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Little data are available on the management of pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) We conducted a retrospective study of 100 pregnant women with SARS-CoV-2 infection in 4 obstetric units in the Paris metropolitan area of France during March 12-April 13, 2020 Among patients, 52 (52%) were hospitalized, 10 (10%) in intensive care units (ICUs) Women with higher body mass indexes (BMIs;median 30 7 kg/m(2)) were more likely to be hospitalized in ICUs than other women (median BMI 26 2 kg/m(2)) Women hospitalized in ICUs had lower lymphocyte count at diagnosis (median 0 77 x 10(9) cells/L) than women not hospitalized in ICUs (median lymphocyte count 1 15 x 10(9) cells/L) All women requiring oxygen >5 L/min were intubated Clinical and laboratory evaluation of SARS-CoV-2-positive pregnant women at the time of diagnosis can identify patients at risk for ICU hospitalization

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Background Placental passage of drugs in twins is poorly understood, and is unknown regarding antiretrovirals (ARVs). In the event of large differences in the exposure of 2 twins to the same maternal therapy, this could have a clinical impact in terms of prevention of perinatal HIV transmission or adverse effects. Objective To describe the frequency of differential transplacental passage of antiretrovirals between twins. Study design The study was performed retrospectively, on data from women included in a multicenter perinatal HIV cohort study. All twin pairs for which the mother received antiretroviral therapy and for which drug concentrations in both of the umbilical cords after cord clamping at delivery were studied. We considered that a difference in concentrations of more than 50 % between twins was a substantial difference (ratios below 0.67 or above 1.50). Results We analyzed 29 twin pairs, 27 dichorionic and 2 monochorionic diamniotic. Cord blood concentrations differed between the 2 twins by more than 50 % for at least one ARV in 9 twin pairs, 8 dichorionic and 1 monochorionic. Discordant concentrations were observed in one or more cases for several nucleoside reverse transcriptase inhibitors (tenofovir, emtricitabine, lamivudine, zidovudine) and protease inhibitors (atazanavir, lopinavir, saquinavir et ritonavir); within individual twin pairs placental transfer was discordant for one or more ARVs, but identical for others. Conclusion Concentrations differed in nearly one third of twin pairs. This may be due to interindividual genetic variability of placental transporters between dizygotic twins as well as physiological differences between twins.

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

Coene, Karlien/0000-0001-9873-1458; Alanay, Yasemin/0000-0003-0683-9731; THOMAS, Sophie/0000-0002-8569-3277; Lyonnet, Stanislas/0000-0001-5426-9417; Akarsu, Nurten/0000-0001-5432-0032; ATTIE-BITACH, Tania/0000-0002-1155-3626; Davis, Erica/0000-0002-2412-8397; Boduroglu, Koray/0000-0001-6260-1942; Cagnard, Nicolas/0000-0002-9051-1896; cormier-daire, valerie/0000-0002-2839-9856; Katsanis, Nicholas/0000-0002-2480-0171; PUTOUX, Audrey/0000-0001-5496-4604 WOS: 000291017000021 PubMed: 21552264 KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies. ANRFrench National Research Agency (ANR) [07-MRAR-010-02, BLAN-1122-01]; E-RARE [07-ERare-001-01]; Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [108S420]; US National Institutes of Health from the National Institute of Child Health and Development [R01HD04260]; National Institute of Diabetes, Digestive and Kidney DisordersUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK072301]; Academie de Medecine; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS039818-07]; Huygens Scholarship Programme; Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [NWO Toptalent-021.001.014]; March of Dimes FoundationMarch of Dimes [1-FY07-422]; Medical Research CouncilMedical Research Council UK (MRC) [G0801843] We are grateful to families and to the French Society of Fetal Pathology (SOFFOET) for participating in the study, to C. Dubourg, P. Wieacker, B. Leroy, N. Laurent, V. Fermeaux, S. Odent for fetuses' referral and to A. Schinzel and A. David for ACLS samples. We thank M. Zarhrate, A. Aguilar, N. Spasky and L. Besse for technical help. We thank N. Boddaert for helpful discussion. This work was supported by grants from ANR (FETALCILIOPATHIES number 07-MRAR-010-02 and FOETOCILPATH number BLAN-1122-01), E-RARE (Cranirare number 07-ERare-001-01) the Scientific and Technological Research Council of Turkey (TUBITAK, grant number 108S420 to N. A. A.), the US National Institutes of Health grant R01HD04260 from the National Institute of Child Health and Development (N. K.), R01DK072301 from the National Institute of Diabetes, Digestive and Kidney Disorders (N. K.) and the European Union (EU-SYSCILIA; E. E. D., N. K. and P. L. B.). A. P. was granted a fellowship from the Academie de Medecine. S. T. is supported by NIH 'Hereditary Basis of Neural Tube Defects' No NS039818-07 to M. Speer. K. L. M. C. is supported by the Huygens Scholarship Programme and the Netherlands Organization for Scientific Research (NWO Toptalent-021.001.014). M. W. was a fellow of the Guggenheim Foundation and was supported by the March of Dimes Foundation (1-FY07-422). P. L. B. is a Wellcome Trust Senior Research Fellow. N. K. is a Distinguished George W. Brumley Professor.