Center for Rare Jewish Genetic Disorders

Brooklyn, NY, United States

Center for Rare Jewish Genetic Disorders

Brooklyn, NY, United States

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PubMed | Hebrew University of Jerusalem, Ohio State University, Center for Rare Jewish Genetic Disorders and University of California at Davis
Type: Journal Article | Journal: Neurogenetics | Year: 2016

Autosomal-recessive cerebellar atrophy is usually associated with inactivating mutations and early-onset presentation. The underlying molecular diagnosis suggests the involvement of neuronal survival pathways, but many mechanisms are still lacking and most patients elude genetic diagnosis. Using whole exome sequencing, we identified homozygous p.Val55Ala in the THG1L (tRNA-histidine guanylyltransferase 1 like) gene in three siblings who presented with cerebellar signs, developmental delay, dysarthria, and pyramidal signs and had cerebellar atrophy on brain MRI. THG1L protein was previously reported to participate in mitochondrial fusion via its interaction with MFN2. Abnormal mitochondrial fragmentation, including mitochondria accumulation around the nuclei and confinement of the mitochondrial network to the nuclear vicinity, was observed when patient fibroblasts were cultured in galactose containing medium. Culturing cells in galactose containing media promotes cellular respiration by oxidative phosphorylation and the action of the electron transport chain thus stimulating mitochondrial activity. The growth defect of the yeast thg1 strain was rescued by the expression of either yeast Thg1 or human THG1L; however, clear growth defect was observed following the expression of the human p.Val55Ala THG1L or the corresponding yeast mutant. A defect in the protein tRNA


Fedick A.,Johnson University | Su J.,Reproductive Medicine Associates of New Jersey | Jalas C.,Center for Rare Jewish Genetic Disorders | Northrop L.,Reproductive Medicine Associates of New Jersey | And 3 more authors.
PLoS ONE | Year: 2013

Members of the Ashkenazi Jewish community are at an increased risk for inheritance of numerous genetic diseases such that carrier screening is medically recommended. This paper describes the development and evaluation of 30 TaqMan allelic discrimination qPCR assays for 29 mutations on 2 different high-throughput platforms. Four of these mutations are in the GBA gene and are successfully examined using short amplicons due to the qualitative nature of TaqMan allelic discrimination. Two systems were tested for their reliability (call rate) and consistency with previous diagnoses (diagnostic accuracy) indicating a call rate of 99.04% and a diagnostic accuracy of 100% (+/-0.00%) from one platform, and a call rate of 94.66% and a diagnostic accuracy of 93.35% (+/-0.29%) from a second for 9,216 genotypes. Results for mutations tested at the expected carrier frequency indicated a call rate of 97.87% and a diagnostic accuracy of 99.96% (+/-0.05%). This study demonstrated the ability of a high throughput qPCR methodology to accurately and reliably genotype 29 mutations in parallel. The universally applicable nature of this technology provides an opportunity to increase the number of mutations that can be screened simultaneously, and reduce the cost and turnaround time for accommodating newly identified and clinically relevant mutations. © 2013 Fedick et al.


Edvardson S.,Hebrew University of Jerusalem | Cinnamon Y.,Hebrew University of Jerusalem | Ta-Shma A.,Hebrew University of Jerusalem | Shaag A.,Hebrew University of Jerusalem | And 9 more authors.
PLoS ONE | Year: 2012

Parkinson disease is caused by neuronal loss in the substantia nigra which manifests by abnormality of movement, muscle tone, and postural stability. Several genes have been implicated in the pathogenesis of Parkinson disease, but the underlying molecular basis is still unknown for ~70% of the patients. Using homozygosity mapping and whole exome sequencing we identified a deleterious mutation in DNAJC6 in two patients with juvenile Parkinsonism. The mutation was associated with abnormal transcripts and marked reduced DNAJC6 mRNA level. DNAJC6 encodes the HSP40 Auxilin, a protein which is selectively expressed in neurons and confers specificity to the ATPase activity of its partner Hcs70 in clathrin uncoating. In Auxilin null mice it was previously shown that the abnormally increased retention of assembled clathrin on vesicles and in empty cages leads to impaired synaptic vesicle recycling and perturbed clathrin mediated endocytosis. Endocytosis function, studied by transferring uptake, was normal in fibroblasts from our patients, likely because of the presence of another J-domain containing partner which co-chaperones Hsc70-mediated uncoating activity in non-neuronal cells. The present report underscores the importance of the endocytic/lysosomal pathway in the pathogenesis of Parkinson disease and other forms of Parkinsonism. © 2012 Edvardson et al.


PubMed | Hebrew University of Jerusalem, Reproductive Medicine Associates of New Jersey Basking Ridge, Rutgers Robert Wood Johnson Medical School Piscataway, GeneDx and 4 more.
Type: Case Reports | Journal: Journal of medical genetics | Year: 2016

Leukodystrophies are genetic white matter disorders affecting the formation or maintenance of myelin. Among the recently discovered genetic defects associated with leukodystrophies, several genes converge on a common mechanism involving protein transcription/translation and ER stress response.The genetic basis of a novel congenital leukodystrophy, associated with early onset spastic paraparesis, acquired microcephaly and optic atrophy was studied in six patients from three unrelated Ashkenazi-Jewish families. To this end we used homozygosity mapping, exome analysis, western blot (Hikeshi, HSF1-pS326 and b-actin) in patient fibroblasts, indirect immunofluorescence (HSP70 and HSF1) in patient fibroblasts undergoing heat shock stress, nuclear injection of plasmids expressing Hikeshi or EGFP in patient fibroblasts, in situ hybridization and Immunoblot analysis of Hikeshi in newborn and adult mouse brain.All the patients were homozygous for a missense mutation, p.Val54Leu, in C11ORF73 encoding HSP70 nuclear transporter protein, Hikeshi. The mutation segregated with the disease in the families and was carried by 1:200 Ashkenazi-Jewish individuals. The mutation was associated with undetectable level of Hikeshi in the patients fibroblasts and with lack of nuclear HSP70 during heat shock stress, a phenomenon which was reversed upon the introduction of normal human Hikeshi to the patients cells. Hikeshi was found to be expressed in central white matter of mouse brain.These data underscore the importance of Hikeshi for HSP70 relocation into the nucleus. It is likely that in the absence of Hikeshi, HSP70 cannot attenuate the multiple heat shock induced nuclear phenotypes, leaving the cells unprotected during heat shock stress. We speculate that the sudden death of three of the six patients following a short febrile illness and the life-threatening myo-pericarditis in the fourth are the result of excess extra-nuclear HSP70 level which initiates cytokine release or provide target for natural killer cells. Alternatively, nuclear HSP70 might play an active role in stressed cells protection.


Fedick A.,Microbiology and Immunology | Su J.,Reproductive Medicine Associates of New Jersey | Jalas C.,Center for Rare Jewish Genetic Disorders | Treff N.R.,Microbiology and Immunology
BMC Research Notes | Year: 2012

Background: While improvements in genotyping technology have allowed for increased throughput and reduced time and expense, protocols remain hindered by the slow upstream steps of isolating, purifying, and normalizing DNA. Various methods exist for genotyping samples directly through blood, without having to purify the DNA first. These procedures were designed to be used on smaller throughput systems, however, and have not yet been tested for use on current high-throughput real-time (q)PCR based genotyping platforms. In this paper, a method of quantitative qPCR-based genotyping on blood without DNA purification was developed using a high-throughput qPCR platform. Findings. The performances of either DNA purified from blood or the same blood samples without DNA purification were evaluated through qPCR-based genotyping. First, 60 different mutations prevalent in the Ashkenazi Jewish population were genotyped in 12 Ashkenazi Jewish individuals using the QuantStudio12K Flex Real-Time PCR System. Genotyping directly from blood gave a call rate of 99.21%, and an accuracy of 100%, while the purified DNA gave a call rate of 92.49%, and an accuracy of 99.74%. Although no statistical difference was found for these parameters, an F test comparing the standard deviations of the wild type clusters for the two different methods indicated significantly less variation when genotyping directly from blood instead of after DNA purification. To further establish the ability to perform high-throughput qPCR based genotyping directly from blood, 96 individuals of Ashkenazi Jewish decent were genotyped for the same 60 mutations (5,760 genotypes in 5 hours) and resulted in a call rate of 98.38% and a diagnostic accuracy of 99.77%. Conclusion: This study shows that accurate qPCR-based high-throughput genotyping can be performed without DNA purification. The direct use of blood may further expedite the entire genotyping process, reduce costs, and avoid tracking errors which can occur during sample DNA purification. © 2012 Fedick et al.; licensee BioMed Central Ltd.


PubMed | Hebrew University of Jerusalem, State University of New York at Stony Brook, Mount Sinai School of Medicine, Center for Rare Jewish Genetic Disorders and Microbiology and Immunology
Type: Journal Article | Journal: Journal of medical genetics | Year: 2016

Leukodystrophies due to abnormal production of myelin cause extensive morbidity in early life; their genetic background is still largely unknown. We aimed at reaching a molecular diagnosis in Ashkenazi-Jewish patients who suffered from developmental regression at 6-13months, leukodystrophy and peripheral neuropathy.Exome analysis, determination of alkaline ceramidase activity catalysing the conversion of C18:1-ceramide to sphingosine and D-ribo-C12-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) (NBD)-phytoceramide to NBD-C12-fatty acid using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and thin layer chromatography, respectively, and sphingolipid analysis in patients blood by LC-MS/MS.The patients were homozygous for p.E33G in the ACER3, which encodes a C18:1-alkaline ceramidase and C20:1-alkaline ceramidase. The mutation abolished ACER3 catalytic activity in the patients cells and failed to restore alkaline ceramidase activity in yeast mutant strain. The levels of ACER3 substrates, C18:1-ceramides and dihydroceramides and C20:1-ceramides and dihydroceramides and other long-chain ceramides and dihydroceramides were markedly increased in the patients plasma, along with that of complex sphingolipids, including monohexosylceramides and lactosylceramides.Homozygosity for the p.E33G mutation in the ACER3 gene results in inactivation of ACER3, leading to the accumulation of various sphingolipids in blood and probably in brain, likely accounting for this new form of childhood leukodystrophy.


Edvardson S.,Hebrew University of Jerusalem | Jalas C.,Center for Rare Jewish Genetic Disorders | Shaag A.,Hebrew University of Jerusalem | Zenvirt S.,Hebrew University of Jerusalem | And 3 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

Autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL) in Ashkenazi Jews, is mainly caused by mutations in the GJB2 and GJB6 genes. Here we describe a novel homozygous mutation of the LOXHD1 gene resulting in a premature stop codon (R1572X) in nine patients of Ashkenazi Jewish origin who had severe-profound congenital non-progressive ARNSHL and benefited from cochlear implants. Upon screening for the mutation among 719 anonymous Ashkenazi-Jews we detected four carriers, indicating a carrier rate of 1:180 Ashkenazi Jews. This is the second reported mutation in the LOXHD1 gene, and its homozygous presence in two of 39 Ashkenazi Jewish families with congenital ARNSHL suggest that it could account for some 5% of the familial cases in this community. © 2011 Wiley-Liss, Inc.


Edvardson S.,Hebrew University of Jerusalem | Cinnamon Y.,Hebrew University of Jerusalem | Jalas C.,Center for Rare Jewish Genetic Disorders | Shaag A.,Hebrew University of Jerusalem | And 3 more authors.
Annals of Neurology | Year: 2012

In 4 infants with a new lethal autonomic sensory neuropathy with clinical features similar to familial dysautonomia as well as contractures, we identified a deleterious mutation in the DST gene, using homozygosity mapping followed by exome sequencing. DST encodes dystonin, a cytoskeleton linker protein, and the mutation results in an unstable transcript. Interestingly, dystonin is significantly more abundant in cells of familial dysautonomia patients with IKBKAP (I-κ-B kinase complex-associated protein) mutation compared to fibroblasts of controls, suggesting that upregulation of dystonin is responsible for the milder course in familial dysautonomia. Homozygosity mapping followed by exome sequencing is a successful approach to identify mutated genes in rare monogenic disorders. Copyright © 2012 American Neurological Association.


Fedick A.,Johnson University | Jalas C.,Center for Rare Jewish Genetic Disorders | Treff N.R.,Johnson University
Clinical Genetics | Year: 2014

Zellweger syndrome is known to be caused by numerous mutations that occur in at least 12 of the PEX genes. While phenotypes vary, many are severely debilitating, and death can result in affected newborns. Since the disease follows an autosomal recessive pattern of inheritance, carrier screening can be done for at-risk couples, but the number of potential mutations sites to screen can be daunting. Ethnicity-specific studies can help narrow this range by highlighting mutations that are present at higher percentages in certain populations. In this article, the carrier frequencies for two mutations causative of the severe Zellweger syndrome spectrum phenotype that occur in the PEX2 gene, c.355C>T and c.550del, were studied in individuals of Ashkenazi Jewish descent in order to advise on inclusion in existing carrier screening mutation panels for this population. The screening was performed for 2093 individuals through the use of TaqMan genotyping assays, real-time PCR, and allelic discrimination. Results indicated a carrier frequency of 0.813% (±0.385%) for the c.355C>T mutation and a carrier frequency of 0.00% (±0.00%) for the c.550del mutation. On the basis of these frequencies, we believe that the c.355C>T mutation should be considered for inclusion in carrier screening panels for the Ashkenazi population. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


PubMed | Mount Sinai School of Medicine and Center for Rare Jewish Genetic Disorders
Type: | Journal: The application of clinical genetics | Year: 2016

Mutations in the OTOF gene have previously been shown to cause nonsyndromic prelingual deafness (DFNB9, OMIM 601071) as well as auditory neuropathy/dys-synchrony. In this study, the OTOF NM_194248.2 c.5332G>T, p.Val1778Phe variant was identified in a large Ashkenazi Jewish family as the causative variant in four siblings with hearing loss. Our analysis reveals a carrier frequency of the OTOF c.5332G>T, p.Val1778Phe variant of 1.27% in the Ashkenazi Jewish population, suggesting that this variant may be a significant contributor to nonsyndromic sensorineural hearing loss and should be considered for inclusion in targeted hearing loss panels for this population. Of note, the degree of hearing loss associated with this phenotype ranged from mild to moderately severe, with two of the four siblings not known to have hearing loss until they were genotyped and underwent pure tone audiometry and auditory brainstem response testing. The phenotypic variability along with the auditory neuropathy/dys-synchrony, which allows for the production of otoacoustic emissions, supports that nonsyndromic hearing loss caused by OTOF mutations may be much more common in the Ashkenazi Jewish population than currently appreciated due to a lack of diagnosis.

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