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Cunningham, L.

Publications and source records attributed to Cunningham, L..

2 recordsLinked to original sources
bioRxiv2023

Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancies in a Natural History Study

Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancies (FPDMM), which is characterized by thrombocytopenia and a life-long risk (35-45%) of hematological malignancies. We recently launched a longitudinal natural history study for patients with FPDMM at the NIH Clinical Center. Among 29 families with research genomic data, 28 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 24 of 54 (44.4%) non-malignant patients, somatic mutations were detected in at least one of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 7 other CHIP or AML driver genes (DNMT3A, TET2, NRAS, SETBP1, SF3B1, KMT2C, and LRP1B) were also found in more than one non-malignant patient. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in elderly patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring dynamic changes of somatic mutations prospectively will benefit patients clinical management and reveal mechanisms for progression to myeloid malignancies. Key PointsO_LIComprehensive genomic profile of patients with FPDMM with germline RUNX1 mutations. C_LIO_LIRising clonal hematopoiesis related secondary mutations that may lead to myeloid malignancies. C_LI

genomics↗
bioRxiv2018

What is the Best Available Science?: Conservation Status of Two California Desert Vertebrates

Scientific progress depends on evidence-based research, and reliance on accurate scholarship is essential when making management decisions for imperiled species. However, erroneous claims are sometimes perpetuated in the scientific and technical literature, which can complicate policy and regulatory judgments. The literature associated with two enigmatic California desert vertebrates, the Panamint alligator lizard Elgaria panamintina and the Inyo Mountains salamander Batrachoseps campi, exemplifies this problem. We produced a comprehensive threat analysis and status assessment for these species, which are both under review for possible listing under the US Endangered Species Act (ESA). Despite uncertainties and limited data, we find that many sources contain factual errors about the status of these two species, particularly the original petition that advocated for ESA listing. Although localized declines may have gone undetected, no evidence exists of population declines, population extirpation, or population-scale habitat conversion for E. panamintina. However, there is evidence of recent flash flood damage to some occupied B. campi habitat, which has possibly led to population declines at those localities. Contrary to inaccurate statements by some authors, all known populations of both species occur exclusively on federal lands, and numerous populations have likely benefited from recent federal management targeted at reducing known threats. Of the 12 threats that we identified for one or both species, only three currently appear to be serious: water diversions, climate change, and flash floods. The remaining threats are neither widespread nor severe, despite numerous contrary yet poorly supported statements in the literature. We thus evaluate the contemporary conservation status of both species as relatively secure, although B. campi is more at-risk compared to E. panamintina. This conclusion is independently supported by a recent review. Nonetheless, ongoing stewardship of these species in a multi-use context by federal agencies remains vital, and we identify several priority management actions and research needs for both species. We also recommend updated determinations on the IUCN Red List, and the Species of Conservation Concern list of the Inyo National Forest. To maximize the quality and effectiveness of conservation planning, we urge government agencies, non-governmental organizations, and individual scientists to maintain high standards of scholarship and decision-making.

zoology↗