Cargando…

Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing

Carbamoylphosphate synthetase 1 (CPS1) deficiency is a rare inborn error of metabolism leading often to neonatal onset hyperammonemia with coma and high mortality. The biochemical features of the disease are nonspecific and cannot distinguish this condition from other defects of the urea cycle, name...

Descripción completa

Detalles Bibliográficos
Autores principales: Isler, Jasmine, Rüfenacht, Véronique, Gemperle, Corinne, Allegri, Gabriella, Häberle, Johannes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052687/
https://www.ncbi.nlm.nih.gov/pubmed/32154057
http://dx.doi.org/10.1002/jmd2.12091
_version_ 1783502905383321600
author Isler, Jasmine
Rüfenacht, Véronique
Gemperle, Corinne
Allegri, Gabriella
Häberle, Johannes
author_facet Isler, Jasmine
Rüfenacht, Véronique
Gemperle, Corinne
Allegri, Gabriella
Häberle, Johannes
author_sort Isler, Jasmine
collection PubMed
description Carbamoylphosphate synthetase 1 (CPS1) deficiency is a rare inborn error of metabolism leading often to neonatal onset hyperammonemia with coma and high mortality. The biochemical features of the disease are nonspecific and cannot distinguish this condition from other defects of the urea cycle, namely N‐acetylglutamate synthase deficiency. Therefore, molecular genetic investigation is required for confirmation of the disease, and nowadays this is done with increasing frequency applying next‐generation sequencing (NGS) techniques. Our laboratory has a long‐standing interest in CPS1 molecular genetic investigation and receives samples from centers in Europe and many other countries. We perform RNA‐based CPS1 molecular genetic investigation as first line investigation and wanted in this study to evaluate our experience with this approach as compared to NGS. In the past 15 years, 297 samples were analyzed, which were referred from 37 countries. CPS1 deficiency could be confirmed in 155 patients carrying 136 different genotypes with only a single mutation recurring more than two times. About 10% of the total 172 variants comprised complex changes (eg, intronic changes possibly affecting splicing, deletions, insertions, or deletions_insertions), which would have been partly missed if only NGS was done. Likewise, RNA analysis was crucial for correct interpretation of at least half of the complex mutations. This study gives highest sensitivity to RNA‐based CPS1 molecular genetic investigation and underlines that NGS should be done together with copy number variation analysis. We propose that unclear cases should be investigated by RNA sequencing in addition, if this method is not used as the initial diagnostic procedure.
format Online
Article
Text
id pubmed-7052687
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley & Sons, Inc.
record_format MEDLINE/PubMed
spelling pubmed-70526872020-03-09 Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing Isler, Jasmine Rüfenacht, Véronique Gemperle, Corinne Allegri, Gabriella Häberle, Johannes JIMD Rep Research Reports Carbamoylphosphate synthetase 1 (CPS1) deficiency is a rare inborn error of metabolism leading often to neonatal onset hyperammonemia with coma and high mortality. The biochemical features of the disease are nonspecific and cannot distinguish this condition from other defects of the urea cycle, namely N‐acetylglutamate synthase deficiency. Therefore, molecular genetic investigation is required for confirmation of the disease, and nowadays this is done with increasing frequency applying next‐generation sequencing (NGS) techniques. Our laboratory has a long‐standing interest in CPS1 molecular genetic investigation and receives samples from centers in Europe and many other countries. We perform RNA‐based CPS1 molecular genetic investigation as first line investigation and wanted in this study to evaluate our experience with this approach as compared to NGS. In the past 15 years, 297 samples were analyzed, which were referred from 37 countries. CPS1 deficiency could be confirmed in 155 patients carrying 136 different genotypes with only a single mutation recurring more than two times. About 10% of the total 172 variants comprised complex changes (eg, intronic changes possibly affecting splicing, deletions, insertions, or deletions_insertions), which would have been partly missed if only NGS was done. Likewise, RNA analysis was crucial for correct interpretation of at least half of the complex mutations. This study gives highest sensitivity to RNA‐based CPS1 molecular genetic investigation and underlines that NGS should be done together with copy number variation analysis. We propose that unclear cases should be investigated by RNA sequencing in addition, if this method is not used as the initial diagnostic procedure. John Wiley & Sons, Inc. 2020-01-09 /pmc/articles/PMC7052687/ /pubmed/32154057 http://dx.doi.org/10.1002/jmd2.12091 Text en © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Reports
Isler, Jasmine
Rüfenacht, Véronique
Gemperle, Corinne
Allegri, Gabriella
Häberle, Johannes
Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing
title Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing
title_full Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing
title_fullStr Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing
title_full_unstemmed Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing
title_short Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing
title_sort improvement of diagnostic yield in carbamoylphosphate synthetase 1 (cps1) molecular genetic investigation by rna sequencing
topic Research Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052687/
https://www.ncbi.nlm.nih.gov/pubmed/32154057
http://dx.doi.org/10.1002/jmd2.12091
work_keys_str_mv AT islerjasmine improvementofdiagnosticyieldincarbamoylphosphatesynthetase1cps1moleculargeneticinvestigationbyrnasequencing
AT rufenachtveronique improvementofdiagnosticyieldincarbamoylphosphatesynthetase1cps1moleculargeneticinvestigationbyrnasequencing
AT gemperlecorinne improvementofdiagnosticyieldincarbamoylphosphatesynthetase1cps1moleculargeneticinvestigationbyrnasequencing
AT allegrigabriella improvementofdiagnosticyieldincarbamoylphosphatesynthetase1cps1moleculargeneticinvestigationbyrnasequencing
AT haberlejohannes improvementofdiagnosticyieldincarbamoylphosphatesynthetase1cps1moleculargeneticinvestigationbyrnasequencing