Clinical genetics articles within Nature Communications

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  • Article
    | Open Access

    The role of type I interferons in bacterial infection is less clear than it is in viral infection. Here, the authors show that genetic variation of the human IFNAR1 gene is associated with decreased susceptibility to tuberculosis and identify a role for the IFNAR1 inter-domain region in the cytokine response.

    • Guoliang Zhang
    • , Nicole A. deWeerd
    •  & Carl G. Feng

  • Article
    | Open Access

    Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.

    • Jean-Louis Guéant
    • , Céline Chéry
    •  & David S. Rosenblatt

  • Article
    | Open Access

    Growth retardation is most commonly caused by genetic defects in the growth hormone pathway. Here, in families with growth retardation and gingival fibromatosis, the authors identify mutations in the potassium channel gene KCNQ1 that cause electrophysiological aberrations and altered ACTH secretion in vitro.

    • Johanna Tommiska
    • , Johanna Känsäkoski
    •  & Taneli Raivio

  • Article
    | Open Access

    Trisomy 21 (T21) is a major cause of Down syndrome but little is known about its impact on the cellular proteome. Here, the authors define the proteome of T21 fibroblasts and its turnover and also map proteomic differences in monozygotic T21-discordant twins, revealing extensive, organelle-specific changes caused by T21.

    • Yansheng Liu
    • , Christelle Borel
    •  & Ruedi Aebersold

  • Article
    | Open Access

    Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.

    • Kashyap A. Patel
    • , Jarno Kettunen
    •  & Michael N. Weedon

  • Article
    | Open Access

    Genome sequencing alone fails to provide a genetic diagnosis for many Mendelian disorder patients. Here, the authors utilize RNA sequencing to complement genotyping of patients with a rare mitochondrial disease by detecting aberrant RNA expression, splicing and allele-specific expression.

    • Laura S. Kremer
    • , Daniel M. Bader
    •  & Holger Prokisch

  • Article
    | Open Access

    LOXL1 is a genetic risk factor for pseudoexfoliation syndrome of the eye but a causal variant has not been identified. Here, Pasutto et al., find intronic LOXL1 risk variants influence transcription factor binding and alternative splicing of LOXL1 in affected tissues reducing levels of LOXL1mRNA.

    • Francesca Pasutto
    • , Matthias Zenkel
    •  & Ursula Schlötzer-Schrehardt

  • Article
    | Open Access

    Primary dysmenorrhoea, the most common gynaecologic complaint, remains genetically and pathophysiologically elusive. Here, Li and colleagues identify common variants inZMIZ1 and near NGFconferring risk for primary dysmenorrhoea using genome-wide association study in a Chinese population.

    • Zhiqiang Li
    • , Jianhua Chen
    •  & Yongyong Shi

  • Article
    | Open Access

    VPS15 is known as a VPS34-associated protein that functions in intracellular trafficking and autophagy. Here the authors identify a role for VPS15 in ciliopathy and ciliary phenotypes, and show that it interacts with GM130 and functions in IFT20-dependent cis-Golgi to cilium trafficking.

    • Corinne Stoetzel
    • , Séverine Bär
    •  & Hélène Dollfus

  • Article
    | Open Access

    The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) aims to better understand population genetics of the African diaspora. Here, it uses deeply sequenced whole-genomes to describe the impact of admixture and potential disease burden of deleterious variants.

    • Rasika Ann Mathias
    • , Margaret A. Taub
    •  & Kathleen C. Barnes

  • Article
    | Open Access

    Breast cancer is separated into multiple subtypes based on the expression of HER2 and hormone receptors. Here, the authors report the whole genome sequence of 64 HER2 positive tumours and show that these can be further separated into four groups with different gene expression profiles and genomic features.

    • Anthony Ferrari
    • , Anne Vincent-Salomon
    •  & Gilles Thomas

  • Article
    | Open Access

    Chromosomal aberrations can be detected by global gene expression analysis. Here, the authors report eSNP-Karyotyping, a new method that can detect chromosomal aberrations by measuring the ratio of expression between the two alleles without comparison to a matched diploid sample.

    • Uri Weissbein
    • , Maya Schachter
    •  & Nissim Benvenisty

  • Article
    | Open Access

    Genetically engineered mouse models of cancer are useful in identifying oncogenes and tumour suppressors. Here, the authors use gene expression profiles to generate a catalogue of copy number aberrations in 45 mouse models, and compare mouse and human tumours to identify additional drivers of tumorigenesis.

    • Uri Ben-David
    • , Gavin Ha
    •  & Todd R. Golub

  • Article
    | Open Access

    More than 90% of genetic variants associated with type 2 diabetes occur in non-coding regions. Scott et al. report genomes, epigenomes and transcriptomes of skeletal muscle from 271 participants with a range of glucose tolerances, revealing a genetic regulatory architecture enriched in muscle stretch/super enhancers.

    • Laura J. Scott
    • , Michael R. Erdos
    •  & Stephen C. J. Parker

  • Article
    | Open Access

    The t(8;21) translocation is often found in acute myeloid leukaemia but is not sufficient for development of the disease. In this study, the authors identify frequent mutations in the transcriptional repressor, ZBTB7A, in these patients and show that the mutations reduce DNA binding activity.

    • Luise Hartmann
    • , Sayantanee Dutta
    •  & Philipp A. Greif

  • Article
    | Open Access

    Here, Dirk Lefeber and colleagues identify functional mutations in ATP6AP1 encoding Ac45. The authors show that Ac45 is the functional ortholog of yeast V-ATPase assembly factor Voa1 and provide evidence for tissue-specific Ac45 processing, associated with the clinical phenotype of immunodeficiency, hepatopathy, and neurocognitive abnormalities.

    • Eric J. R. Jansen
    • , Sharita Timal
    •  & Dirk J. Lefeber

  • Article
    | Open Access

    Analysing multiple tumours from the same patient permits the study of the germline contribution to cancer. Here, the authors sequence multiple renal tumours from VHL patients and find that intra-patient tumours are clonally distinct but share some genetic features, suggesting that patient-specific factors influence tumour formation.

    • Suzanne S. Fei
    • , Asia D. Mitchell
    •  & Paul T. Spellman

  • Article
    | Open Access

    Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.

    • Fergus J. Couch
    • , Karoline B. Kuchenbaecker
    •  & Antonis C. Antoniou

  • Article
    | Open Access

    Ian Blair and colleagues use genome-wide linkage analysis and whole exome sequencing to identify mutations in the CCNF gene in large cohorts of amyotrophic lateral sclerosis and frontotemporal dementia patients. In addition to validating the mutations in international cohorts, the authors also show that mutant CCNFgene product affects ubiquitination and protein degradation in cultured cells.

    • Kelly L. Williams
    • , Simon Topp
    •  & Ian P. Blair

  • Article
    | Open Access

    Here, Michael Gollob and colleagues perform a whole exome sequencing study to identify a mutation in the atrial-specific myosin light chain gene MYL4 in a small family with autosomal dominant familial atrial fibrillation. They also test the functionality of this MYL4mutation in zebrafish cardiac function and recapitulate disease-related phenotypes.

    • Nathan Orr
    • , Rima Arnaout
    •  & Michael H. Gollob

  • Article
    | Open Access

    Peter's Anomaly is a developmental disorder of the eye and has been linked to mutations in a range of genes, including the transcription factor FOXE3. Here the authors use next-generation RNA sequencing and mass spectrometry to identify an autophagy-associated protein, DNAJB1 as the transcriptional target of FOXE3.

    • Shahid Y. Khan
    • , Shivakumar Vasanth
    •  & S. Amer Riazuddin

  • Article
    | Open Access

    The developmental potential of mosaic embryos of euploid and aneuploid cells is unknown. Here, the authors create a mouse model of chromosome mosaicism, showing that aneuploid cells in the fetus are eliminated by apoptosis and developmental potential is dependent on the presence of sufficient euploid cells.

    • Helen Bolton
    • , Sarah J. L. Graham
    •  & Magdalena Zernicka-Goetz

  • Article
    | Open Access

    Using forward genetic screen in fetal mice, Gregory Pazour and colleagues describe mutants affecting kidney/urinary tract development. The authors also show that mutants that cause kidney defects overlaps with those leading to congenital heart defects, thus linking renal anomalies and congenital heart disease.

    • Jovenal T. San Agustin
    • , Nikolai Klena
    •  & Gregory J. Pazour

  • Article
    | Open Access

    Polycystic kidney disease (PKD) is a ciliopathy resulting from defective localization of membrane proteins such as PC-1 to the primary cilium, resulting in renal cysts, and is associated with another cystic genetic disease called tuberous sclerosis complex (TSC). Here the authors use kidney-specific Tsc1 and Pkd1 mice to show that mTORC1 signalling inhibits PC-1 biogenesis as a potential mechanism of TSC/PKD contiguous gene syndrome.

    • Monika Pema
    • , Luca Drusian
    •  & Alessandra Boletta

  • Article
    | Open Access

    Steroid-sensitive nephrotic syndrome (SRNS) can cause CKD and necessitate kidney transplant. Here the authors identify FAT1 mutations by homozygosity mapping and whole-exome sequencing in families with SRNS and provide functional mouse and zebrafish evidence that FAT1 is required for normal glomerular and tubular function and that FAT1 mutations can cause SRNS.

    • Heon Yung Gee
    • , Carolin E. Sadowski
    •  & Friedhelm Hildebrandt

  • Article
    | Open Access

    Cancer cells that survive initial drug treatment can persist in the presence of drugs. Here, the authors generate persister cells that are resistant to the EGFR tyrosine kinase inhibitor erlotinib and show by single cell analysis that multiple mechanism give rise to the drug-resistant persister state.

    • Michael Ramirez
    • , Satwik Rajaram
    •  & Steven J. Altschuler

  • Article
    | Open Access

    One of the hallmarks of cancer cells is aneuploidy, however the molecular effects are poorly understood. Here the authors show that trisomic and tetrasomic cells display increased genomic instability and reduced levels of the helicase MCM2-7.

    • Verena Passerini
    • , Efrat Ozeri-Galai
    •  & Zuzana Storchová

  • Article
    | Open Access

    Phenome-wide association is a novel method that links sequence variants to a spectrum of phenotypes and diseases. Here the authors generate detailed mouse genetic and phenome data which links their phenome-wide association study (PheWAS) of mouse to corresponding PheWAS in human.

    • Xusheng Wang
    • , Ashutosh K. Pandey
    •  & Robert W. Williams

  • Article
    | Open Access

    Tsai et al. here utilize a multi-stage genome-wide association study in Taiwanese population to show a copy number variation in the intron of potassium interacting channel 1 gene (KCNIP1) to be strongly associated with atrial fibrillation. The study also examines the functionality of KCNIP1 in heart electrophysiological function using cultured myocytes and zebrafish.

    • Chia-Ti Tsai
    • , Chia-Shan Hsieh
    •  & Jiunn-Lee Lin

  • Article
    | Open Access

    This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.

    • Tuomas O. Kilpeläinen
    • , Jayne F. Martin Carli
    •  & Ruth J. F. Loos

  • Article
    | Open Access

    Dietary choline metabolites, such as trimethylamine N-oxide and betaine, have been associated with coronary artery disease (CAD). Here, Hartiala et al. identify two genetic loci for betaine levels on chromosomes 2q34 and 5q14.1 and find that the 2q34 locus was also associated with other pathway intermediates, and decreased risk of CAD in women.

    • Jaana A. Hartiala
    • , W. H. Wilson Tang
    •  & Hooman Allayee

  • Article
    | Open Access

    Altered epigenetics is a feature of cancer but whether these changes occur early in tumour development is unclear. Here, the authors analyse methylation events in breast cancer and adjacent normal pairs, and show that methylation changes in the normal tissue are also found in the tumour, suggesting that some of these events occur early in cancer.

    • Andrew E Teschendorff
    • , Yang Gao
    •  & Martin Widschwendter

  • Article
    | Open Access

    Next generation sequencing allows the identification of oncogenic driver genes in pancreatic cancer. Here, in an effort to identify additional causal genes, the authors develop a high throughput in vivoscreen and identify genes that whilst infrequently mutated in pancreatic cancer contribute to tumour formation.

    • Yiu Huen Tsang
    • , Turgut Dogruluk
    •  & Kenneth L. Scott

  • Article
    | Open Access

    The domestic dog is an important model organism for our understanding of cancer and other diseases. Here the authors conduct a genome-wide association study across multiple breeds and identify novel loci significantly associated with several complex diseases and morphological traits.

    • Jessica J. Hayward
    • , Marta G. Castelhano
    •  & Adam R. Boyko

  • Article
    | Open Access

    Muscular Dystrophy can be caused by mutations in the dystrophingene, causing the severe Duchenne form or the mild Becker form depending on if the transcript is in or out-of-frame. Here the authors identify a Duchenne-type mutation that gives a Becker-like phenotype due to skipping of exon 45.

    • J. Martone
    • , F. Briganti
    •  & I. Bozzoni

  • Article
    | Open Access

    Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

    • Cristian Pattaro
    • , Alexander Teumer
    •  & Caroline S. Fox

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