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Tel Aviv, Israel

Thiel C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Kessler K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Giessl A.,Friedrich - Alexander - University, Erlangen - Nuremberg | Dimmler A.,Institute of Pathology | And 15 more authors.
American Journal of Human Genetics | Year: 2011

Defects of ciliogenesis have been implicated in a wide range of human phenotypes and play a crucial role in signal transduction and cell-cycle coordination. We used homozygosity mapping in two families with autosomal-recessive short-rib polydactyly syndrome Majewski type to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia. NEK1 encodes a serine/threonine kinase with proposed function in DNA double-strand repair, neuronal development, and coordination of cell-cycle-associated ciliogenesis. We found that absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo. We further substantiate a proposed digenic diallelic inheritance of ciliopathies by the identification of heterozygous mutations in NEK1 and DYNC2H1 in an additional family. Notably, these findings not only increase the broad spectrum of ciliar disorders, but suggest a correlation between the degree of defective microtubule or centriole elongation and organization and the severity of the resulting phenotype. © 2011 The American Society of Human Genetics. Source

Davis C.,University of Maryland University College | Cuckle H.,Columbia University | Yaron Y.,Genetic Institute
Prenatal Diagnosis | Year: 2014

Objective: Down syndrome screening programmes lead to the prenatal diagnosis of other chromosomal abnormalities, some of which would not be detected by the secondary use of cell-free (cf)DNA testing in screen positives. This study aims to assess the number of these incidental diagnoses. Method: This study is a systematic review of the literature to identify large prospective screening studies that reported diagnoses other than trisomies 21 and 18. Results: There were ten informative prospective studies in which a total of 1500999 women were screened, and there were 3689 aneuploidy cases detected in the screen positives. Trisomy 21 was estimated to comprise only 58% of detected aneuploidies, trisomies 21 and 18 comprised 72%, and the common trisomies - 21, 18 and 13 - comprised 76%. Common trisomies and sex chromosome abnormalities, now included in all commercial cfDNA tests, were estimated to comprise 87% of aneuploidies in the Down syndrome screen positives. All these proportions were higher for second trimester protocols compared with those carried out wholly or partly in the first trimester. Conclusion: Secondary use of cfDNA testing will lead to about one-fifth reduction in diagnoses, taking account of both undetectable aneuploidies and false-negatives. This loss might be overcome by contingent cfDNA testing. © 2014 John Wiley & Sons, Ltd. Source

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. Source

Zlotogora J.,Hebrew University of Jerusalem | Shalev S.A.,Genetic Institute | Shalev S.A.,Technion - Israel Institute of Technology
American Journal of Medical Genetics, Part A | Year: 2010

The rate ofmalformations and major medical conditions in early childhood was analyzed in a single village according to the degree of relationship between the parents. In the village, 70-80% of the marriages are between descendants of the founders and therefore consanguineous. In the period 1992-2003, in 99 of 2,610 children, a major malformation was diagnosed at birth and seven additional fetuses were aborted because of a severe malformation. A significant medical condition was diagnosed in 38 additional children in early childhood. The total of 144 cases with malformations or a major medical condition represented 5.52% (95% CI: 4.64-6.4) of the live births. Three malformations/disorders were relatively frequent: Down syndrome, esophageal atresia, and profound deafness. The rate of malformations and significant medical conditions was 7.77% (95 CI: 5.68-9.86) when the parents were first cousins and 3.63% (95% CI: 2.11-5.15) when they were not related (P=0.002, Fisher's exact test). Offspring of parents that were second cousins or closer but less than first cousin had a risk that was similar to the one of offspring of couples that were more distantly related. We propose therefore, that in inbred populations, all the couples that are not related as first cousins but in which the spouses are both descendants of the founders should be considered as related. The high prevalence of profound deafness in the village is due to mutations in the Connexin 26 gene, while the relatively high frequency of Down syndrome is not explained by maternal age only. © 2010 Wiley-Liss, Inc. Source

Kedmi M.,Genetic Institute | Orr-Urtreger A.,Genetic Institute | Orr-Urtreger A.,Tel Aviv University
Age | Year: 2011

Aging is accompanied by expression changes in multiple genes, and the brain is one of the tissues most vulnerable to aging. Since the α7 nicotinic acetylcholine receptor (nAChR) subunit has been associated with neurodevelopmental disorders and cognitive decline during aging, we hypothesized that its absence might affect gene expression profiles in aged brains. To study whether transcriptional changes occur due to aging, α7 deficiency, or both, we analyzed whole-brain transcriptomes of young (8 weeks) and aged (2 years) α7-deficient and wild-type control mice, using Mouse Genome 430 2.0 microarray. Highly significant expression changes were detected in 47 and 1,543 genes [after Bonferroni and false discovery rate (FDR) correction] in the brains of aged mice compared to young mice, regardless of their genotype. These included genes involved in immune system function and ribosome structure, as well as genes that were previously demonstrated as differentially expressed in aging human brains. Genotype-dependent changes were detected in only three genes, Chrna7 which encodes the α7 nAChR subunit, and two closely linked genes, likely due to a "mouse background effect." Expression changes dependent on age-genotype interaction were detected in 207 genes (with a low significance threshold). Age-dependent differential expression levels were approved in all nine genes that were chosen for validation by real-time RT-PCR. Our results suggest that the robust effect of aging on brain transcription clearly overcomes the almost negligible effect of α7 nAChR subunit deletion and that germ line deficiency of this subunit has a minor effect on brain expression profile in aged mice. © 2010 American Aging Association, Media, PA, USA. Source

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