1 research outputs found
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, namely Nâacetylglutamate synthase deficiency. Therefore, molecular genetic investigation is required for confirmation of the disease, and nowadays this is done with increasing frequency applying nextâgeneration sequencing (NGS) techniques. Our laboratory has a longâstanding interest in CPS1 molecular genetic investigation and receives samples from centers in Europe and many other countries. We perform RNAâbased 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 15âyears, 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 RNAâbased 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