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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2018
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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. |
format | Online Article Text |
id | pubmed-6105555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
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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