, 10599, USA.

PTPN23 is a His-domain protein-tyrosine phosphatase implicated in ciliogenesis, the endosomal sorting complex required for transport (ESCRT) pathway, and RNA splicing. Until recently, no defined human phenotype had been associated with alterations in this gene. We identified and report a cohort of seven patients with either homozygous or compound heterozygous rare deleterious variants in PTPN23. Combined with four patients previously reported, a total of 11 patients with this disorder have now been identified. We expand the phenotypic and variation spectrum associated with defects in this gene. Patients have strong phenotypic overlap, suggesting a defined autosomal recessive syndrome caused by reduced function of PTPN23. Shared characteristics of affected individuals include developmental delay, brain abnormalities (mainly ventriculomegaly and/or brain atrophy), intellectual disability, spasticity, language disorder, microcephaly, optic atrophy, and seizures. We observe a broad range of variants across patients that are likely strongly reducing the expression or disrupting the function of the protein. However, we do not observe any patients with an allele combination predicted to result in complete loss of function of PTPN23, as this is likely incompatible with life, consistent with reported embryonic lethality in the mouse. None of the observed or reported variants are recurrent, although some have been identified in homozygosis in patients from consanguineous populations. This study expands the phenotypic and molecular spectrum of PTPN23 associated disease and identifies major shared features among patients affected with this disorder, while providing additional support to the important role of PTPN23 in human nervous and visual system development and function.
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http://dx.doi.org/10.1038/s41431-019-0487-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906308PMC
January 2020

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.

Genet Med 2020 02 7;22(2):389-397. Epub 2019 Aug 7.

Wessex Clinical Genetics Service, University Hospital Southampton NHS Trust. Department of Human Genetics and Genomic Medicine, Southampton University, Southampton, UK.

Purpose: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function.

Methods: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.

Results: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.

Conclusion: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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http://dx.doi.org/10.1038/s41436-019-0612-0DOI Listing
February 2020

Identification of a novel PCNT founder pathogenic variant in the Israeli Druze population.

Eur J Med Genet 2020 Feb 25;63(2):103643. Epub 2019 Mar 25.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Majewski Osteodysplastic Primordial Dwarfism type II (MOPDII) is a form of dwarfism associated with severe microcephaly, characteristic skeletal findings, distinct dysmorphic features and increased risk for cerebral infarctions. The condition is caused by bi-allelic loss-of-function variants in the gene PCNT. Here we describe the identification of a novel founder pathogenic variant c.3465-1G > A observed in carriers from multiple Druze villages in Northern Israel. RNA studies show that the variant results in activation of a cryptic splice site causing a coding frameshift. The study was triggered by the diagnosis of a single child with MOPDII and emphasizes the advantages of applying next generation sequencing technologies in community genetics and the importance of establishing population-specific sequencing databases.
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http://dx.doi.org/10.1016/j.ejmg.2019.03.007DOI Listing
February 2020

Late diagnosis of Alstrom syndrome in a Yemenite-Jewish child.

Ophthalmic Genet 2019 02 2;40(1):7-11. Epub 2019 Jan 2.

a The Krieger Eye Research Laboratory , Felsenstein Medical Research Center , Petach Tikva , Israel.

Background: We describe the ophthalmologic, clinical, and genetic findings in a patient of Yemenite-Jewish origin diagnosed with Alstrom syndrome due to a novel splice-site mutation 10 years after a clinical misdiagnosis of Leber congenital amaurosis.

Methods: Ophthalmological evaluations included visual acuity, cycloplegic refraction, slit-lamp, and optical coherent tomography. Genetic analyses included whole exome sequencing followed by bioinformatics analysis and segregation analysis. An in vitro splicing assay was used to evaluate the effect of the identified mutation on splicing. Taqman assay was used to determine the need for population screening for the identified mutation.

Results: Ophthalmologic findings at age 6 were impaired vision, nystagmus, and hyperopia. At age 16 years, the patient presented with obesity, hypothyroidism, and elevated transaminase levels in addition to reduced vision, wandering nystagmus, disc pallor, and degenerative retinal changes. Targeted genetic analysis of ALMS1 revealed a homozygous transversion, c.11544 + 3A>T, suggesting a novel splicing mutation, with elimination of the donor splice site and insertion of 73 nucleotides at the end of exon 16. These changes were validated by Sanger sequencing and co-segregation on family members.

Conclusions: Ophthalmologists should be alert to the differential diagnosis of inherited retinal degeneration in young patients who present with impaired vision, especially if systemic symptoms are mild and there is no known family history. In the present case, targeted genetic analysis of a child with a syndromic cone-rod dystrophy yielded a novel splicing mutation in ALMS1 causing Alstrom syndrome.
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http://dx.doi.org/10.1080/13816810.2018.1561900DOI Listing
February 2019

Postoperative analgesia by adding acupuncture to conventional therapy, a non-randomized controlled trial.

J Complement Integr Med 2018 Oct 12;16(2). Epub 2018 Oct 12.

Internal Medicine Department B, Bnai Zion Medical Center, Haifa, Israel.

Background Postoperative pain is common in patients hospitalized in surgical departments, yet it is currently not sufficiently controlled by analgesics. Acupuncture, a complementary medical practice, has been evaluated for its benefits in postoperative pain with heterogeneous results. We tested the feasibility of a controlled study comparing the postoperative analgesic effect of acupuncture together with standard-of-care to standard-of-care only. Methods In this pilot non-randomized controlled study conducted at a tertiary medical center in Israel, patients received either acupuncture with standard-of-care pain treatment (acupuncture group) or standard-of-care treatment only (control group) following surgery. Visual Analogue Scale (VAS) ratings for pain level at rest and in motion were evaluated both at recruitment and two hours after treatment. Acupuncture-related side effects were reported as well. Results We recruited 425 patients; 336 were assigned to the acupuncture group and 89 to the control group. The acupuncture group exhibited a decrease of at least 40% in average level of pain both at rest (1.8±2.4, p<0.0001) and in motion (2.1±2.8, p<0.0001) following acupuncture, whereas the control group exhibited no significant decrease (p=0.92 at rest, p=0.98 in motion). Acupuncture's analgesic effect was even more prominent in reducing moderate to severe pain at baseline (VAS ≥4), with a decrease of 49% and 45% of pain level at rest and in motion respectively (p<0.001), compared with no significant amelioration in the control group (p=0.20 at rest, p=0.12 in motion). No major side effects were reported. Conclusion Integrating acupuncture with standard care may improve pain control in the postoperative setting.
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http://dx.doi.org/10.1515/jcim-2018-0028DOI Listing
October 2018

Variant in SCYL1 gene causes aberrant splicing in a family with cerebellar ataxia, recurrent episodes of liver failure, and growth retardation.

Eur J Hum Genet 2019 02 26;27(2):263-268. Epub 2018 Sep 26.

Department of Pediatrics C, Schneider Children Medical Center, Petah Tikva, 4920235, Israel.

Herein, we describe two members of one family who presented with recurrent episodes of hepatic failure, cerebellar ataxia, peripheral neuropathy, and short stature. Liver transplantation was considered. Whole-exome sequencing (Trio) revealed a synonymous variant in exon 4 of SCYL1:c.459C>T p. (Gly153Gly), which did not appear to affect the protein sequence. Computational prediction analysis suggested that this modification could alter the SCYL1 mRNA splicing processing to create a premature termination codon. The SCYL1 mRNAs in our patient's lymphocytes were analyzed and aberrant splicing was found. Molecular analysis of family members identified the parents as heterozygous recessive carriers and the proband as well as an affected aunt as homozygous. Evidently, harmless synonymous variants in the SCYL1 gene can damage gene splicing and hence the expression. We confirmed that the pathogenicity of this variant in the SCYL1 gene was associated with spinocerebellar ataxia, autosomal recessive 21 (SCAR21). Other reported cases (accept one) of liver failure found in the SCYL1 variants resolved during childhood, therefore orthotropic liver transplantation was no longer appropriate.
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http://dx.doi.org/10.1038/s41431-018-0268-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336772PMC
February 2019

A pilot randomized clinical trial of cognitive behavioral therapy versus attentional bias modification for social anxiety disorder: An examination of outcomes and theory-based mechanisms.

J Anxiety Disord 2018 10 7;59:1-9. Epub 2018 Aug 7.

Department of Psychology, The Hebrew University of Jerusalem, Israel.

No studies have compared face-to-face cognitive-behavioral therapy (CBT) and attention bias modification (ABM) for social anxiety disorder (SAD) and their purported mechanisms. We asked: 1) Is CBT more effective than ABM? and 2) Are changes in attentional biases and cognitions temporally related to symptom change? Forty-three patients were randomly assigned to 8 sessions of ABM or up to 20 sessions of individual CBT. Intent-to-treat results revealed that CBT was superior to ABM in response rates and on symptom measures at endpoint, but not on other measures. No differences were found on measures in rates of change between CBT and ABM. Frequency of negative cognitions changed in both groups and negative beliefs changed only in CBT. Attentional bias did not change in either group. Cognitive changes bidirectionally correlated with symptom change in cross-lagged analyses in CBT, but not in ABM, suggesting a reciprocal relationship. Trial-level bias away from negative faces was simultaneously related to symptom change in ABM only. Results suggest that CBT is superior to ABM when administered at their typical doses, but raise questions given the similar rates of change. In addition, results support theories of cognitive change and raise questions about changes in attentional biases in CBT.
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http://dx.doi.org/10.1016/j.janxdis.2018.08.002DOI Listing
October 2018

CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability.

Mol Metab 2018 07 16;13:1-9. Epub 2018 May 16.

CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France; Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, United Kingdom. Electronic address:

Objective: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step.

Methods: CoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (n = 145).

Results: CoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations.

Conclusions: CoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.
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http://dx.doi.org/10.1016/j.molmet.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026315PMC
July 2018

Behavior: Oxytocin Promotes Fearless Motherhood.

Curr Biol 2018 04;28(8):R359-R361

Sagol Department of Neurobiology, University of Haifa, Haifa 3498838, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa 3498838, Israel. Electronic address:

In mammals, lactating mothers show reduced fear and anxiety. A new study reveals the way by which the lactation-inducing neuropeptide oxytocin attenuates social fear in lactating female mice by inhibiting activity in a single brain area.
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http://dx.doi.org/10.1016/j.cub.2018.02.063DOI Listing
April 2018

Assessing Sociability, Social Memory, and Pup Retrieval in Mice.

Curr Protoc Mouse Biol 2017 Dec 20;7(7):287-305. Epub 2017 Dec 20.

Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

Adaptive social behavior is important in mammals, both for the well-being of the individual and for the thriving of the species. Dysfunctions in social behavior occur in many neurodevelopmental and psychiatric diseases, and research into the genetic components of disease-relevant social deficits can open up new avenues for understanding the underlying biological mechanisms and therapeutic interventions. Genetically modified mouse models are particularly useful in this respect, and robust experimental protocols are needed to reliably assess relevant social behavior phenotypes. Here we describe in detail three protocols to quantitatively measure sociability, one of the most frequently investigated social behavior phenotypes in mice, using a three-chamber sociability test. These protocols can be extended to also assess social memory. In addition, we provide a detailed protocol on pup retrieval, which is a particularly robust maternal behavior amenable to various scientific questions. © 2017 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpmo.36DOI Listing
December 2017

Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45.

Am J Med Genet A 2017 Nov 8;173(11):3109-3113. Epub 2017 Sep 8.

St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.

SPG45 is a rare form of autosomal recessive spastic paraplegia associated with mental retardation. Detailed phenotyping and mutation analysis was undertaken in three individuals with SPG45 from a consanguineous family of Arab Muslim origin. Using whole-exome sequencing, we identified a novel homozygous missense mutation in NT5C2 (c.1379T>C; p.Leu460Pro). Our data expand the molecular basis of SPG45, adding the first missense mutation to the current database of nonsense, frameshift, and splice site mutations. NT5C2 mutations seem to have a broad clinical spectrum and should be sought in patients manifesting either as uncomplicated or complicated HSP.
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http://dx.doi.org/10.1002/ajmg.a.38414DOI Listing
November 2017

[UTILIZATION OF WHOLE EXOME SEQUENCING IN DIAGNOSTICS OF GENETIC DISEASE: RABIN MEDICAL CENTER'S EXPERIENCE].

Harefuah 2017 Apr;156(4):212-216

Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel.

Introduction: Whole exome sequencing is a diagnostic approach for the identification of molecular etiology in patients with suspected monogenic diseases. In this article we report on our experience with whole-exome sequencing (WES) of DNA samples taken from patients referred for genetic evaluation due to suspected undiagnosed genetic conditions.

Methods: Exome enrichment was achieved by Nextera Rapid Capture Expanded Exome Kit. Whole-exome sequencing was performed on Illumina HiSeq 2500. Potentially damaging rare variants were selected for familial cosegregation analysis.

Results: A total of 39 patients presenting a wide range of phenotypes suspected to have a genetic cause were sent to WES. Approximately 80% were children with neurological phenotypes. Variations having a high probability of being causative were identified in 20 families, achieving a 51.3% molecular diagnostic rate. Among these, 7 exhibited autosomal dominant disease, 12 autosomal recessive diseases and one X-linked disease; 28% of the patients (11/39) were found to carry a novel mutation located in previously reported genes. Novel mutations located in genes not known to be associated with genetic disease were identified in 23% of the patients (9/39).

Conclusions: Whole exome sequencing identified the underlying genetic cause in more than half of the patients referred for evaluation in the genetics clinic at the tertiary hospital. These data demonstrate the utility of WES as a powerful tool for effective diagnostics of monogenic genetic diseases.
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April 2017

A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis.

J Clin Endocrinol Metab 2017 02;102(2):681-688

Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel.

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 Israeli Muslim Arab ancestry presented with a lack of normal progression of puberty, high gonadotropin levels, and hypoplastic or absent ovaries on ultrasound. Blood samples for DNA extraction were obtained from all family members.

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 γH2AX-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.
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http://dx.doi.org/10.1210/jc.2016-2714DOI Listing
February 2017

De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms.

Am J Hum Genet 2016 Oct 8;99(4):934-941. Epub 2016 Sep 8.

Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.
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http://dx.doi.org/10.1016/j.ajhg.2016.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065651PMC
October 2016

Is one diagnosis the whole story? patients with double diagnoses.

Am J Med Genet A 2016 09 8;170(9):2338-48. Epub 2016 Jun 8.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37799DOI Listing
September 2016

Exome sequencing identified a novel de novo OPA1 mutation in a consanguineous family presenting with optic atrophy.

Genet Res (Camb) 2016 06 6;98:e10. Epub 2016 Jun 6.

Sackler School of Medicine,Tel Aviv University,Israel.

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.
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http://dx.doi.org/10.1017/S0016672316000070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865152PMC
June 2016

Adherence to acne treatment guidelines in the military environment - a descriptive, serial cross-sectional study.

Mil Med Res 2015 23;2:37. Epub 2015 Dec 23.

Israel Defense Forces Medical Corps, IDF, P.O. Box 02149, Te Hashomer, Israel ; Department of Military Medicine, Faculty of Medicine, Hebrew University, Jerusalem, Israel.

Background: Acne vulgaris, a common skin disease, affects up to 80 % of the population. Moderate to severe acne requires treatment with a combination of topical and oral drugs such as antibiotics, hormones and retinoids. Retinoids have many contraindications and adverse effects requiring close monitoring. The study's objectives were to describe prescribing trends in acne medication over time in a military setting, and assess physician adherence to guidelines for acne treatment, including drug precautions, clinical monitoring, and treatment progression.

Methods: We conducted a descriptive, serial cross-sectional study of acne drugs prescribed in the Israel Defense Forces (IDF) in the years 2002-2007, analyzing the classes of drugs prescribed and patient characteristics. In addition, the clinical quality of the medical encounter was assessed by examining physician adherence to IDF guidelines.

Results: Between 2002 and 2007, 64,281 patients were treated for acne. Treatment courses generally persisted for 1-2 months. Over 70 % of female patients receiving oral retinoids were not concomitantly receiving oral contraceptives.

Conclusion: This study provides a unique perspective of acne treatment in a military setting, overall displaying good adherence to general guidelines. The common prescription of oral retinoids to young females without concomitant contraception is alarming.
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http://dx.doi.org/10.1186/s40779-015-0063-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690295PMC
December 2015

Mutations in TAX1BP3 cause dilated cardiomyopathy with septo-optic dysplasia.

Hum Mutat 2015 Apr 16;36(4):439-42. Epub 2015 Mar 16.

The Raphael Recanati Genetic Institute, Rabin Medical Center, Israel; Sackler School of Medicine, Tel Aviv University, Israel.

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.
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http://dx.doi.org/10.1002/humu.22759DOI Listing
April 2015

Plasticity during motherhood: changes in excitatory and inhibitory layer 2/3 neurons in auditory cortex.

J Neurosci 2015 Jan;35(4):1806-15

Department of Neurobiology, Institute of Life Sciences, Edmond and Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram Jerusalem, 91904, Israel

Maternal behavior can be triggered by auditory and olfactory cues originating from the newborn. Here we report how the transition to motherhood affects excitatory and inhibitory neurons in layer 2/3 (L2/3) of the mouse primary auditory cortex. We used in vivo two-photon targeted cell-attached recording to compare the response properties of parvalbumin-expressing neurons (PVNs) and pyramidal glutamatergic neurons (PyrNs). The transition to motherhood shifts the average best frequency of PVNs to higher frequency by a full octave, with no significant effect on average best frequency of PyrNs. The presence of pup odors significantly reduced the spontaneous and evoked activity of PVN. This reduction of feedforward inhibition coincides with a complimentary increase in spontaneous and evoked activity of PyrNs. The selective shift of PVN frequency tuning should render pup odor-induced disinhibition more effective for high-frequency stimuli, such as ultrasonic vocalizations. Indeed, pup odors increased neuronal responses of PyrNs to pup ultrasonic vocalizations. We conclude that plasticity in the mothers is mediated, at least in part, via modulation of the feedforward inhibition circuitry in the auditory cortex.
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http://dx.doi.org/10.1523/JNEUROSCI.1786-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795264PMC
January 2015

Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6.

Am J Hum Genet 2015 Feb 22;96(2):295-300. Epub 2015 Jan 22.

Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.ajhg.2014.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320262PMC
February 2015