Brief Communications

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.

Hajime Okita and colleagues show that clear-cell sarcoma of the kidney (CCSK) is characterized by recurrent in-frame, internal tandem duplications in BCOR. They detected BCOR alterations in all 20 CCSK tumors analyzed but not in any other pediatric renal tumors, suggesting a specific role for these in-frame duplications in driving CCSK oncogenesis.

Jean-Luc Battini, Giovanni Coppola and colleagues identify XPR1 mutations in several families with primary brain calcification. They further show that these mutations alter phosphate export activity, implicating defective phosphate homeostasis in the etiology of this disease.

Cisca Wijmenga and colleagues report fine mapping of the association signal in the MHC region in individuals with celiac disease. They identify five additional risk factors that are independent of HLA-DQ alleles and that account for 18% of the genetic risk for this disease.

Stacy Steinberg, Hreinn Stefansson, Thorlakur Jonsson and colleagues found that rare variants predicted to alter the function of ABCA7 are associated with risk of Alzheimer's disease. The association was found in Iceland and replicated in northern Europe and the United States.

Levi Garraway and colleagues report the identification of somatic mutations of RNF43, which encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling, in over 18% of colorectal adenocarcinomas and endometrial carcinomas.

Chetan Bettegowda, Bert Vogelstein and colleagues identify somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors from individuals with and without neurofibromatosis. SUZ12 encodes a chromatin-modifying protein and is located adjacent to the NF1 gene on chromosome 17q11. The data support a 'three-hit' model of tumor suppression.

Jorge Reis-Filho and colleagues identify recurrent mutations in PRKD1 in 73% of polymorphous low-grade adenocarcinoma, a malignant tumor of the minor salivary glands. The mutations cause activation of the PRKD1 serine-threonine kinase.

Paul Khavari and colleagues identify recurrent mutations concentrated at an ultraviolet signature hotspot in the KNSTRN gene in 19% of cutaneous squamous cell carcinomas. KNSTRN encodes a kinetochore protein.

Andrew Hattersley, Noel Morgan, Juha Kere and colleagues identify de novo activating germline STAT3 mutations in five unrelated individuals with early-onset multi-organ autoimmune disease.

Marco Tartaglia, Raoul Hennekam and colleagues show that de novo mutations in ZBTB20 cause Primrose syndrome, a disorder characterized by tall stature, macrocephaly, intellectual disability, diabetes, deafness, progressive muscle wasting and ectopic calcifications.

André Oliveira and colleagues identify a recurrent translocation in biphenotypic sinonasal sarcomas generating a PAX3-MAML3 fusion gene. The resulting protein is a potent transcriptional activator of PAX3 response elements and is associated with aberrant expression of genes involved in neuroectodermal and myogenic differentiation.

Douglas Levine and colleagues identify recurrent inactivating mutations in the SWI/SNF complex member SMARCA4 in 12 of 12 samples of small cell carcinoma of the ovary, hypercalcemic type. These findings open the door for the development of targeted therapies to treat this rare but deadly cancer.

Jeffrey Trent, David Huntsman and colleagues identify the SWI/SNF chromatin-remodeling gene SMARCA4 as commonly mutated in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Their results implicate SMARCA4 as a crucial factor in the oncogenesis of SCCOHT, a rare but highly malignant cancer.

Richard Thompson, Melissa Sambrotta and colleagues show that biallelic mutations in TJP2 cause severe cholestatic liver disease. Their findings suggest that loss of TJP2 protein disrupts the structural integrity of tight junctions in liver tissue, resulting in progressive liver damage.

Paul Meltzer and colleagues report the results of an exome sequencing study of variant and IGHV4-34–expressing hairy-cell leukemias. They identify a high frequency of activating MAP2K1 mutations in these malignancies, suggesting potential therapeutic strategies.

Todd Waldman and colleagues screened 2,214 tumors for loss of STAG2 expression using immunohistochemistry. They followed up by sequencing STAG2 in 111 urothelial carcinomas and found mutations in 23 of the cases, identifying STAG2 as one of the most commonly mutated genes in bladder cancer.

Claire Rougeulle and colleagues report the discovery of a long noncoding RNA, XACT, that coats the active X chromosome in human embryonic stem cells.

Matthew Meyerson and colleagues report exome sequencing of solitary fibrous tumor (SFT), a rare mesenchymal tumor. They identify a NAB2-STAT6 fusion in 55% of cases.

William Harbour, Anne Bowcock and colleagues identify recurrent mutations at codon 625 of SF3B1 in uveal melanomas. These mutations occur in low-grade tumors and are associated with favorable prognosis.