Kongenitalne anomalije zahvaćaju 3 – 5 % sve novorođene djece, te čine značajan postotak morbiditeta i mortaliteta u prenatalnom razdoblju i dojenačkoj dobi. Iako bolesnik s multiplim kongenitalnim ...anomalijama predstavlja dijagnostički izazov za pedijatre i kliničke genetičare, nužno je prepoznati specifične kombinacije kliničkih znakova, simptoma ili obrazaca ponašanja, koji bi upućivali na dijagnozu genetičkog poremećaja. Sve veći broj genetičkih poremećaja (više od 6.000 opisanih) s još većim brojem opisanih specifičnih kombinacija kliničkih obilježja doveo je do pokušaja njihovog sistematiziranja u baze podataka koje na jednom mjestu okupljaju relevantne informacije o svim poznatim genetičkim poremećajima. Elektroničke genetičke baze podataka zbog svoje su sveobuhvatnosti i jednostavnosti korištenja izvrstan medij za edukaciju iz kliničke genetike, ali i neizostavan dio svakodnevnog rada u kojem služe kao pomoć pri evaluaciji bolesnika i postavljanju ispravne diferencijalne dijagnoze malformacijskih sindroma i genetičkih poremećaja općenito. Klinička genetika je umjetnost i vještina vizualnog prepoznavanja i uspoređivanja obilježja; dijagnoza genetičkog poremećaja uvijek je zahtjevan, a ponekad i dugotrajan proces u kojem genetičke baze podataka mogu znatno pomoći. Iako sve baze podataka omogućuju pretraživanje po kliničkim obilježjima (simptomima i znakovima), odnosno njihovim kombinacijama, čime se dobiva ispis najizglednijih genetičkih poremećaja, dobiveni popis samo je prvi korak u dijagnostičkom procesu, te zahtijeva daljnje proučavanje medicinski relevantne literature, kao i ponovne preglede djeteta kada se ciljano traže specifična obilježja i dodatna klinička obrada.
Congenital anomalies occur in 3-5 % of all newborn children and
represent a significant part of prenatal and infant mortality and
morbidity. Although patients with multiple congenital anomalies
...represent a diagnostic challenge for pediatricians and clinical
geneticists, it is necessary to recognize specific combinations of
clinical signs, simptoms and behaviour patterns which leads to the
diagnosis of a genetic disorder. The constantly increasing number of
genetic disorders (over 6.000 described) with an even larger number of
specific combinations of clinical features has led to an attempt of
systematization of all known genetic disorders into several genetic
databases. The comprehensiveness and simple organization of electronic
genetic databases makes them an exceptional educational media for the
training of clinical genetics and an inevitable part of everyday work
in clinical genetics where they are used in the evaluation of patients
and establishment of proper differential diagnosis of malformation
syndromes and genetic diseases in general. Clinical genetics is a
combination of art and skills in visual recognition and comparison of
features, and the diagnosis of a genetic disorder is always a demanding
and sometimes a time-consuming process where genetic databases can be
of significant help. However, although all genetic databases can be
searched according to clinical features and their specific combinations
which will provide a list of the most likely syndromes, the obtained
list of disorders is only a first step in the diagnostic process and
demands further investigation of medically relevant literature, as well
as repeated examinations of the patient when specific features an
additional analyses are sought.
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes ...from the 1000 Genomes Project, we report a GWAS meta-analysis of ~185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
Single-cell gene expression analyses hold promise for characterizing cellular heterogeneity, but current methods compromise on either the coverage, the sensitivity or the throughput. Here, we ...introduce Smart-seq2 with improved reverse transcription, template switching and preamplification to increase both yield and length of cDNA libraries generated from individual cells. Smart-seq2 transcriptome libraries have improved detection, coverage, bias and accuracy compared to Smart-seq libraries and are generated with off-the-shelf reagents at lower cost.
Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes ...(T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10
) and candidate genes from knockout mice (P = 5.2 × 10
). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.
Cytogenetic aberrations have been reported in 45,000 human neoplasms. Structural balanced rearrangements are associated with distinct tumor subtypes with remarkable specificity and have been ...essential for identifying genes involved in tumorigenesis. All balanced rearrangements that have been characterized molecularly act by deregulating a gene in one of the breakpoints or by creating a fusion gene. Because most recurrent aberrations and rearranged genes have been found in hematological disorders, whereas numerous genomic imbalances have been identified in solid tumors, it has become generally accepted that there are pathogenetic differences between these neoplasms. We here show that in every tumor type, the numbers of recurrent balanced chromosome abnormalities, fusion genes and genes rearranged as a consequence of balanced aberrations are simply a function of the number of cases with an abnormal karyotype. Hence, there may not be any fundamental tissue-specific differences in the genetic mechanisms by which neoplasia is initiated.
Det finns många uppfattningar om hur man bäst förbättrar konditionen. Ofta förlitar idrottare sig mer på beprövad erfarenhet än på vetenskapen. Men under de senaste åren har idrottsforskningen, med ...hjälp av molekylärbiologisk teknik, gjort framsteg i hur man kan effektivisera sin träning genom kosten och sättet att träna.
Utvecklingen inom genetiken har möjliggjort att prediktiva genetiska tester kan utföras för ett antal mer eller mindre svåra sjukdomstillstånd. Det innebär att individer kan få reda på att de är ...bärare av ett sjukdomsanlag innan detta anlag ger upphov till konkreta och klara symptom. I spåren av dessa test uppstår ett gränsland mellan vad de genetiska testresultaten visar och uppkomsten av tydliga symptom. I artikeln analyseras detta motsägelsefulla och spänningsfyllda gränsland med avseende på frågan om friskt och sjukt utifrån de genetiska begreppen genotyp och fenotyp.
Synovial sarcoma is a morphologically, clinically and genetically distinct entity that accounts for 5–10% of all soft tissue sarcomas. The t(X;18)(p11.2;q11.2) is the cytogenetic hallmark of synovial ...sarcoma and is present in more than 90% of the cases. It produces three types of fusion gene formed in part by SS18 from chromosome 18 and by SSX1, SSX2 or, rarely, SSX4 from the X chromosome. The SS18–SSX fusions do not seem to occur in other tumor types, and it has been shown that in synovial sarcoma a clear correlation exists between the type of fusion gene and histologic subtype and, more importantly, clinical outcome. Previous analyses regarding the type of fusion genes have been based on PCR amplification of the fusion transcript, requiring access to good-quality RNA. In order to obtain an alternative tool to diagnose and follow this malignancy, we developed a fluorescence in situ hybridization (FISH) assay that could distinguish between the two most common fusion genes, that is, SS18–SSX1 and SS18–SSX2. The specificity of the selected bacterial artificial chromosome clones used in the detection of these fusion genes, as well as the sensitivity of the analysis in metaphase and interphase cells, was examined in a series of 28 synovial sarcoma samples with known fusion gene status. In all samples, the type of fusion was correctly identified by FISH. Thus, the assay described here should be useful for clarifying unresolved chromosome markers and for identifying fusion gene status in samples from which RNA of sufficient quality for PCR could not be extracted.
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