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author:("Yaron, duval")
1.  Carrier testing for spinal muscular atrophy 
Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general.
doi:10.1097/GIM.0b013e3181ef6079
PMCID: PMC4277882  PMID: 20808230
spinal muscular atrophy; carrier screening; national standards; policy; meeting report
2.  Two novel mutations identified in familial cases with Donohue syndrome 
Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype–phenotype issues playing a role in the pathophysiology of DS. A female infant born to first-degree cousins Muslim Arab parents and two brothers born to first-degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy. Each patient was found homozygous for one missense mutation within the extracellular domain of the INSR gene. Western blot analysis identified the proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Muslims, no heterozygous was found and of 52 healthy Druze from the same village, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post-translational processing of the INSR, resulting loss of its function. Both mutations cause DS with hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease.
doi:10.1002/mgg3.43
PMCID: PMC3907912  PMID: 24498630
Cardiomyopathy; Donohue syndrome; genotype–phenotype; insulin receptor.
3.  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.
doi:10.1038/ng.594
PMCID: PMC2894012  PMID: 20512146
4.  Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog 
European Journal of Human Genetics  2009;17(9):1112-1120.
Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we also describe a New Zealand family, which carries the ‘Farabee' founder mutation and haplotype. All of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH and are in contrast to those mutations causing an autosomal recessive acrocapitofemoral dysplasia, whose mutations are located at the distal N- and C-terminal regions of IHH-N and are physically separated from the BDA1-causing mutations. The identification of multiple independent mutations in codons 95, 100, and now in 131, implicate a discrete function for this region of the protein. Finally, we present a clinical review of all reported and confirmed cases of BDA1, highlighting features of the disorder, which add to the spectrum of the IHH mutations.
doi:10.1038/ejhg.2009.18
PMCID: PMC2986602  PMID: 19277064
brachydactyly; Indian Hedgehog; mutational clustering
5.  Novel causative mutations in patients with Nance-Horan syndrome and altered localization of the mutant NHS-A protein isoform 
Molecular Vision  2008;14:1856-1864.
Purpose
Nance-Horan syndrome is typically characterized by severe bilateral congenital cataracts and dental abnormalities. Truncating mutations in the Nance-Horan syndrome (NHS) gene cause this X-linked genetic disorder. NHS encodes two isoforms, NHS-A and NHS-1A. The ocular lens expresses NHS-A, the epithelial and neuronal cell specific isoform. The NHS-A protein localizes in the lens epithelium at the cellular periphery. The data to date suggest a role for this isoform at cell-cell junctions in epithelial cells. This study aimed to identify the causative mutations in new patients diagnosed with Nance-Horan syndrome and to investigate the effect of mutations on subcellular localization of the NHS-A protein.
Methods
All coding exons of NHS were screened for mutations by polymerase chain reaction (PCR) and sequencing. PCR-based mutagenesis was performed to introduce three independent mutations in the NHS-A cDNA. Expression and localization of the mutant proteins was determined in mammalian epithelial cells.
Results
Truncating mutations were found in 6 out of 10 unrelated patients from four countries. Each of four patients carried a novel mutation (R248X, P264fs, K1198fs, and I1302fs), and each of the two other patients carried two previously reported mutations (R373X and R879X). No mutation was found in the gene in four patients. Two disease-causing mutations (R134fs and R901X) and an artificial mutation (T1357fs) resulted in premature truncation of the NHS-A protein. All three mutant proteins failed to localize to the cellular periphery in epithelial cells and instead were found in the cytoplasm.
Conclusions
This study brings the total number of mutations identified in NHS to 18. The mislocalization of the mutant NHS-A protein, revealed by mutation analysis, is expected to adversely affect cell-cell junctions in epithelial cells such as the lens epithelium, which may explain cataractogenesis in Nance-Horan syndrome patients. Mutation analysis also shed light on the significance of NHS-A regions for its localization and, hence, its function at epithelial cell junctions.
PMCID: PMC2571945  PMID: 18949062
6.  Prospective Randomized Comparison of Two Embryo Culture Systems: P1 Medium by Irvine Scientific and the Cook IVF Medium 
Purpose: To compare the efficacy of two commercially available in vitro fertilization (IVF) and embryo culture media systems: the glucose-free P1 Medium supplemented with 20% synthetic serum substitute (SSS) (Irvine Scientific), and the Cook IVF Medium (Cook, Australia).
Methods: A prospective randomized study. Medical center-based IVF Unit affiliated to the Faculty of Medicine of Tel Aviv University. IVF patients were randomly assigned to either P1 Medium supplemented with 20% SSS (182 patients, 196 cycles) or Cook Medium (167 patients, 179 cycles).
Results: Fertilization rates were similar with both media (52.3 ± 26.1 and 53.8 ± 27.6, respectively). Likewise, no difference was found in morphological characteristics and grading of cultured embryos. However, a significantly higher proportion of the embryos incubated in the P1 Medium reached the four-cell stage on day 2 or the 6-cell stage on day 3 postfertilization, compared to those incubated in Cook Medium (54.3% vs. 41.9%, p<0.0001). Clinical pregnancy and delivery rates were improved when oocytes and embryos were cultured in P1 Medium. Finally, Implantation rate was significantly higher in the P1 Medium Group (9.9% vs. 6%, respectively).
Conclusions: Our results suggest that the P1 Medium may be associated with a higher embryo cleavage rate and improved implantation rates compared to the Cook IVF Medium.
doi:10.1023/B:JARG.0000043702.35570.56
PMCID: PMC3455441  PMID: 15568329
IVF; culture media; preimplantation embryo development; implantation rate
7.  The Mitochondrial DNA Mutation (ΔmtDNA5286) in Human Oocytes: Correlation with Age and IVF Outcome 
Purpose: To evaluate the correlation between the presence of a newly described mitochondrial DNA (mtDNA) mutation (ΔmtDNA5286), patients' age, and in vitro fertilization (IVF) outcomes.
Methods: The presence of ΔmtDNA5286 was analyzed by nested-primer PCR in 224 unfertilized oocytes of 81 women undergoing IVF for various reasons. Age, number of oocytes retrieved, fertilization and embryo cleavage, number of embryos transferred, and pregnancy rates were compared between patients with and without a mtDNA mutation in their oocytes.
Results: The 23 patients in which ΔmtDNA5286 was detected in at least one oocyte were significantly younger than the other 58 with no mutations (30.9 years vs. 33.8 years, respectively, P = 0.03), and had a significantly lower fertilization rate (28.9% vs. 42.1%, respectively, P = 0.01). No other outcome variable was significantly different between the two groups.
Conclusion(s): The mtDNA mutation ΔmtDNA5286 may serve as a marker of decreased oocyte quality in IVF.
doi:10.1023/A:1014439529813
PMCID: PMC3468229  PMID: 11958506
Fertilization; human oocytes; mitochondrial DNA; mutations
8.  Paternal deletion of the 11p15.5 centromeric-imprinting control region is associated with alteration of imprinted gene expression and recurrent severe intrauterine growth restriction 
Journal of Medical Genetics  2012;50(2):99-103.
Background
Heterogeneous molecular defects affecting the 11p15.5 imprinted gene cluster are associated with the opposite growth disorders Beckwith-Wiedemann Syndrome (BWS) and Silver Russell syndrome (SRS). Maternal deletions of the centromeric domain usually result in BWS, but paternal deletions have been so far associated with normal phenotype. Here we describe a case of recurrent severe Intra-Uterine Growth Restriction (IUGR) with paternal transmission of an 11p15.5 60 kb deletion.
Methods and results
Chromosome microarray (CMA), PCR and DNA sequencing analyses showed that two fetuses conceived by a normal couple inherited from their father a 60 kb deletion encompassing the Imprinting Control Region of the 11p15.5 centromeric domain. The two fetuses died in utero with severe growth restriction. PCR amplification of parental DNAs indicated that the father carried the mutation in the mosaic state. DNA methylation and gene expression analyses showed that the deletion led to an imprinting alteration restricted to the centromeric domain and resulting in silencing of KCNQ1OT1 and activation of CDKN1C and PHLDA2.
Conclusions
Our data demonstrate that the phenotype associated with 11p15.5 deletions is strongly influenced by the size of the region involved and indicate imprinting defects leading to CDKN1C and PHLDA2 activation as cause of severe IUGR.
doi:10.1136/jmedgenet-2012-101352
PMCID: PMC3585485  PMID: 23243085
Epigenetics; Imprinting; Chromosomal; Molecular genetics

Results 1-8 (8)