Identification of Medically Actionable Secondary Findings in the 1000 Genomes

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.     

Reproductive morphology of the male Tuatara,Sphenodon punctatus

Over the past decade, studies on reproductive morphology in the Squamata (snakes and lizards) have expanded tremendously. With the accumulation of these studies and revisions of the terminology based on structural similarities and differences, it is imperative to review the work on tuataras to determine whether the structural organization fits the revised terminology of vertebrates. We investigated the morphology of the male reproductive system in the Tuatara, Sphenodon punctatus (Rhynchocephalia), the sister taxon to the Squamata. Previous studies on the Tuatara used a nomenclature for the testicular ducts different from the current terminology for amniotes. The reproductive system in the Tuatara is consistent with reports in the Squamata. Two rete testis tubules exit the testis within a connective tissue sheath similar to that shown in other squamate species and the protherian Echidna. Each rete testis divides into multiple ductuli efferentes that fuse with the epididymis. The epididymis transitions into the ductus deferens where the sperm become more concentrated into spherical bundles. The ductus deferens enters the cloacal urodeum separately from the ureter. An ampulla ureter or ampulla urogenital papilla was not observed, which differs from previous studies of lepidosaurians. Furthermore, a sexual segment of the kidney (SSK) was not observed, consistent with previous studies on the Tuatara.     

Morphological changes of an inflammatory myopathy in rhesus monkeys with simian acquired immunodeficiency syndrome

Eleven of 25 rhesus monkeys which died of simian acquired immunodeficiency syndrome (SAIDS) caused by infection with a type D retrovirus related to Mason-Pfizer monkey virus showed evidence of muscle weakness and atrophy and had elevated levels of muscle enzymes. Biopsies of affected muscle studied with enzyme histochemistry showed the characteristic features of polymyositis. Inflammatory cells consisting of lymphocytes, macrophages, and large vacuolated bizarre-shaped cells of undetermined type were surrounding or invading muscle fibers and were present in the perivascular spaces and endomysia septa. Within the perivascular infiltrates, lymphocytes were abundant but very few macrophages were present. Other myopathic features including profound proliferation of fibrous tissue, necrosis, and phagocytosis of muscle fibers were noted to a variable degree. The retrovirus was isolated from affected muscles. The clinical and historical features of polymyositis in rhesus monkeys with SAIDS are very similar to those of human polymyositis. The polymyositis in SAIDS induced by a type D retrovirus related to Mason-Pfizer monkey virus is an excellent primate model to study the mechanism and morphological changes of viral-induced muscle damage.     

Phenotypic features of a strain of Yersinia pseudotuberculosis with the pVM82 plasmid, detected at pseudotuberculosis outbreak foci]

The phenotypic properties conferred to Yersinia pseudotuberculosis cells by the genetical determinants of a 25Md fragment of the plasmid pVM82 coding for the modified cellular immune response in the infected organism. The fragment was shown to determine the conjugative properties of the plasmid, the resistance of bacterial cells to a number of hydrophobic agents and cellular ability to absorb the Congo red dye. The latter confirms the presence of additional structural components in the cell wall of the strain harbouring the plasmid pVM82. The increased resistance of the plasmid-containing strain to bactericidal effect of the blood plasma was demonstrated as compared with the resistance of the strains harbouring the p57 plasmid lacking the 25Md fragment or no plasmid at all.     

Endoderm-secreted factor stimulates growth of embryonal carcinoma stem cells

Summary Stem cells of the embryonal carcinoma cell line called H6 can be induced to differnetiate to endoderm-like cells by retinoic acid (3×10⁻⁶ M). We have detected a diffusible and stable factor which is secreted by H6 endoderm-like cells and stimulates the growth of H6 stem cells. The stimulation by the endoderm-like cells is considereably greater than that by mouse fibroblasts or H6 stem cells themselves. No reciprocal stimulation of endoderm-like cells by stem cells occurs. Part but not all of the stimulation might be due to extracellular matrix proteins or to insulin-like growth factor type 2, each of which also stimulates the growth of H6 stem cells. Insulin causes no such stimulation. This work was supported by research rant no. CA-16754 from the National Cancer Institute to J. W. L. E. L. G. was supported by an American Heart Association Medical Student Research Award. Editor's Statement This paper presents a good example of cooperativity between undifferentiated teratoma stem cells and differentiated parietal endoderm-derived countrparts in terms of growth support. It raises the interesting question of the relationship between factors produced by paprietal and visceral endoderm cells. Gordon H. Sato     

Immunologic alterations in monkeys with simian acquired immunodeficiency syndrome (SAIDS)

Levels of lymphocyte responsiveness to T- and B-cell-specific mitogens and expressions of Ia, T4, T8, and T11 surface markers were monitored during the course of Simian acquired immunodeficiency syndrome (SAIDS) in four Rhesus macaques that either died or became ill and survived. The monkey that died showed progressively suppressed responses to concanavalin A (Con A), phytohemagglutinin (PHA), pokeweed mitogen (PWM), and Staphylococcus aureus Cowan I strain (SAC) through the time of death (5 1/2 weeks). For the three animals that survived, the responses of peripheral blood mononuclear cell (PBMC) to the same mitogens were decreased significantly during the period 4-6 weeks after inoculation. Levels of Ia-bearing cells in the PBMC population were markedly reduced in the moribund monkey but were not significantly decreased in the three survivors. There was no significant change in the percentage of T11-bearing cells in any of the study animals. The ratio of T4- and T8-positive cells did not vary significantly during the 18 weeks of observation in any of the animals. The infected animals showed other evidence of immunosuppression including neutropenia, lymphopenia, and depletion of lymphocytes in lymph nodes. The animal that had progressive disease and death also had Kaposi-like lesions and staphylococcal septicemia. These results indicated that in vitro evidence of immunosuppression due to SAIDS appears within a few weeks after infection and this may progress in animals that die.     

A new species of Sicyos (Cucurbitaceae) from Chiapas,Mexico

Sicyos motozintlensis is described from the vicinity of Motozintla de Mendoza, Chiapas. It shows a strong similarity toS. chiriquensis Hammel & D’Arcy from Panama.