The Task Force for the Promotion of the Status of Women in Medicine in Israel.

BACKGROUND: In this article, we offer a brief summary of the report from the Task Force for the Promotion of the Status of Women in Medicine in Israel. The task force, formed by the Israel Medical Association in 2013, published a comprehensive report in May 2015 dedicated to the promotion of equal opportunities for female doctors in the Israeli healthcare system and in the academic world. The aim of this paper is to present the work of the task force and to highlight its main principles and recommendations against the backdrop of the gender revolution in the Israeli healthcare system and worldwide.

Congenital glaucoma: CYP1B1 mutations in Israeli Bedouin kindreds.

PURPOSE: To investigate CYP1B1 gene mutations in Arab-Bedouin Israeli patients with primary congenital glaucoma (PCG). METHODS: Testing linkage to candidate genes using adjacent polymorphic markers and sequencing of genomic DNA samples by standard methods. RESULTS: In 9 of 11 unrelated affected Israeli Bedouin families, PCG was associated with homozygosity of 3 different CYP1B1 mutations. As in Saudi Arabian families, the 3987G>A CYP1B1 substitution accounted for approximately 50% of cases. A novel CYP1B1 mutation, 8405G>A, was found in 2 unrelated families. In 2 consanguineous families, there was no evidence of homozygosity or mutations in CYP1B1. CONCLUSIONS: CYP1B1 mutations account for the majority of cases of PCG in the Israeli Bedouin population. The most frequently found CYP1B1 mutation (3987G>A) in our study is also the commonest CYP1B1 mutation in the Saudi Arabian population, in line with the common genetic background of both populations. The absence of homozygosity in the CYP1B1 locus in the affected individuals in 2 consanguineous inbred families, suggests that other genes take part in the causation of congenital glaucomas. This is the first study describing the genetic basis of PCG among Israeli Arab-Bedouin individuals, in whom the frequency of the disease is the highest in the world. Further similar studies based on new diagnosed patients are needed to possibly prevent, screen, and treat (antenatal and postnatal) this sight-devastating childhood disease.

A targeted population carrier screening program for severe and frequent genetic diseases in Israel.

A national carrier screening program targeted at communities in which severe genetic diseases are present with a frequency higher than 1/1000 live births, has been in existence in Israel since 2002. Within the communities at risk, carrier screening is voluntary whereas genetic counseling and testing is provided free of charge. During the first 5 years of the program more than 13 000 tests were performed, and at the end of 2007 it was offered in 35 different localities/communities for a total of 36 diseases. Many of the couples identified to be at risk opted for prenatal diagnosis and in two cases an affected pregnancy was terminated. In some cases the couples declined prenatal diagnosis and two of those families gave birth to an affected child. Based on the experience learnt from this targeted screening program it appears that a knowledge-based, voluntary screening program operated within the community is an effective way to provide genetic services and test referrals. The community program directed toward couples in their reproductive period does not seem to have led to stigmatization at either the individual or the community level.

Attitudes toward the acceptability of reasons for pregnancy termination due to fetal abnormalities among prenatal care providers and consumers in Israel.

OBJECTIVES/BACKGROUND: Current prenatal diagnostic abilities confront parents and health professionals with complicated issues regarding termination of pregnancy (TOP) due to fetal abnormalities. 1. To assess and compare attitudes of consumers (women) and providers (health professionals) of prenatal care regarding TOP due to fetal abnormality.2. To identify factors related to these attitudes. METHODS: The study was conducted in southern Israel. Consumers (596) were interviewed by phone 5-8 weeks postpartum. Health professionals (351) filled out a self-administrated questionnaire. RESULTS: More than half of the interviewees approved of TOP due to mental retardation, death during infancy, severe physical disability and very low quality of life (in descending order). For each condition, care providers were significantly more supportive of TOP than women, and had far fewer hesitations. The hierarchy of 'TOP acceptability' was similar in both populations. Factors associated with women's attitudes were degree of religiosity, Ashkenazi origin and country of birth. Two approaches toward TOP were identified: 'consistent' versus 'ad hoc'. CONCLUSIONS: Prenatal care providers and consumers differ in their attitudes regarding acceptability of reasons for TOP. Care providers offering prenatal tests should be aware of their patients' attitudes, in order to guide informed decisions regarding the tests.

Population history and infrequent mutations: how old is a rare mutation? GUCY2D as a worked example.

The mosaic pattern of haplotypes observed around a single mutation results from one or several founder events. The difficulties involved in calculating the age of the variant are greatly reduced by assuming a single event, but this simplification may bias analysis of the genealogy of the mutation. However, if it is assumed that more than one founder event occurred, the number of genealogies is very large and the likelihood of every possible tree could not be realistically calculated. A multipoint approach is required, given the number of independent variables needed to describe a complex bifurcating genealogy. Starting from the observation that a limited number of parameters is needed for calculation of the simplest models of bifurcating genealogies, we show that the probability density of a two-ancestor model genealogy can be simply described as an algebraic function in a closed form, two coalescence times being calculated simultaneously without compromising accuracy. Implementation in a Bayesian framework is facilitated by the simplicity of the function, which describes the reciprocal relationship between the region of complete linkage disequilibrium and the branch length of the tree. We illustrate the use of haplotype information about allele-sharing decay around a mutation as a genetic clock, using data for two GUCY2D mutations in Mediterranean populations.

Different perceptions and attitudes regarding prenatal testing among service providers and consumers in Israel.

INTRODUCTION: The increasing number of prenatal tests for fetal abnormalities calls for a prenatal care policy which will reflect not only medical values, but also the needs and attitudes of the services' consumers. OBJECTIVES: To compare attitudes of prenatal service consumers and providers regarding extent of prenatal testing and to evaluate these attitudes in relation to sociodemographic and professional characteristics. METHODS: Women were interviewed by phone 5-8 weeks postpartum (n = 596) using a structured questionnaire. Health professionals (n = 351) completed a parallel questionnaire. RESULTS: Health professionals were significantly more supportive of comprehensive prenatal testing than women (61.1 vs. 34.1%, respectively). In a multivariable analysis, age over 35, Ashkenazi origin and being better informed regarding tests, predicted a preference for comprehensive testing among women. Among health professionals, predictors of that attitude were secularism and a paramedical profession. CONCLUSIONS: Providers and consumers of prenatal services differ in their perceptions and opinions. Policy makers should have mechanisms in place to properly represent this diversity.

Homozygous CRYBB1 deletion mutation underlies autosomal recessive congenital cataract.

PURPOSE: Some 30% of cases of congenital cataract are genetic in origin, usually transmitted as an autosomal dominant trait. The molecular defects underlying some of these autosomal dominant cases have been identified and were demonstrated to be mostly mutations in crystallin genes. The autosomal recessive form of the disease is less frequent. To date, only four genes and three loci have been associated with autosomal recessive congenital cataract. Two extended unrelated consanguineous inbred Bedouin families from southern Israel presenting with autosomal recessive congenital nuclear cataract were studied. METHODS: Assuming a founder effect, homozygosity testing was performed using polymorphic microsatellite markers adjacent to each of 32 candidate genes. RESULTS: A locus on chromosome 22 surrounding marker D22S1167 demonstrated homozygosity only in affected individuals (lod score > 6.57 at theta = 0 for D22S1167). Two crystallin genes (CRYBB1 and CRYBA4) located within 0.1 cM on each side of this marker were sequenced. No mutations were found in CRYBA4. However, an identical homozygous delG168 mutation in exon 2 of CRYBB1 was discovered in affected individuals of both families, generating a frameshift leading to a missense protein sequence at amino acid 57 and truncation at amino acid 107 of the 252-amino-acid CRYBB1 protein. Denaturing [d]HPLC analysis of 100 Bedouin individuals unrelated to the affected families demonstrated no CRYBB1 mutations. CONCLUSIONS: CRYBB1 mutations have been shown to underlie autosomal dominant congenital cataract. The current study showed that a different mutation in the same gene causes an autosomal recessive form of the disease.

Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11).

The identification of mutations in genes that cause human diseases has largely been accomplished through the use of positional cloning, which relies on linkage mapping. In studies of rare diseases, the resolution of linkage mapping is limited by the number of available meioses and informative marker density. One recent advance is the development of high-density SNP microarrays for genotyping. The SNP arrays overcome low marker informativity by using a large number of markers to achieve greater coverage at finer resolution. We used SNP microarray genotyping for homozygosity mapping in a small consanguineous Israeli Bedouin family with autosomal recessive Bardet-Biedl syndrome (BBS; obesity, pigmentary retinopathy, polydactyly, hypogonadism, renal and cardiac abnormalities, and cognitive impairment) in which previous linkage studies using short tandem repeat polymorphisms failed to identify a disease locus. SNP genotyping revealed a homozygous candidate region. Mutation analysis in the region of homozygosity identified a conserved homozygous missense mutation in the TRIM32 gene, a gene coding for an E3 ubiquitin ligase. Functional analysis of this gene in zebrafish and expression correlation analyses among other BBS genes in an expression quantitative trait loci data set demonstrate that TRIM32 is a BBS gene. This study shows the value of high-density SNP genotyping for homozygosity mapping and the use of expression correlation data for evaluation of candidate genes and identifies the proteasome degradation pathway as a pathway involved in BBS.

Promoting Arab and Israeli cooperation: peacebuilding through health initiatives.

This article describes a positive experience in building Arab and Israeli cooperation through health initiatives. Over the past 10 years Israeli, Jordanian, and Palestinian health professionals have worked together through the Canada International Scientific Exchange Program (CISEPO). In the initial project, nearly 17,000 Arab and Israeli newborn babies were tested for early detection of hearing loss, an important health issue for the region. The network has grown to address additional needs, including mother-child health, nutrition, infectious diseases, and youth health. Our guiding model emphasises two goals: project-specific outcomes in health improvement, and broader effects on cross-border cooperation. Lessons learned from this experience and the model provide direction for ways that health professionals can contribute to peacebuilding.

Primary congenital glaucoma presenting within the first three months of life in a Bedouin population: prognostic factors.

OBJECTIVES: To analyze the final outcome of surgery in Arab-Bedouin children with primary congenital glaucoma (PCG) presenting within the first three months of life, and to search for prognostic factors for success. DESIGN: Retrospective study of all cases with follow-up of at least 24 months. PATIENTS: Twenty-five Arab-Bedouin children (45 eyes) with PCG presenting within the first three months of life who underwent surgical procedures at the Soroka University Medical Center from January 1988 to December 1998. METHODS: Patient's age, family history, main presenting features, data from examinations under anesthesia, including intraocular pressure (IOP), horizontal corneal diameter, and cup/disc (c/d) ratio, and the type of surgery performed were reviewed. MAIN OUTCOME MEASURES: Success of the first operation, defined as final IOP < 21 mm Hg achieved after only one surgical procedure without anti-glaucoma medication, and final outcome, defined as good when IOP was < 21 mm Hg and > 5 mm Hg at the end of a 24-month follow-up period without anti-glaucoma medication, irrespective of the number of procedures performed. RESULTS: At presentation mean IOP was 36.2 +/- 8.0 mm Hg, corneal diameter was 12.62 +/- 0.98 mm, and c/d ratio was 0.41 +/- 0.16. The mean age at first operation was 17 +/- 20 days, and median of 5 days. The mean follow-up period was 37.4 +/- 25.4 months. The success of the first operation performed was not related to the type of operation (P = 0.22), gender (P = 0.47), consanguinity (P = 1.0), family history (P = 0.12), clinical presentation (P = 0.81), or age at first operation (P = 0.38). Eyes with high initial IOP and greater c/d ratio were at a significantly higher risk for failure (P = 0.05, P = 0.04, respectively). A final outcome of IOP under 21 mm Hg and above 5 mm Hg was achieved in 39 eyes (86.5%). There was no statistical association between final outcome and the type of first surgical procedure performed, gender, consanguinity, clinical presentation, and age at first operation. Cases with no family history had a significantly better final outcome (P = 0.05). In multivariate analysis only initial IOP showed borderline significance as an independent risk factor for final outcome (P = 0.06). CONCLUSIONS: Initial high IOP and higher c/d ratio were found to be predictive factors for failure of the first procedure. Final outcome was significantly better in cases with no family history, yet initial IOP was the only independent predictive factor for failure at the final outcome in a multivariate model. Findings of this type have not been previously reported, and they may constitute an important tool in predicting the treatment outcome of very young children with PCG.

Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a genetically heterogeneous multisystem disorder that causes severe visual impairment. Retinitis pigmentosa (RP), hypogonadism, digit and renal anomalies, obesity, and a variable degree of mental retardation characterize the disorder. Eight different loci have been identified on 2q31(BBS5), 3p13 (BBS3), 4q27 (BBS7), 11q13 (BBS1), 14q32 (BBS8), 15q22.3 (BBS4), 16q21 (BBS2), and 20p12 (BBS6). The ocular manifestations of Bardet-Biedl syndrome include an early and severe rod-cone dystrophy causing legal blindness in the second decade. Features of systemic phenotypic variability were proposed to distinguish patients mapped to either the BBS2, BBS3, or BBS4 loci but no phenotype-genotype correlation has been established for the ocular phenotype. We studied the three original families used for the identification of BBS2, BBS3, and BBS4 loci to define the ocular phenotypes of patients (n = 34) and obligate carriers (n = 32) using clinical examination and electroretinography (ERG). RP was severe and early in all cases. Myopia was associated with BBS3 and BBS4, but not BBS2. One patient with Bardet-Biedl syndrome also had iris and chorioretinal colobomata, features suggestive of Biemond syndrome.

Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin.

Bardet-Biedl syndrome (BBS) is a heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, hypogenitalism, and an increased incidence of diabetes and hypertension. No information is available regarding the specific function of BBS2. We show that mice lacking Bbs2 gene expression have major components of the human phenotype, including obesity and retinopathy. In addition, these mice have phenotypes associated with cilia dysfunction, including retinopathy, renal cysts, male infertility, and a deficit in olfaction. With the exception of male infertility, these phenotypes are not caused by a complete absence of cilia. We demonstrate that BBS2 retinopathy involves normal retina development followed by apoptotic death of photoreceptors, the primary ciliated cells of the retina. Photoreceptor cell death is preceded by mislocalization of rhodopsin, indicating a defect in transport. We also demonstrate that Bbs2(-/-) mice and a second BBS mouse model, Bbs4(-/-), have a defect in social function. The evaluation of Bbs2(-/-) mice indicates additional phenotypes that should be evaluated in human patients, including deficits in social interaction and infertility.

Homozygosity mapping of lethal congenital contractural syndrome type 2 (LCCS2) to a 6 cM interval on chromosome 12q13.

We have recently described a novel autosomal recessive disorder, lethal congenital contractural syndrome type 2 (LCCS2) (OMIM 607598), in a large Israeli Bedouin kindred. The phenotype, which is lethal in the neonatal period, is distinguished by the presence of a markedly distended urinary bladder. Association of LCCS2 to the known loci associated with arthogryposis was excluded. In the present study, we set out to determine the genetic locus harboring the gene defective in this disease. We performed genome-wide linkage analysis, demonstrating linkage to a approximately 6 cM (corresponding to approximately 7.2 Mb) homozygosity region on chromosome 12q13 between markers D12S1604 and D12S83. Based on recombination events, the interval harboring the disease-associated locus was further narrowed to a region spanning approximately 6 cM ( approximately 6.4 Mb) between D12S325 and D12S1072. Linkage of LCCS2 to that locus was established, with two significant maximum peaks at markers D12S1604 (Z(max) = 10.56 at theta = 0.01) and D12S1700 (Z(max) = 9.23 at theta = 0.00).