Research articles

Elliot Stieglitz, Mignon Loh and colleagues report the whole-exome sequencing of diagnostic and relapsed samples from patients with juvenile myelomonocytic leukemia. They identify new recurrent mutations for this disease and find that the number of somatic alterations present at diagnosis may be predictive of clinical outcome.

Hélène Cavé and colleagues genetically profile a cohort of 118 juvenile myelomonocytic leukemia (JMML) samples and uncover mutations in multiple components of the RAS signaling pathway and the PRC2 network. Their study demonstrates an association between JMML clinical outcome and mutational profile and suggests a dose-dependent effect for RAS pathway activation.

Bernhard Radlwimmer and colleagues report whole-genome bisulfite sequencing of 13 Burkitt lymphomas and nine follicular lymphomas. They find that both types of germinal center B cell lymphomas show global hypomethylation compared to normal germinal center B cell precursors and identify regions of differential methylation that correlate with somatic mutations and differential gene expression.

Seishi Ogawa and colleagues report the results of a large-scale sequencing study of adult T cell leukemia/lymphoma. They find recurrent alterations enriched for T cell receptor/NF-κB signaling, T cell trafficking and other T cell pathways and highlight targets for the development of new therapeutics for this intractable cancer.

Matthew Hurles, David FitzPatrick and colleagues report the discovery of four novel Mendelian disorders based on their analysis of exome sequence data from 4,125 families with diverse rare developmental disorders. They present their analytical pipeline as a general strategy for the discovery of genetic causes of autosomal recessive disorders.

Christopher Gordon, Cecilia Lo, Patrice Bouvagnet and colleagues report loss-of-function mutations in the MMP21 gene (encoding matrix metallopeptidase 21) that cause human heterotaxy with associated complex congenital heart defects. The authors confirm the role of MMP21 in heterotaxy and left-right patterning in zebrafish and mouse models.

Eunjung Lee, Peter Park, Dongwan Hong and colleagues report an analysis of cancer RNA sequencing data identifying approximately 900 somatic coding variants that cause disrupted splicing in cancer, leading to intron retention or exon skipping in many cases. Variants causing intron retention are enriched for loss-of-function mutations in tumor-suppressor genes.

Bin Tean Teh and colleagues report the genomic characterization of 100 breast fibroepithelial tumors, including benign fibroadenomas and benign, borderline and malignant phyllodes tumors. They identify mutations specific to phyllodes tumors and find somatic mutation patterns that distinguish borderline and malignant phyllodes tumors from the other tumor types.

Hilary Finucane, Brendan Bulik-Sullivan, Benjamin Neale, Alkes Price and colleagues introduce a new method, called stratified LD score regression, for partitioning heritability by functional category using genome-wide association study summary statistics. They observe a substantial enrichment of heritability in conserved regions and illustrate how this approach can provide insights into the biological basis of disease and direction for functional follow-up.

Brendan Bulik-Sullivan, Benjamin Neale, Hilary Finucane, Alkes Price and colleagues introduce a new technique for estimating genetic correlation that requires only genome-wide association summary statistics and that is not biased by sample overlap. Using this method, they find genetic correlations between anorexia nervosa and schizophrenia, and between educational attainment and autism spectrum disorder.

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response.

Christina Leslie and colleagues report an integrative analysis of the enhancer landscape and gene expression dynamics during hematopoietic differentiation. They also develop a quantitative model to predict gene expression changes from DNA sequence content and the lineage history of active enhancers and suggest a new mechanistic role for PU.1 at transition peaks during B cell specification.

John Chambers, Jaspal Kooner, Pim van der Harst, Shyong Tai, Paul Elliott, Jiang He, Norihiro Kato and colleagues performed a genome-wide association study of blood pressure phenotypes in individuals of European, East Asian and South Asian ancestry. They find trait-associated SNPs at 12 loci, some of which are associated with methylation at nearby CpG sites.

Francesco Cucca, Serena Sanna, David Schlessinger, Gonçalo Abecasis and colleagues report genome-wide association analysis results for the levels of A1, A2 and fetal hemoglobin in a large Sardinian cohort. By integrating high-density array genotyping and whole-genome sequencing, they detect 23 associations at 10 loci and observe a wide range of pleiotropic effects of variants across the 3 hemoglobin types.

Gonçalo Abecasis, Francesco Cucca, David Schlessinger, Serena Sanna and colleagues report ~17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians. They assess the impact of these variants on circulating lipid levels and five inflammatory biomarkers.

Matthew Robinson and colleagues report an analysis of population genetic differences in human height and body mass index (BMI) across 14 European populations. They estimate the proportion of additive genetic variance attributable to population genetic differences and find evidence for selection increasing height while reducing BMI in European nations.

Francesco Cucca, David Schlessinger, John Novembre, Gonçalo Abecasis and colleagues present sequencing-based whole-genome association analyses for stature in Sardinia and identify two variants that lead to reduced height. Their findings suggest that shorter stature was selected for in Sardinia.

Gil McVean and colleagues report a meta-analysis of Immunochip studies including over 17,000 multiple sclerosis cases and 30,000 controls, with imputation of classical HLA alleles. They find two interactions involving class II HLA alleles but no evidence for significant epistatic interactions or interactions between HLA and non-HLA risk variants.

Francois Le Loarer, Franck Tirode and colleagues identify a new class of undifferentiated thoracic sarcomas characterized by inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. They further show that these tumors exhibit transcriptional profiles similar to those of other BAF-deficient malignancies.

Boris Bastian and colleagues report the results of exome sequencing of desmoplastic melanoma. They identify recurrent NFKBIE promoter mutations and diverse mutations leading to activation of the MAPK pathway.