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

JIMD Reports
Jasmine IslerJohannes Häberle

Abstract

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_...Continue Reading

References

Feb 21, 2007·Journal of Human Genetics·Keiji KurokawaTatsutoshi Nakahata
Jul 31, 2008·Human Mutation·Sabrina MitchellUNKNOWN Urea Cycle Disorder Consortium
Apr 3, 2009·Nucleic Acids Research·François-Olivier DesmetChristophe Béroud
Sep 22, 2010·Molecular Genetics and Metabolism·Jing WangLee-Jun C Wong
May 12, 2012·Molecular Genetics and Metabolism·Rita KretzJohannes Häberle
Apr 1, 2014·Nature Methods·Jana Marie SchwarzDominik Seelow
Jul 29, 2016·Molecular Genetics & Genomic Medicine·Tania DjémiéUNKNOWN EuroEPINOMICS‐RES Dravet working group
Apr 16, 2019·Journal of Inherited Metabolic Disease·Johannes HäberleCarlo Dionisi-Vici

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Methods Mentioned

BETA
biopsies
exome sequencing

Software Mentioned

Human Splicing Finder
MutationTaster

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