9th Annual Seminar on Legal Issues for Financial Institutions

Outline of speakers\u27 presentations from the 9th Annual Seminar on Legal Issues for Financial Institutions held by UK/CLE on March 10-11, 1989

Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome

Genome-wide association analysis identifies six new loci associated with forced vital capacity

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR129-2–HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease

Association of Forced Vital Capacity with the Developmental Gene <i>NCOR2</i>

Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 chi

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.Peer reviewe

Proceedings of the Fourth Caldwell Conference, St. Catherines Island, Georgia, March 27-29, 2009.

391 p. : ill. (chiefly col.), maps (chiefly col.) ; 26 cm. "Issued March 23, 2011."This edited volume addresses the geoarchaeology of St. Catherines Island (Georgia). The field of geoarchaeology has typically been defined as either geology pursued within an archaeological framework or (sometimes the reverse) as archaeology framed with the help of geological methodology. Either way, the formalized objectives of geoarchaeology define a broad range of pursuits, from placing archaeological sites into relative and absolute temporal context through the application of stratigraphic principles and absolute dating techniques, to understanding the natural processes of site formation, to reconstructing the landscapes that existed around a site or group of sites at the time of occupation. The editors of this volume have generally followed the lead of G.R. Rapp and C.L. Hill (2006, Geoarchaeology : the earth-science approach to archaeological interpretation) by stressing the importance of multiple viewpoints and methodologies in applying geoscience techniques to evaluate the archaeological record. In the broadest sense, then, Geoarchaeology of St. Catherines Island applies multiple earth science concepts, techniques, or knowledge bases to the known archaeological record and the processes that created that record. This volume consists of 16 papers presenting the newest research on the stratigraphic and geomorphological evolution of the St. Catherines Island landscape. Of particular interest are presentations addressing the relative timing and nature of sedimentation, paleobiology, sea level change, stream capture, hydrology, and erosional patterning evident on St. Catherines Island (and to some degree the rest of the Georgia Bight). These papers were initially presented at the Fourth Caldwell Conference, cosponsored by the American Museum of Natural History and the St. Catherines Island Foundation, held on St. Catherines Island (Georgia), March 27-29, 2009. Table of contents: Why this archaeologist cares about geoarchaeology : some pasts and futures of St. Catherines Island / David Hurst Thomas -- Evolution of late Pleistocene-Holocene climates and environments of St. Catherines Island and the Georgia Bight / Fredrick J. Rich, Anthony Vega, and Frank J. Vento -- Geoarchaeological research at St. Catherines Island : defining the geological foundation / Gale A. Bishop, Brian K. Meyer, R. Kelly Vance, and Fredrick J. Rich -- Development of a late Pleistocene-Holocene genetic stratigraphic framework for St. Catherines Island : archaeological implications / Frank J. Vento and Patty A. Stahlman -- Ichnological diagnosis of ancient storm-washover fans, Yellow Banks Bluff, St. Catherines Island / Anthony J. Martin and Andrew K. Rindsberg -- Quaternary vegetation and depositional history of St. Catherines Island / Fredrick J. Rich and Robert K. Booth -- Recent shoreline erosion and vertical accretion patterns, St. Catherines Island / Donald B. Potter Jr. -- Role of storm events in beach ridge formation, St. Catherines Island / Harold B. Rollins, Kathi Beratan, and James E. Pottinger -- Drainage changes at Ossabaw, St. Catherines, and Sapelo sounds and their influence on island morphology and spit building on St. Catherines Island / Timothy M. Chowns -- Vibracores and vibracore transects : constraining the geological and cultural history of St. Catherines Island / Gale A. Bishop, David Hurst Thomas, Matthew C. Sanger, Brian K. Meyer, R. Kelly Vance, Robert K. Booth, Fredrick J. Rich, Donald B. Potter, and Timothy Keith-Lucas -- Application of ground penetrating radar to investigations of the stratigraphy, structure, and hydrology of St. Catherines Island / R. Kelly Vance, Gale A. Bishop, Fredrick J. Rich, Brian K. Meyer, and Eleanor J. Camann -- Postsettlement dispersal and dynamic repopulation of estuarine habitats by adult Mercenaria mercenaria, St. Catherines Island / Robert S. Prezant, Harold B. Rollins, and Ronald B. Toll -- The foundation for sea turtle geoarchaeology and zooarchaeology : morphology of recent and ancient sea turtle nests, St. Catherines Island, Georgia, and Cretaceous Fox Hills Sandstone, Elbert County, Colorado / Gale A. Bishop, Fredric L. Pirkle, Brian K. Meyer, and William A. Pirkle -- Sea turtle habitat deterioration on St. Catherines Island : defining the modern transgression / Gale A. Bishop and Brian K. Meyer -- Modeling indigenous hunting and harvesting of sea turtles and their eggs on the Georgia Coast / Gale A. Bishop, David Hurst Thomas, and Brian K. Meyer -- Geomorphology, sea level, and marine resources : St. Catherines Island / Harold B. Rollins and David Hurst Thomas -- Appendix 1. Noncultural radiocarbon record from St. Catherines Island : a compendium -- Appendix 2. Vibracore record from St. Catherines Island : a compendium.Conference sponsored by the American Museum of Natural History and the St. Catherines Island Foundation

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD

Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n = 849, 39.9% CMH) and without COPD (n = 1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p = 5.43×10(-5)) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p = 0.007). In non-COPD subjects, four SNPs had a p-value <10(-5) in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p = 7.57×10(-6), OR 1.48) and with significantly increased MAML3 expression in lung tissue (p = 2.59×10(-12)). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD