A founder heterozygous MBD4 mutation prevalent among Israeli Christian Arabs predisposes to somatic mutagenesis
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Homo sapiens
SUBMITTER: Noa Chapal
PROVIDER: E-MTAB-14787 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:A founder heterozygous MBD4 mutation prevalent among Israeli Christian Arabs predisposes to somatic mutagenesis
| PRJEB85303 | ENA
Project description:The tendency of 5-methylcytosine (5mC) to undergo spontaneous deamination has had a major role in shaping the human genome, and this methylation damage remains the primary source of somatic mutations that accumulate with age. How 5mC deamination contributes to cancer risk in different tissues remains unclear. Genomic profiling of 3 early-onset acute myeloid leukemias (AMLs) identified germ line loss of MBD4 as an initiator of 5mC-dependent hypermutation. MBD4-deficient AMLs display a 33-fold higher mutation burden than AML generally, with >95% being C>T in the context of a CG dinucleotide. This distinctive signature was also observed in sporadic cancers that acquired biallelic mutations in MBD4 and in Mbd4 knockout mice. Sequential sampling of germ line cases demonstrated repeated expansion of blood cell progenitors with pathogenic mutations in DNMT3A, a key driver gene for both clonal hematopoiesis and AML. Our findings reveal genetic and epigenetic factors that shape the mutagenic influence of 5mC. Within blood cells, this links methylation damage to the driver landscape of clonal hematopoiesis and reveals a conserved path to leukemia. Germ line MBD4 deficiency enhances cancer susceptibility and predisposes to AML.
| S-EPMC6172562 | biostudies-literature
Project description:Sotorasib-resistant cells were established by exporsure of LU65 and MiaPACA-2 cells to increasing dose of sotorasib, up to 5 micromole. Exome sequencing was done to study the genetic changes.
2023-01-01 | E-MTAB-12144 | biostudies-arrayexpress
Project description:BACKGROUND: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genodermatosis caused by more than 500 different mutations in the COL7A1 gene and characterized by blistering of the skin following a minimal friction or mechanical trauma.The identification of a cluster of RDEB pedigrees carrying the c.6527insC mutation in a specific area raises the question of the origin of this mutation from a common ancestor or as a result of a hotspot mutation. The aim of this study was to investigate the origin of the c.6527insC mutation. METHODS: Haplotypes were constructed by genotyping nine single nucleotides polymorphisms (SNPs) throughout the COL7A1 gene. Haplotypes were determined in RDEB patients and control samples, both of Spanish origin. RESULTS: Sixteen different haplotypes were identified in our study. A single haplotype cosegregated with the c.6527insC mutation. CONCLUSION: Haplotype analysis showed that all alleles carrying the c.6527insC mutation shared the same haplotype cosegregating with this mutation (CCGCTCAAA_6527insC), thus suggesting the presence of a common ancestor.
| S-EPMC2957067 | biostudies-literature
Project description:Whole-exome sequencing of induced murine squamous cell carcinoma. 26 samples are included.
2014-09-11 | E-MTAB-2887 | biostudies-arrayexpress
Project description:The transcriptomic innate immune response derived from human nasal epithelial cells depends on how Streptococcus pneumoniae colonises the nasopharynx. This study compared three wild type strains and one deficient in pneumolysin to explore the pathways of epithelial activation following a three hour infection in vitro.
2019-05-01 | E-MTAB-7841 | biostudies-arrayexpress
Project description:We have performed ChIP-sequencing analysis on human FOXN2 and RFX1 target sequences in human embryonic kidney HEK293T cells stably expressing Streptavidin-S-FLAG (SFB) triple-tagged proteins. The NGS sequencing were performed on Illumina MiSeq desktop sequencer.
2015-01-01 | E-MTAB-3120 | biostudies-arrayexpress
Project description:ObjectiveBi-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. We set out to identify and determine the carrier rate of the p.R75G variant among clinically euthyroid Bene Israel Indian Jews, to examine the possible founder origin of this variant worldwide, and to determine the phenotypic effects of its heterozygosity.DesignMolecular genetic studies of Bene Israel Jews and comparative studies with South Asian cohort.MethodsTSHB p.R75G variant tested by Sanger sequencing and restriction fragment length polymorphism (RFLP). Haplotype analysis in the vicinity of the TSHB gene performed using SNP arrays.ResultsClinically euthyroid individuals with low or undetectable TSH levels from three apparently unrelated Israeli Jewish families of Bene Israel ethnicity, originating from the Mumbai region of India, were found heterozygous or homozygous for the p.R75G TSHB variant. Extremely high carrier rate of p.R75G TSHB in Bene Israel Indian Jews (~4%) was observed. A haplotype block of 239.7 kB in the vicinity of TSHB shared by Bene Israel and individuals of South Asian origin was detected.ConclusionsOur findings highlight the high prevalence of the R75G TSHB variant in euthyroid Bene Israel Indian Jews, demonstrate that heterozygosity of this variant can cause erroneous detection of subnormal TSH levels, and show that R75G TSHB is an ancient founder variant, delineating shared ancestry of its carriers.
| S-EPMC9142811 | biostudies-literature
Project description:PurposeNonsyndromic retinitis pigmentosa (RP) is the most common inherited retinal degeneration, and prevalence of the disease has been reported in populations of American and European origin with a relatively low consanguinity rate. Our aim was to determine the prevalence of nonsyndromic RP in the Jerusalem region, which has a population of about 1 million individuals with a high rate of consanguinity.MethodsThe patients' clinical data included eye exam findings (visual acuity, anterior segment, and funduscopy) as well as electroretinographic (ERG) testing results under scotopic and photopic conditions. Mutation analysis on a subgroup of patients was performed mainly with candidate gene analysis and homozygosity mapping.ResultsWe evaluated the medical records of patients with degenerative retinal diseases residing in the Jerusalem region who were examined over the past 20 years in a large tertiary medical center. A total of 453 individuals affected with nonsyndromic RP were diagnosed at our center, according to funduscopic findings and ERG testing. Based on the estimated population size of 945,000 individuals who reside in the vicinity of Jerusalem, the prevalence of nonsyndromic RP in this region is 1:2,086. The prevalence of RP was higher among Arab Muslims (1:1,798) compared to Jews (1:2,230), mainly due to consanguineous marriages that are more common in the Arab Muslim population. To identify the genetic causes of RP in our cohort, we recruited 383 patients from 183 different families for genetic analysis: 70 with autosomal recessive (AR) inheritance, 15 with autosomal dominant, 86 isolate cases, and 12 with an X-linked inheritance pattern. In 64 (35%) of the families, we identified the genetic cause of the disease, and we revised the inheritance pattern of 20 isolate cases to the AR pattern; 49% of the families in our cohort had AR inheritance. Interestingly, in 42 (66%) of the genetically identified families, the cause of disease was a founder mutation.ConclusionsPrevious studies showed an approximate prevalence of 1:5,260 on average for nonsyndromic RP in American and European populations. We show that the prevalence in the vicinity of Jerusalem is two-and-a-half times higher due to a high rate of consanguinity and highly prevalent founder mutations within the historically semi-isolated subpopulations we serve.
| S-EPMC4506056 | biostudies-literature
Project description:BackgroundRAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer.MethodsFive female HBOC probands sequenced negative for moderate- and high-risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors.ResultsThe RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52-fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease-associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild-type relative. Sanger sequencing of tumors from two probands indicates loss-of-heterozygosity, suggesting loss of function.ConclusionThe RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re-classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.
| S-EPMC7005661 | biostudies-literature