A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion.

Autor:	Chai G; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Szenker-Ravi E; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Chung C; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Li Z; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Wang L; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Khatoo M; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Marshall T; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Jiang N; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Yang X; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., McEvoy-Venneri J; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Stanley V; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Anzenberg P; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Lang N; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Wazny V; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Yu J; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Virshup DM; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Nygaard R; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Mancia F; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Merdzanic R; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Toralles MBP; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Pitanga PML; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Puri RD; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Hernan R; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Chung WK; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Bertoli-Avella AM; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Al-Sannaa N; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Zaki MS; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Willert K; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Reversade B; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.)., Gleeson JG; From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.).
Jazyk:	angličtina
Zdroj:	The New England journal of medicine [N Engl J Med] 2021 Sep 30; Vol. 385 (14), pp. 1292-1301.
DOI:	10.1056/NEJMoa2033911
Abstrakt:	Background: Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. Methods: We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring. Results: We identified homozygous mutations in WLS , which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development. Conclusions: Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.). (Copyright © 2021 Massachusetts Medical Society.)
Databáze:	MEDLINE
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