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Autosomal Recessive Noonan Syndrome Associated with Biallelic LZTR1Variants

PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to i...

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Autores principales: Johnston, Jennifer J., van der Smagt, Jasper J., Rosenfeld, Jill A., Pagnamenta, Alistair T., Alswaid, Abdulrahman, Baker, Eva H., Blair, Edward, Borck, Guntram, Brinkmann, Julia, Craigen, William, Dung, Vu Chi, Emrick, Lisa, Everman, David B., van Gassen, Koen L., Gulsuner, Suleyman, Harr, Margaret H., Jain, Mahim, Kuechler, Alma, Leppig, Kathleen A., McDonald-McGinn, Donna M., Ngoc, Can Thi Bich, Peleg, Amir, Roeder, Elizabeth R., Rogers, R. Curtis, Sagi-Dain, Lena, Sapp, Julie C., Schäffer, Alejandro A., Schanze, Denny, Stewart, Helen, Taylor, Jenny C., Verbeek, Nienke E., Walkiewicz, Magdalena A., Zackai, Elaine H., Zweier, Christiane, Zenker, Martin, Lee, Brendan, Biesecker, Leslie G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105555/
https://www.ncbi.nlm.nih.gov/pubmed/29469822
http://dx.doi.org/10.1038/gim.2017.249
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author Johnston, Jennifer J.
van der Smagt, Jasper J.
Rosenfeld, Jill A.
Pagnamenta, Alistair T.
Alswaid, Abdulrahman
Baker, Eva H.
Blair, Edward
Borck, Guntram
Brinkmann, Julia
Craigen, William
Dung, Vu Chi
Emrick, Lisa
Everman, David B.
van Gassen, Koen L.
Gulsuner, Suleyman
Harr, Margaret H.
Jain, Mahim
Kuechler, Alma
Leppig, Kathleen A.
McDonald-McGinn, Donna M.
Ngoc, Can Thi Bich
Peleg, Amir
Roeder, Elizabeth R.
Rogers, R. Curtis
Sagi-Dain, Lena
Sapp, Julie C.
Schäffer, Alejandro A.
Schanze, Denny
Stewart, Helen
Taylor, Jenny C.
Verbeek, Nienke E.
Walkiewicz, Magdalena A.
Zackai, Elaine H.
Zweier, Christiane
Zenker, Martin
Lee, Brendan
Biesecker, Leslie G.
author_facet Johnston, Jennifer J.
van der Smagt, Jasper J.
Rosenfeld, Jill A.
Pagnamenta, Alistair T.
Alswaid, Abdulrahman
Baker, Eva H.
Blair, Edward
Borck, Guntram
Brinkmann, Julia
Craigen, William
Dung, Vu Chi
Emrick, Lisa
Everman, David B.
van Gassen, Koen L.
Gulsuner, Suleyman
Harr, Margaret H.
Jain, Mahim
Kuechler, Alma
Leppig, Kathleen A.
McDonald-McGinn, Donna M.
Ngoc, Can Thi Bich
Peleg, Amir
Roeder, Elizabeth R.
Rogers, R. Curtis
Sagi-Dain, Lena
Sapp, Julie C.
Schäffer, Alejandro A.
Schanze, Denny
Stewart, Helen
Taylor, Jenny C.
Verbeek, Nienke E.
Walkiewicz, Magdalena A.
Zackai, Elaine H.
Zweier, Christiane
Zenker, Martin
Lee, Brendan
Biesecker, Leslie G.
author_sort Johnston, Jennifer J.
collection PubMed
description PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify mutations. The molecular consequences of observed splice variants were evaluated by reverse-transcription PCR. RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 liveborn patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss of function, missense, and canonical and non-canonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
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spelling pubmed-61055552018-11-22 Autosomal Recessive Noonan Syndrome Associated with Biallelic LZTR1Variants Johnston, Jennifer J. van der Smagt, Jasper J. Rosenfeld, Jill A. Pagnamenta, Alistair T. Alswaid, Abdulrahman Baker, Eva H. Blair, Edward Borck, Guntram Brinkmann, Julia Craigen, William Dung, Vu Chi Emrick, Lisa Everman, David B. van Gassen, Koen L. Gulsuner, Suleyman Harr, Margaret H. Jain, Mahim Kuechler, Alma Leppig, Kathleen A. McDonald-McGinn, Donna M. Ngoc, Can Thi Bich Peleg, Amir Roeder, Elizabeth R. Rogers, R. Curtis Sagi-Dain, Lena Sapp, Julie C. Schäffer, Alejandro A. Schanze, Denny Stewart, Helen Taylor, Jenny C. Verbeek, Nienke E. Walkiewicz, Magdalena A. Zackai, Elaine H. Zweier, Christiane Zenker, Martin Lee, Brendan Biesecker, Leslie G. Genet Med Article PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify mutations. The molecular consequences of observed splice variants were evaluated by reverse-transcription PCR. RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 liveborn patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss of function, missense, and canonical and non-canonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1. 2018-02-22 2018-10 /pmc/articles/PMC6105555/ /pubmed/29469822 http://dx.doi.org/10.1038/gim.2017.249 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Johnston, Jennifer J.
van der Smagt, Jasper J.
Rosenfeld, Jill A.
Pagnamenta, Alistair T.
Alswaid, Abdulrahman
Baker, Eva H.
Blair, Edward
Borck, Guntram
Brinkmann, Julia
Craigen, William
Dung, Vu Chi
Emrick, Lisa
Everman, David B.
van Gassen, Koen L.
Gulsuner, Suleyman
Harr, Margaret H.
Jain, Mahim
Kuechler, Alma
Leppig, Kathleen A.
McDonald-McGinn, Donna M.
Ngoc, Can Thi Bich
Peleg, Amir
Roeder, Elizabeth R.
Rogers, R. Curtis
Sagi-Dain, Lena
Sapp, Julie C.
Schäffer, Alejandro A.
Schanze, Denny
Stewart, Helen
Taylor, Jenny C.
Verbeek, Nienke E.
Walkiewicz, Magdalena A.
Zackai, Elaine H.
Zweier, Christiane
Zenker, Martin
Lee, Brendan
Biesecker, Leslie G.
Autosomal Recessive Noonan Syndrome Associated with Biallelic LZTR1Variants
title Autosomal Recessive Noonan Syndrome Associated with Biallelic LZTR1Variants
title_full Autosomal Recessive Noonan Syndrome Associated with Biallelic LZTR1Variants
title_fullStr Autosomal Recessive Noonan Syndrome Associated with Biallelic LZTR1Variants
title_full_unstemmed Autosomal Recessive Noonan Syndrome Associated with Biallelic LZTR1Variants
title_short Autosomal Recessive Noonan Syndrome Associated with Biallelic LZTR1Variants
title_sort autosomal recessive noonan syndrome associated with biallelic lztr1variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105555/
https://www.ncbi.nlm.nih.gov/pubmed/29469822
http://dx.doi.org/10.1038/gim.2017.249
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