Utility of copy number variants in the classification of intracranial ependymoma.

Ependymomas are neuroepithelial tumors that differentiate along the ependymal cell lineage, a lining of the ventricles of the brain and the central canal of the spinal cord. They are rare in adults, but account for around 9% of brain tumors in children, where they usually have an aggressive course. Efficient stratification could lead to improved care but remains a challenge even in the genomic era.

Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events.

Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm.

Pathogenic germline mutations in ELN can be detected in patients with supravalvular aortic stenosis. The mutation might occur de novo or be inherited following an autosomal dominant pattern of inheritance. In this report we describe a three-generation family suffering from supravalvular aortic stenosis, various other arterial stenoses, sudden death, and intracranial aneurysms.

Genetic alterations in renal cell carcinoma with rhabdoid differentiation.

Renal cell carcinoma with rhabdoid differentiation (RCC-R) in adult patients is an aggressive variant of renal cancer with no known specific genetic alterations. The aim of this study was to characterize genome-wide genetic aberrations in RCC-R via utilization of high-density single-nucleotide polymorphism (SNP) arrays. We identified 20 cases of RCC-R, which displayed both clear cell renal cell carcinoma and rhabdoid histomorphologic components.

Germinal center B-cells resist transformation by Kras independently of tumor suppressor Arf.

Activating mutations in Ras (N- and K-) are the most common point mutations found in patients with multiple myeloma (MM) and are associated with poor clinical outcome. We sought to directly examine the role of Ras activation in MM pathogenesis and used two different tissue-specific Cre recombinase mouse lines (Cγ1-Cre and AID-Cre), to generate mice with mutant Kras (Kras(G12D) ) activated specifically in germinal center B-cells. We also generated mice with activation of the Kras(G12D) allele in a tumor-prone Arf-null genetic background.

Resequencing analysis of the candidate tyrosine kinase and RAS pathway gene families in multiple myeloma.

Multiple myeloma (MM) is an incurable, B-cell malignancy characterized by the clonal proliferation and accumulation of malignant plasma cells in bone marrow. Despite recent advances in the understanding of genomic aberrations, a comprehensive catalogue of clinically actionable mutations in MM is just beginning to emerge. The tyrosine kinase (TK) and RAS oncogenes, which encode important regulators of various signaling pathways, are among the most frequently altered gene families in cancer.

Chromosome 2p15p16.1 microdeletion syndrome: 2.5 Mb deletion in a patient with renal anomalies, intractable seizures and a choledochal cyst.

Chromosome 2p15p16.1 microdeletion is an emerging syndrome recently described in patients with dysmorphic facial features, congenital microcephaly, mild to moderate developmental delay and neurodevelopmental abnormalities. Using clinical ultra-high resolution Affymetrix SNP 6.

New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.

Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28-34 of the ELN gene in five probands with ADCL features and found five de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.

Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development.

We report recessive mutations in the gene for the latent transforming growth factor-beta binding protein 4 (LTBP4) in four unrelated patients with a human syndrome disrupting pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All patients had severe respiratory distress, with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Three of the four patients died of respiratory failure.

Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival.

Autosomal recessive cutis laxa type 2 (ARCL2), a syndrome of growth and developmental delay and redundant, inelastic skin, is caused by mutations in the a2 subunit of the vesicular ATPase H+-pump (ATP6V0A2). The goal of this study was to define the disease mechanisms that lead to connective tissue lesions in ARCL2. In a new cohort of 17 patients, DNA sequencing of ATP6V0A2 detected either homozygous or compound heterozygous mutations.

Population differences in elastin maturation in optic nerve head tissue and astrocytes.

Purpose: Glaucomatous optic neuropathy is characterized by remodeling of the extracellular matrix with disorganization of elastic fibers in the optic nerve head (ONH). There are significant differences in prevalence of glaucomatous optic neuropathy between African Americans (AAs) and Caucasian Americans (CAs). The goal of this study was to evaluate differences in elastin synthesis and maturation in ONH tissue and cells of AA and CA donors with no eye disease, to provide a basis for underlying racial differences in susceptibility to elevated intraocular pressure.

Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome.

Cutis laxa is a condition characterized by redundant, pendulous, and inelastic skin. We identified a patient with recessive inheritance of a missense mutation (169G-->A; E57K) in the Fibulin-4 gene. She had multiple bone fractures at birth and was diagnosed with cutis laxa, vascular tortuosity, ascending aortic aneurysm, developmental emphysema, inguinal and diaphragmatic hernia, joint laxity, and pectus excavatum by age 2 years.