Showing papers by "Noam Shomron published in 2020"

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

Abstract: Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone-rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.

Ethnic differences in alpha-1 antitrypsin deficiency allele frequencies may partially explain national differences in COVID-19 fatality rates.

Abstract: Infection rates, severity, and fatalities due to COVID-19, the pandemic mediated by SARS-CoV-2, vary greatly between countries. With few exceptions, these are lower in East and Southeast Asian and Sub-Saharan African countries compared with other regions. Epidemiological differences may reflect differences in border closures, lockdowns, and social distancing measures taken by each county, and by cultural differences, such as common use of face masks in East and Southeast Asian countries. The plasma serine protease inhibitor alpha-1 antitrypsin was suggested to protect from COVID-19 by inhibiting TMPRSS2, a cell surface serine protease essential for the SARS-CoV-2 cell entry. Here, we present evidence that population differences in alpha-1 antitrypsin deficiency allele frequencies may partially explain national differences in the COVID-19 epidemiology. Our study compared reported national estimates for the major alpha-1 antitrypsin deficiency alleles PiZ and PiS (SERPINA1 rs28929474 and rs17580, respectively) with the Johns Hopkins University Coronavirus Resource Center dataset. We found a significant positive correlation (R = .54, P = 1.98e-6) between the combined frequencies of the alpha-1 antitrypsin PiZ and PiS deficiency alleles in 67 countries and their reported COVID-19 mortality rates. Our observations suggest that alpha-1 antitrypsin deficiency alleles may contribute to national differences in COVID-19 infection, severity, and mortality rates. Population-wide screening for carriers of alpha-1 antitrypsin deficiency alleles should be considered for prioritizing individuals for stricter social distancing measures and for receiving a SARS-CoV-2 vaccine once it becomes available.

Genome-wide noninvasive prenatal diagnosis of monogenic disorders: Current and future trends.

Abstract: Noninvasive prenatal diagnosis (NIPD) is a risk-free alternative to invasive methods for prenatal diagnosis, e.g. amniocentesis. NIPD is based on the presence of fetal DNA within the mother's plasma cell-free DNA (cfDNA). Though currently available for various monogenic diseases through detection of point mutations, NIPD is limited to detecting one mutation or up to several genes simultaneously. Noninvasive prenatal whole exome/genome sequencing (WES/WGS) has demonstrated genome-wide detection of fetal point mutations in a few studies. However, Genome-wide NIPD of monogenic disorders currently has several challenges and limitations, mainly due to the small amounts of cfDNA and fetal-derived fragments, and the deep coverage required. Several approaches have been suggested for addressing these hurdles, based on various technologies and algorithms. The first relevant software tool, Hoobari, recently became available. Here we review the approaches proposed and the paths required to make genome-wide monogenic NIPD widely available in the clinic.

COVID-19 diagnosis prediction by symptoms of tested individuals: a machine learning approach

Abstract: Motivation Effective screening of SARS-CoV-2 enables quick and efficient diagnosis of COVID-19 and can mitigate the burden on healthcare systems. Prediction models that combine several features to estimate the risk of infection have been developed in hopes of assisting medical staff worldwide in triaging patients when allocating limited healthcare resources. Results We established a machine learning approach that trained on records from 51,831 tested individuals (of whom 4,769 were confirmed COVID-19 cases) while the test set contained data from the following week (47,401 tested individuals of whom 3,624 were confirmed COVID-19 cases). Our model predicts COVID-19 test results with high accuracy using only eight features: gender, whether age is above 60, known contact with an infected individual, and five initial clinical symptoms. Summary Overall, based on the nationwide data publicly reported by the Israeli Ministry of Health, we developed a model that detects COVID-19 cases by simple features accessed by asking basic questions. Our framework can be used, among other considerations, to prioritize testing for COVID-19 when allocating limited testing resources. Availability All data used in this study was retrieved from the Israeli Ministry of Health website. Contact yazeed@tauex.tau.ac.il, nshomron@tauex.tau.ac.il

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1

Abstract: Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results demonstrate that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

MicroRNAs in ascending thoracic aortic aneurysms.

Abstract: Thoracic Aortic Aneurysm (TAA) is characterized by the dilation of the aorta and is fatal if not diagnosed and treated appropriately. The underlying genetic mechanisms have not been completely delineated, so better knowledge of the physiopathology of TAAs is needed to improve detection and therapy. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and are known to be involved in cardiovascular diseases (CVDs). The current study aimed to identify miRNAs that can be used as possible biomarkers for the early diagnosis of patients with ascending TAAs (ATAAs). MiRNA expression was profiled by NanoString nCounter technology using 12 samples including tissue and pre- and post-surgical plasma from ATAA patients. Four miRNAs were selected and further validated by real time polymerase chain reaction (RT-PCR) in 22 plasma samples from which three miRNAs (hsa-miR140-5p, hsa-miR-191-5p and hsa-miR-214-3p) showed significant expression level differences between the two types of plasma samples. Further analyses of the corresponding predicted target genes by these miRNAs, revealed two genes (Myotubularin-related protein 4 (MTMR4) and Phosphatase 1 catalytic subunit β (PPP1CB)) whose expression was inversely correlated with the expression of their respective miRNAs. Overall, in this pilot study, we identified three miRNAs that might serve as potential biomarkers and therapeutic targets in ATAA.

The Contribution of MicroRNAs to the Inflammatory and Neoplastic Characteristics of Erdheim-Chester Disease.

Abstract: The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim–Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.

Proteogenomics of glioblastoma associates molecular patterns with survival

Abstract: Summary Glioblastoma (GBM) is the most aggressive form of glioma, with poor prognosis exhibited by most patients, and a median survival time of less than two years. To examine survival-associated patterns, we assembled a cohort of 87 GBM patients whose survival ranges from less than 3 months and up to 10 years, most of which are not bearing isocitrate-dehyderogenase (IDH)-1 mutation and did not undergo prior treatment. We integrated high-resolution mass-spectrometry proteomics and RNA-sequencing to examine the yet unresolved proteomic contribution to poor patient outcome, and compared it to the more established transcriptomic contribution and to published single-cell RNA-sequencing data. Discovering both layer-specific and shared processes, we found that immune, metabolic and developmental processes distinguish short and long survival periods. Additionally, we observed a significant discrepancy in tumor classification between expression layers. Overall, our integrative findings establish proteomic heterogeneity in GBM as a gateway to understanding poor patient survival.

Multi-Modal Single-Molecule Imaging with Continuously Controlled Spectral-resolution (CoCoS) Microscopy

Abstract: Color is a fundamental contrast mechanism in fluorescence microscopy, providing the basis for numerous imaging and spectroscopy techniques. The ever-growing need to acquire high-throughput, dynamic data from multicolor species is driving the development of optical schemes that optimize the achievable spectral, temporal, and spatial resolution needed in order to follow biological, chemical and physical processes. Here we introduce Continuously Controlled Spectral-resolution (CoCoS) microscopy, an imaging scheme that encodes color into spatial read-out in the image plane, with continuous control over the spectral resolution. The concept enables single-frame acquisition of multiple color channels, allowing simultaneous, single-molecule colocalization for barcoding and Forster resonance energy transfer (FRET) experiments. The simple control over the spectral dispersion allows switching between imaging modalities at a click of a button. We demonstrate the utility of CoCoS for multicolor localization microscopy of microRNA barcodes in clinical samples, single-molecule FRET measurements, and single-molecule spectroscopy. CoCoS may be integrated as a simple add-on to existing microscopes and will find use in applications that aim to record dynamic, multicolor localization events such as in multiplex FRET and tracking of multi-component, interacting complexes.

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1

Abstract: Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results demonstrate that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis.

Abstract: Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell-cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell-cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.

Linear mycosis fungoides in a blaschkoid distribution

Abstract: INTRODUCTION Mycosis fungoides (MF) is the most common type of primary cutaneous T cell lymphoma. Many clinicopathological variants of MF have been described in the literature, though only a few presented in a segmental pattern. There are several unique patterns of distribution of skin diseases, one of which is the Blaschko Lines. Congenital skin diseases develop in a Blaschkoid pattern due to mosaicism. In contrast, according to Happle, the development of acquired skin diseases in a similar pattern is explained by superimposed segmental manifestation - a process which involves mosaicism overlapping a preexisting congenital mutation. The theories by which previous case reports explained the segmental appearance of MF did not cover the molecular basis for their development. We report a case of a patient who presented with MF in a unique segmental distribution consistent with the Blaschko lines. The patient was found to have an acquired mosaic mutation in GNAS gene exclusively in the involved skin which represents a superimposed segmental manifestation according to Happle's theory. This case demonstrates the hidden potential of these rare cases which allows a better understanding of the pathogenesis by which acquired diseases develop. This is a basis for further research that could help identify new therapeutic targets for MF and other diseases that share its genetic etiology.

Method and system for identifying gene disorder in maternal blood

Abstract: A method of fetal genotyping, comprises receiving maternal genomic DNA (gDNA) data, maternal cell-free DNA (cfDNA) data, and paternal gDNA data of a pair parenting to a fetus. The data are analyzed to identify a first set of sites at which the parents are homozygous for different alleles, and a second set at which at least one of the parents has a mutation. For each site of the first set, a probability that a respective portion of the maternal cfDNA data is derived from the fetus is determined. Each site of the second set is classified according to the determined probabilities as being either fetal or maternal to genotype the fetus.