Letters in 2015

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.

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.

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.

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.

Sarah Elderkin and colleagues show that PRC1 acts as a master regulator of genome architecture in mouse embryonic stem cells by organizing genes in three-dimensional interaction networks. They find that the strongest spatial network is composed of the four Hox clusters and key early developmental transcription factor genes, and they propose that selective release of genes from this spatial network underlies cell fate specification during embryonic development.

Christian Dina, Nabila Bouatia-Naji, Xavier Jeunemaitre and colleagues from the Leducq Transatlantic MITRAL Network report the results of a genome-wide association study of nonsyndromic mitral valve prolapse. They identify six susceptibility loci and provide functional evidence implicating LMCD1 and TNS1 as genes influencing mitral valve development.

Jessica Zucman-Rossi and colleagues identify clonal integrations of adeno-associated virus type 2 (AAV2) in hepatocellular carcinomas. These AAV2 integrations occurred within known cancer driver genes, suggesting a pathogenic role of AAV2 in these patients.

Soumya Raychaudhuri, Paul de Bakker and colleagues test the non-additive disease contributions of classical HLA alleles to five common autoimmune diseases. In four of the five diseases, they observe highly significant non-additive dominance and interaction effects.

Paul Khavari and colleagues report genomic analyses of cutaneous T cell lymphomas. They identify recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of tumors and show that expression of a recurrent TNFR2 mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib.

Dmitry Gordenin and colleagues use a yeast reporter strain to identify distinct mutagenic signatures for the cytosine deaminases APOBEC3A and APOBEC3B. They find that cancer samples with APOBEC3A-like mutation signatures have greater than tenfold more APOBEC signature mutations than those with APOBEC3B-like signatures.

Colin Ross and colleagues report the results of a genome-wide association study of anthracycline-induced cardiotoxicity in children treated for cancer. They identify a nonsynonymous coding variant in RARG associated with roughly fivefold higher risk of developing this severe adverse drug reaction.

Olivier Delattre and colleagues show that a Ewing sarcoma susceptibility variant at 10q21.3 influences EGR2 expression by altering the activity of an enhancer bound by EWSR1-FLI1. They further show that EGR2 knockdown inhibits growth of Ewing sarcoma cells in vitro and induces complete regression of xenografts in vivo, establishing a critical role for EGR2 in Ewing sarcomagenesis.

Zhu Chen, Sai-Juan Chen, Wei-Li Zhao and colleagues identify recurrent loss-of-function mutations in the RNA helicase gene DDX3X in 20% of subjects with natural killer/T-cell lymphoma (NKTCL) in their study. The results suggest that DDX3X acts as a tumor suppressor and that its inactivation leads to poor clinical outcome.

Stephan Zuchner, Taosheng Huang and colleagues show that recessive mutations in SLC25A46 cause optic atrophy with additional neurological symptoms. They further show that SLC25A46 encodes a modified mitochondrial solute transporter linked to mitochondrial dynamics.

Pierre Coulombe and colleagues show that the autoimmune regulator Aire is induced in tumor keratinocytes in a keratin 17 (K17)-dependent manner and promotes skin tumorigenesis in mice. They further show that K17 and Aire colocalize in the nucleus and bind a subset of proinflammatory genes, providing a molecular explanation for the K17-dependent amplification of inflammatory responses in diseased epithelia.

Jiayang Li, Xudong Zhu, Qian Qian and colleagues report cloning of the Grain Length on Chromosome 7 (GL7) locus in rice and identify a copy number variant that increases grain length and improves grain quality. They demonstrate how interactions with other grain length–related genes may be used to improve breeding.

Xiangdong Fu and colleagues show that variation in GW7 influences rice grain shape and yield. They further show that GW7 expression is directly regulated by OsSPL16, a transcription factor encoded by the grain-width locus GW8.

Regie Lyn Santos-Cortez and colleagues identify a duplication variant within A2ML1 that cosegregates with otitis media in an indigenous Filipino pedigree. They also identify seven additional A2ML1 variants in otitis-prone children.