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author:("shale, shavit")
1.  A long-term follow up of premarital counseling in the Israeli Arab population 
Journal of Community Genetics  2014;5(4):377-381.
A follow up study of 168 Arab counselees that received premarital genetic counseling between 2001 and 2009, mostly since they planned to marry with a relative, was performed in 2013. Among the 156 cases in which the counselee married, 30 changed their marital plans (19.2 %). Those who changed their marital plans were more often Muslim Arabs that came for counseling since they were related in particular first cousins. Among the 126 counselee that married as planned, 66 were interviewed. From these interviews, it appears that many of the counselees that were related as first cousins or closer came to premarital genetic counseling in order to decide whether to marry. Most of the couples interviewed followed the recommendations concerning the use of folic acid and genetic tests. Among the 53 consanguineous couples interviewed, 49 women had 118 children. Among these 118 children, 8 (6.8 %) were born with a severe disease in 8 different families. This rate of malformations/genetic diseases is similar to the one observed for consanguineous couples from the general Arab population in the region, suggesting therefore that the premarital counseling and the adherence to the recommendations did not change the final risk to the counselees.
PMCID: PMC4159478  PMID: 24974306
Premarital genetic counseling; Consanguinity; Arabs
2.  Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response 
Nature genetics  2009;41(7):829-832.
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
PMCID: PMC4154505  PMID: 19525956
3.  Extreme clinical variability of dilated cardiomyopathy in two siblings with Alström syndrome 
Pediatric cardiology  2012;34(2):455-458.
Alström syndrome (ALMS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report on two brothers, 2 and 3 years of age, diagnosed with Alström syndrome who initially presented in infancy with severe dilated cardiomyopathy during febrile respiratory infection. The disease course in the two siblings was marked by significant intra-familial variability. While cardiomyopathy in the older sibling has mainly resolved allowing for the discontinuation of medical therapy, heart function in the younger sibling continues to deteriorate despite maximal drug support with furosemide, carvedilol, captopril and aldospirone. Genetic analysis revealed homozygous mutations, c.8008C>T (R2670X), in ALMS1 resulting in premature protein truncation. This report further emphasizes the exceptional intra-familial variability of ALMS, mainly in the natural course of cardiac disease.
PMCID: PMC3779600  PMID: 22447358
Alström syndrome; dilated cardiomyopathy; autosomal recessive; ALMS1 gene
4.  Prevention of β Thalassemia in Northern Israel - a Cost-Benefit Analysis 
β Thalassemia major is characterized by hemolytic anemia, ineffective erythropoiesis and hemosiderosis. About 4% of the world population carries a Thalassemia gene. Management includes blood transfusions and iron chelation. However, this treatment is costly, and population screening may be significantly more cost beneficial.
The purpose of the current study is to analyze the cost of running a prevention program for β Thalassemia in Israel and to compare it to the actual expenses incurred by treating Thalassemia patients.
Three cost parameters were analyzed and compared: the prevention program, routine treatment of patients and treatment of complications. An estimation of the expenses needed to treat patients who present with complications was calculated based on our ongoing experience in treating deteriorating patients.
Results and Conclusions
The cost of preventing one affected newborn was $63,660 compared to $1,971,380 for treatment of a patient during 50 years (mean annual cost: $39,427). Thus, the prevention of 45 affected newborns over a ten year period represents a net saving of $88.5 million to the health budget. Even after deducting the cost of the prevention program ($413.795/year), the program still represents a benefit of $76 million over ten years. Each prevented case could pay the screening and prevention program for 4.6 years.
PMCID: PMC3965716  PMID: 24678389
5.  The Coffin-Siris syndrome: A Proposed Diagnostic Approach and Assessment of 15 Overlapping Cases 
Coffin-Siris syndrome (CSS) is a rare, clinically heterogeneous disorder often considered in the setting of cognitive/developmental delay and 5th finger/nail hypoplasia. Due to the clinical variability of facial and other features, this diagnosis is often difficult to confirm clinically and the existence of this disorder as a specific diagnosis has been at times an issue of debate.
In an effort to further delineate the spectrum and key phenotypic features, we reviewed 80 previously reported cases to define features in patients that most closely correlated with a convincing diagnosis. There appear to be two subtypes of CSS, one which displays the “classic” coarse facial features previously described; another displays “variant” facial features which are less striking. Using these features, we defined an algorithm to rank the confidence of diagnosis and applied it to fifteen additional patients who had been previously characterized by chromosome microarray. This approach will also facilitate uniform categorization for whole-exome analysis.
PMCID: PMC3402612  PMID: 22711679
Coffin-Siris syndrome; fifth digit hypoplasia; developmental delay; cognitive delay; algorithm
6.  Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3 
Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive condition, which was defined recently with identification of the causative mutations in G6PC3. To date there are only three reports in the literature describing patients with SCN4 with mutations in the G6PC3 gene. We report four individuals with SCN4 who belong to a single large consanguineous kindred. We provide an overview of the non-haematological features of the condition with a focus on the adult phenotype, which has not been previously described in detail. We show that the superficial venous changes seen in SCN4 patients can develop into varicose veins and venous ulcers in adulthood. We review the range of congenital anomalies associated with SCN4. We demonstrate that secundum atrial septal defect, patent ductus arteriosus and valvular defects are the most frequent cardiac anomalies in SCN4. Drawing parallels with type 1 glycogen storage disease, we propose that poor growth of prenatal onset, mild-to-moderate learning disability, primary pulmonary hypertension, delayed or incomplete puberty, hypothyroidism and dysmorphism likely represent features of this syndrome. We also suggest monitoring for lipid anomalies, and kidney and liver function in affected patients. Delineation of the SCN4 phenotype may help in appropriate treatment and management and provide further insights into the pathogenesis of this multisystem disease.
PMCID: PMC3039503  PMID: 20717171
neutropenia; severe congenital neutropenia; G6PC3; glucose-6-phosphatase; glycogen storage disease
7.  Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in middle eastern families 
Genome Biology  2011;12(9):R89.
Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity.
A custom 1.46 MB design of cRNA oligonucleotides was constructed containing 246 genes responsible for either human or mouse deafness. Paired-end libraries were prepared from 11 probands and bar-coded multiplexed samples were sequenced to high depth of coverage. Rare single base pair and indel variants were identified by filtering sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. Critical mutations of the probands co-segregated with hearing loss. Screening of additional families in a relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of genetic hearing loss in the Moroccan Jewish population.
Critical mutations were identified in 6 of the 11 original probands and their families, leading to the identification of causative alleles in 20 additional probands and their families. The integration of genomic analysis into early clinical diagnosis of hearing loss will enable prediction of related phenotypes and enhance rehabilitation. Characterization of the proteins encoded by these genes will enable an understanding of the biological mechanisms involved in hearing loss.
PMCID: PMC3308052  PMID: 21917145
8.  Holoprosencephaly and Craniosynostosis: A Report of Two Siblings and Review of the Literature 
Holoprosencephaly and craniosynostosis are separate conditions that have occasionally been observed to occur simultaneously in the same patient. Here, we compile patients with both conditions that have been documented in the literature thus far; moreover, we report on two additional siblings who have not been previously described. We also compare the clinical features of these patients and discuss the previously hypothesized possibility of an independent association including both holoprosencephaly and craniosynostosis.
PMCID: PMC2814953  PMID: 20104614
Holoprosencephaly; craniosynostoses; cranial sutures; receptors; fibroblast growth factor
9.  Novel mutations of MYO7A and USH1G in Israeli Arab families with Usher syndrome type 1 
Molecular Vision  2011;17:3548-3555.
This study investigated the genetic basis for Usher syndrome type 1 (USH1) in four consanguineous Israeli Arab families.
Haplotype analysis for all known USH1 loci was performed in each family. In families for which haplotype analysis was inconclusive, we performed genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array. For mutation analysis, specific primers were used to PCR amplify the coding exons of the MYO7A, USH1C, and USH1G genes including intron-exon boundaries. Mutation screening was performed with direct sequencing.
A combination of haplotype analysis and genome-wide homozygosity mapping indicated linkage to the USH1B locus in two families, USH1C in one family and USH1G in another family. Sequence analysis of the relevant genes (MYO7A, USH1C, and USH1G) led to the identification of pathogenic mutations in all families. Two of the identified mutations are novel (c.1135–1147dup in MYO7A and c.206–207insC in USH1G).
USH1 is a genetically heterogenous condition. Of the five USH1 genes identified to date, USH1C and USH1G are the rarest contributors to USH1 etiology worldwide. It is therefore interesting that two of the four Israeli Arab families reported here have mutations in these two genes. This finding further demonstrates the unique genetic structure of the Israeli population in general, and the Israeli Arab population in particular, which due to high rates of consanguinity segregates many rare autosomal recessive genetic conditions.
PMCID: PMC3250379  PMID: 22219650
10.  Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes 
Nature genetics  2010;42(7):619-625.
Joubert syndrome (JBTS), related disorders (JSRD) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and JBTS2 loci are allelic and due to mutations in TMEM216, encoding an uncharacterized tetraspan transmembrane protein. JBTS2 patients displayed frequent nephronophthisis and polydactytly, and two cases conformed to the Oro-Facio-Digital type VI phenotype, whereas skeletal dysplasia was common in MKS fetuses. A single p.R73L mutation was identified in all patients of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in patient fibroblasts or following siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 complexed with Meckelin, encoded by a gene also mutated in JSRD and MKS. Abrogation of tmem216 expression in zebrafish led to gastrulation defects that overlap with other ciliary morphants. The data implicate a new family of proteins in the ciliopathies, and further support allelism between ciliopathy disorders.
PMCID: PMC2894012  PMID: 20512146
11.  Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews 
European Journal of Human Genetics  2009;17(9):1200-1203.
NADH:ubiquinone oxidoreductase (complex I; EC, the largest respiratory chain complex is composed of 45 proteins and is located at the mitochondrial inner membrane. Defects in complex I are associated with energy generation disorders, of which the most severe is congenital lactic acidosis. We report on four infants from two unrelated families of Jewish Caucasus origin with fatal neonatal lactic acidemia due to isolated complex I deficiency. Whole genome homozygosity mapping, identified a 2.6 Mb region of identical haplotype in the affected babies. Sequence analysis of the nuclear gene encoding for the NDUFS6 mitochondrial complex I subunit located within this region identified the c.344G>A homozygous mutation resulting in substitution of a highly evolutionary conserved cysteine residue by tyrosine. This is the second report of NDUFS6 mutation in humans. Both reports describe three diverse homozygous mutations with variable consequential NDUFS6 protein defects that result in similar phenotype. Our study further emphasizes that NDUFS6 sequence should be analyzed in patients presenting with lethal neonatal lactic acidemia due to isolated complex I deficiency.
PMCID: PMC2986593  PMID: 19259137
congenital lactic acidemia; NADH:ubiquinone oxidoreductase deficiency; OXPHOS; NDUFS6; homozygosity mapping; Caucasus Jews
12.  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.
PMCID: PMC2986253  PMID: 19107146
population screening; consanguinity

Results 1-12 (12)