Publications by authors named "Marina Eskin-Schwartz"

Introduction: Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix.

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  • Developmental dysplasia of the hip (DDH) is a common congenital musculoskeletal disorder in newborns, with genetic factors, but its molecular mechanisms remain unclear.
  • Research identified a specific genetic variant in a Bedouin family that could lead to DDH through pathways related to bone formation, specifically focusing on the TRIM33 gene.
  • The study's results indicate that this genetic variant impacts the expression of key genes in the BMP pathway, providing insight into how DDH can develop genetically.
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With the increasing importance of genomic data in understanding genetic diseases, there is an essential need for efficient and user-friendly tools that simplify variant analysis. Although multiple tools exist, many present barriers such as steep learning curves, limited reference genome compatibility, or costs. We developed VARista, a free web-based tool, to address these challenges and provide a streamlined solution for researchers, particularly those focusing on rare monogenic diseases.

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  • POT1 is an important gene involved in protecting and regulating the length of telomeres, and mutations in this gene can increase cancer risk, particularly for melanoma and chronic lymphocytic leukemia (CLL).
  • A specific mutation, p.(I78T), has been identified as a common pathogenic variant among Ashkenazi Jews, linked to a range of cancers and recurrent melanoma in individuals aged 25 to 67.
  • Research suggests that this variant should be included in genetic testing for high-risk patients of Ashkenazi Jewish descent due to its association with early-onset severe cancers.
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Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal.

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  • Rapid trio genome sequencing (rtGS) is being implemented in Israeli neonatal intensive care units (NICUs) to provide advanced care for critically ill newborns suspected of having genetic issues.
  • A study conducted from October 2021 to December 2022 involved 130 neonates, leading to a diagnostic rate of 50% for disease-causing genetic variants and 11% for variants of unknown significance (VUS).
  • Results showed a mean turnaround time for rapid reports of 7 days, with high engagement from medical staff regarding the clinical utility of the results (82% response rate to questionnaires).
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Background: Sex-specific predilection in neurological diseases caused by mutations in autosomal genes is a phenomenon whose molecular basis is poorly understood. We studied females of consanguineous Bedouin kindred presenting with severe global developmental delay and epilepsy.

Methods: Linkage analysis, whole exome sequencing, generation of CRISPR/cas9 knock-in mice, mouse behaviour and molecular studies RESULTS: Linkage analysis and whole exome sequencing studies of the affected kindred delineated a ~5 Mbp disease-associated chromosome 2q35 locus, containing a novel homozygous frameshift truncating mutation in , in line with recent studies depicting similar putative loss-of-function human phenotypes with female preponderance.

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  • Next-generation sequencing and data exchange platforms have greatly improved molecular diagnoses for families by using a semi-automated genematching algorithm focused on genotype and phenotype matching.
  • The study involved analyzing rare homozygous variants from a database of about 12,000 exomes and calculating phenotype similarity scores to identify correlations between affected individuals.
  • The approach successfully identified 33,792 genotype-matched pairs across unique genes, highlighting the effectiveness of this method in isolating candidates for disease-related genes and improving the understanding of variants of uncertain significance.
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Hypertrophic and dilated cardiomyopathy (HCM, DCM) are leading causes of cardiovascular morbidity and mortality in children. The pseudokinase alpha-protein kinase 3 (ALPK3) plays an essential role in sarcomere organization and cardiomyocyte differentiation. ALPK3 coding mutations are causative of recessively inherited pediatric-onset DCM and HCM with variable expression of facial dysmorphism and skeletal abnormalities and implicated in dominantly inherited adult-onset cardiomyopathy.

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Background: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane. Based on the level of separation within the dermal-epidermal junction, EB is sub-classified into four major types including EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB) with 16 EB-associated genes reported to date.

Methods: We ascertained a cohort of 151 EB patients of various Middle Eastern ethnic backgrounds.

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  • Neonatal ichthyosis and sclerosing cholangitis syndrome (NISCH) is a rare autosomal recessive disorder linked to mutations in the claudin-1 gene, impacting liver and skin health.
  • Recent research highlights seven patients from North African Jewish families with a specific claudin-1 variant (p.Arg81His), expanding the understanding of the disease's symptoms beyond skin issues to also include dental, hair, and liver problems.
  • Transmission electron microscopy studies show that the p.Arg81His variant disrupts tight junctions in skin cells, suggesting it’s a prevalent and founder mutation among this specific Jewish population, with a carrier rate of about 1 in 220.
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Frontonasal dysplasia (FND) refers to a group of rare developmental disorders characterized by abnormal morphology of the craniofacial region. We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole-exome sequencing analysis identified a novel heterozygous frameshift insertion in ALX4 (c.

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  • - Piebaldism is a genetic skin disorder marked by stable white patches of skin and localized white hair, primarily affecting areas like the forehead, chest, abdomen, and limbs.
  • - The condition is caused mostly by mutations in the KIT gene, which is important for skin and hair pigmentation.
  • - Piebaldism shows incomplete penetrance and variable expressivity, meaning not everyone with the mutation will show the same symptoms or severity.
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Hyperinsulinism/hyperammonemia (HI/HA) syndrome has been known to be caused by dominant gain-of-function mutations in GLUD1, encoding the mitochondrial enzyme glutamate dehydrogenase. Pathogenic GLUD1 mutations enhance enzymatic activity by reducing its sensitivity to allosteric inhibition by GTP. Two recent independent studies showed that a similar HI/HA phenotype can be caused by biallelic mutations in SLC25A36, encoding pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine and guanine nucleotides across the inner mitochondrial membrane: one study reported a single case caused by a homozygous truncating mutation in SLC25A36 resulting in lack of expression of SLC25A36 in patients' fibroblasts.

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  • Hemolytic-uremic syndrome (HUS) is a significant cause of acute kidney injury in children, primarily resulting from infections, especially Shiga toxin-producing E. Coli, and less commonly from Streptococcus pneumonia.
  • The syndrome features acute kidney failure, nonimmune hemolytic anemia, and low platelet counts due to thrombotic microangiopathy, with pHUS being linked to a specific mechanism involving bacterial neuraminidase A.
  • Atypical HUS (aHUS) can be genetic and severe, and recent studies reveal a novel X-linked form caused by a mutation in the C1GALT1C1 gene, suggesting common pathways for pHUS and aHUS that could
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  • * A study analyzed 107 patients to understand the genetic factors of UHS, discovering that 74.8% had harmful gene variants in three specific genes related to hair structure.
  • * The majority of the identified variants were in the PADI3 gene, indicating a possible common genetic origin for some of the cases, highlighted by the presence of certain repeated variants.
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Background: Hypoparathyroidism, retardation, and dysmorphism (HRD) Syndrome is a rare disease composed of hypoparathyroidism, retardation of both growth and development, and distinctive dysmorphic features. Here, we describe the long-term morbidity and mortality in a large cohort of HRD patients and suggest recommendations for follow up and treatment.

Methods: Medical records of 63 HRD syndrome patients who were followed at Soroka Medical Center during 1989-2019 were reviewed retrospectively.

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Proteasome 26S, the eukaryotic proteasome, serves as the machinery for cellular protein degradation. It is composed of the 20S core particle and one or two 19S regulatory particles, composed of a base and a lid. To date, several human diseases have been associated with mutations within the 26S proteasome subunits; only one of them affects a base subunit.

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Tricho-hepato-enteric syndrome (THES) (OMIM #222,470) is a rare autosomal recessive syndromic enteropathy whose primary manifestations are dysmorphism, intractable diarrhea, failure to thrive, hair abnormalities, liver disease, and immunodeficiency with low serum IgG concentrations. THES is caused by mutations of either Tetratricopeptide Repeat Domain 37 (TTC37) or Ski2 like RNA Helicase (SKIV2L), genes that encode two components of the human SKI complex. Here, we report a patient with a TTC37 homozygous mutation phenotypically typical for tricho-hepato-enteric syndrome in whom extremely elevated IgM with low IgG was present at the time of diagnosis.

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Objective: Bi-allelic loss-of-function mutations in TSHB, encoding the beta subunit of thyroid-stimulating hormone (TSH), cause congenital hypothyroidism. Homozygosity for the TSHB p.R75G variant, previously described in South Asian individuals, does not alter TSH function but abrogates its detection by some immune detection-based platforms, leading to erroneous diagnosis of hyperthyroidism.

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Background: Generalized pustular psoriasis of von Zumbusch is a rare variant of psoriasis often accompanied by systemic, sometimes life-threatening, symptoms. Generalized pustular psoriasis sometimes arises in pregnancy.

Case Report: A 31-year-old female, with a history of schizophrenia and recurrent episodes of gestation-associated pustular psoriasis, was admitted to our department because of a generalized pustular rash during the 22nd week of her fifth pregnancy.

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Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype-phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds.

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  • Ciliopathies are diverse disorders linked to problems with cilia, and recent research highlights a severe form caused by mutations in the TTC26 gene, showing symptoms like polydactyly and cholestasis.
  • Four patients with a specific TTC26 mutation also exhibited Pituitary Stalk Interruption Syndrome (PSIS), a condition affecting the pituitary gland that hasn't been associated with this ciliopathy before.
  • This study expands the understanding of TTC26's role in physical development, particularly in relation to the pituitary gland.
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Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in the F13A1 gene encoding factor XIII subunit A (FXIII-A), a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis.

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