Volume 46 Issue 5, May 2014

A new study shows that gain-of-function mutations in IFIH1, which encodes the cytosolic double-stranded RNA sensor MDA5, lead to upregulated type I interferon responses. Individuals with these mutations exhibit phenotypes consistent with autoimmune diseases, including Aicardi-Goutières syndrome and systemic lupus erythematosus.

Many inherited human DNA repair deficiency syndromes involve pronounced neurological dysfunction, although the DNA lesions responsible are generally unknown. A new study shows that the phosphodiesterase TDP2 has a key role in protecting the nervous system by preventing DNA breaks induced by aberrant topoisomerase II activity.

Pediatric diffuse gliomas are rare but aggressive brain tumors for which effective therapies are unavailable. New studies identify recurrent mutations of the ACVR1 gene in these tumors, identify molecular subtypes and highlight differences between gliomas affecting children and adults.

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.

Fred Wright, Patrick Sullivan and colleagues present the results of a large expression QTL study of peripheral blood using a classic twin design with follow-up replication in independent samples. Their results enable a more precise estimate of the heritability of gene expression and provide a useful resource for exploring the genetic control of transcription.

William Foulkes and colleagues identify germline inactivating mutations in familial cases of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Through additional analysis of non-familial tumors, the authors find that nearly 100% of tumors carry SMARCA4 mutations and 38 of 40 lack protein expression, implicating SMARCA4 loss as the major cause of SCCOHT.

Suzanne Baker, Jinghui Zhang and colleagues report the identification of recurrent somatic mutations in the bone morphogenetic protein (BMP) receptor ACVR1 in 32% of diffuse intrinsic pontine gliomas.

Cynthia Hawkins, Oren Becher and colleagues report the identification of recurrent mutations in ACVR1 in 20% of diffuse intrinsic pontine gliomas.

Chris Jones, Jacques Grill and colleagues report the identification of recurrent activating mutations in ACVR1 in diffuse intrinsic pontine gliomas.

Nada Jabado and colleagues report identification of gain-of-function mutations in ACVR1, which encodes activin A receptor type I, in midline pediatric high-grade astrocytomas.

De-Chen Lin, Ming-Rong Wang and colleagues report exome sequencing, RNA sequencing, and copy number analyses of esophageal squamous cell carcinoma. They identified recurrent mutations in FAT1, FAT2, ZNF750, EP300 and KMT2D.

Karolin Nord and colleagues report that GRM1 recombines with multiple genes in promoter swapping and gene fusion events in 90% of the chondromyxoid fibroma cases analyzed, resulting in GRM1 overexpression. These results implicate GRM1 rearrangement as a driver of CMF and a biomarker for this tumor type.

David Adams, Julia Newton-Bishop, Timothy Bishop, Nicholas Hayward and colleagues identify loss-of-function variants in POT1 in several families with early onset multiple primary melanoma. They further show that these variants disrupt telomere binding by POT1 and are associated with increased telomere length.

Maria Teresa Landi and colleagues identify a rare missense variant in POT1 shared by five melanoma-prone families from Italy and associated with increased telomere length and telomere fragility. They also identify additional familial melanoma cases with rare missense variants in POT1 and find a significant excess of rare exonic POT1 variants in melanoma cases compared to controls, implicating POT1 variants in melanoma susceptibility.

Mike Stratton and colleague show that carriers of a germline copy number polymorphism involving APOBEC3A and APOBEC3B, which has been associated with increased risk of breast cancer, show more mutations characteristic of APOBEC-dependent mutational processes than cancers in non-carriers.

Mario Falchi, Philippe Froguel and colleagues report association of a multi-allelic copy number variant encompassing the salivary amylase gene AMY1 with body mass index and risk of obesity.

Kari Stefansson and colleagues performed a genome-wide association study for severe hand osteoarthritis and found associated variants within the ALDH1A2 gene and at 1p31.

Yanick Crow, Sun Hur and colleagues show that gain-of-function mutations in IFIH1 cause a spectrum of neural and immunological phenotypes associated with enhanced interferon signaling. The mutations increase the affinity of IFIH1 for RNA, leading to immune upregulation and inflammatory disease.

Eamonn Sheridan, Elizabeth Ross and colleagues report discovery of a new megalencephaly syndrome caused by de novo missense mutations in CCND2. They show that these mutations lead to stabilization of cyclin D2, and they present evidence that cyclin D2 stabilization may be a common downstream mechanism in PI3K-AKT–associated megalencephaly syndromes.

Keith Caldecott, Bert de Vries, Sherif El-Khamisy, Gianpiero Cavalleri and colleagues identify homozygous TDP2 mutations in individuals with intellectual disability, seizures and ataxia. Their follow-up studies suggest that TDP2 is required to maintain normal transcription in response to the DNA double-strand breaks induced by abortive TOP2 activity.