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.
CRISPR är en revolutionerande teknik som möjliggör effektiv redigering av DNA.Kliniska studier med CRISPR-baserade terapier för blodsjukdomar och cancer pågår redan.Framtida tillämpningar av CRISPR ...kan förväntas bli breda men förutsätter etiska, juridiska och hälsoekonomiska överväganden.
Due to recent advances in molecular genetic testing, massive parallel sequencing has become possible at an affordable cost for health care. Thus, it is now possible to test healthy young persons for ...carriership of mutations in many genes for severe recessive genetic conditions – extended genetic carrier testing. The introduction of this test in Swedish health care must be accompanied by ethical considerations, education of stakeholders, health care staff and the public.
Utvecklingen inom gentekniken har gjort det möjligt att inom sjukvårdens ram undersöka många gener samtidigt genom helgenom-/helexomanalyser. Detta har hittills främst utnyttjats för diagnostik av personer, framför allt barn, med misstänkt ärftliga syndrom.Under de senaste tre åren har tekniken utnyttjats för att bygga upp plattformar att användas för kartläggning av recessiva sjukdomsanlag hos friska individer inför reproduktion (utvidgad anlagsbärartestning).Metoden ger föräldrapar en möjlighet till fosterdiagnostik redan innan de fått ett barn med svåra funktionshinder.Det är viktigt att ett sådant test introduceras i den svenska hälso- och sjukvården på ett samordnat och etiskt godtagbart sätt.
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