100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)

Wpływ osadu ściekowego na wzrost i skład gatunkowy runi oraz na zawartość metali ciężkich w roślinach i glebie

The determination of the sludge fertilising influence for the growth and composition of the urban grasslands’ swards and heavy metals concentration in above-ground parts of the plants was the aim of the study. The study was conducted on four research plots along the main roads in Białystok. The plots were seeded with two mixtures of lawn grasses (Eko and Roadside) and three doses of sludge were applied: 0 (control), 7.5 and 15 kg/m2. The study also included the determination of concentrations of Cd, Cr, Cu, Pb and Zn in soil and in the above-ground parts of lawn grasses and selected physical and chemical properties of soils fertilized with different doses of sludge. The dose of 7.5 kg/m2 increased the plant dry matter on average by 53%, the dose of 15 kg/m2 – on average by 90%. The largest effect of fertilization was found for lightest soil. Under these conditions, grass dry matter fertilized with 7.5 kg/m2 sludge was almost doubled, and fertilized with the dose of 15 kg/m2 was almost three times larger than in not fertilized areas. Perennial ryegrass (Lolium perenne L.) was the dominant species in the sward. Perennial ryegrass constituted on average 71% of all grass species in the areas fertilized with sewage sludge in the dose of 7.5 kg/m2, while on the areas fertilized with 15 kg/m2 – about 81%, and on not fertilized ones – 50% on average. Bioconcentration factor in the study allowed for estimating the plants ability to collect heavy metals present in the soil. Based on these results, it was found that the rate of bioconcentration of Cd, Cr, Cu and Pb was the highest in August, which may indicate the ease of downloading these metals by plants, particularly high mobility of metals during this period, and lower in October and June.Celem badań było określenie wpływu nawożenia komunalnym osadem ściekowym z Miejskiej Oczyszczalni Ścieków w Sokółce na wzrost i skład gatunkowy runi trawników przyulicznych oraz zawartość metali w częściach nadziemnych tych roślin. Badania przeprowadzono na czterech powierzchniach badawczych, wzdłuż głównych ciągów komunikacyjnych na terenie Białegostoku. Zastosowano dwie mieszanki gazonowych odmian traw (Eko i Roadside) oraz trzy dawki osadu ściekowego: 0 (kontrola), 7,5 i 15 kg/m2. Dawka 7,5 kg/m2 zwiększyła masę części nadziemnych średnio o 53%, a dawka 15 kg/m2 – średnio o 90%. Największy efekt nawożenia stwierdzono na glebie najlżejszej. W tych warunkach siedliskowych masa runi nawożonej dawką 15 kg/m2 osadu była prawie dwukrotnie, a dawką 7,5 kg/m2 prawie 58% większa niż na powierzchniach nienawożonych. Gatunkiem dominującym w runi badanych powierzchni była życica trwała (Lolium perenne L.). Stanowiła ona w masie runi na powierzchniach nawożonych dawką 7,5 kg/m2 średnio 71%, dawką 15 kg/m2 – średnio 81%, a na powierzchniach nienawożonych – średnio 50%. Wartość wskaźnika biokoncentracji Cd, Cr, Cu i Pb była największa w sierpniu, co może świadczyć o łatwości pobierania tych metali przez rośliny i szczególnie dużej ruchliwości metali w tym okresie, najmniejsza natomiast w październiku oraz czerwcu