Background Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches.
Methods We designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs.
Results In 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses. Causal mutations were identified significantly more frequently when the biochemical phenotype suggested a specific IEM or a group of IEMs (p<0.0001), demonstrating the pivotal role of prior biochemical testing in guiding NGS analysis. The NGS panel helped to avoid further invasive, hazardous, lengthy or expensive investigations in 69% individuals (p<0.0001). Additional functional testing due to novel or unexpected findings had to be undertaken in only 3% of subjects, demonstrating that the use of NGS does not significantly increase the burden of subsequent follow-up testing. Even where a molecular diagnosis could not be achieved, NGS-based approach assisted in the management and counselling by reducing the likelihood of a high-penetrant genetic cause.
Conclusion NGS has significant clinical utility for the diagnosis of IEMs. Biochemical testing and NGS analysis play complementary roles in the diagnosis of IEMs. Incorporating NGS into the diagnostic algorithm of IEMs can improve the accuracy of diagnosis.
- Inborn Errors of Metabolism
- Metabolic disorders
- Next Generation Sequencing
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Contributors Study design was conceived by SB and SAJ. AG, SB and SAJ designed the panel. AB, AM, EJ, BS, JW, SD, HM, CH, RS, GW, EC, AAM, RM, AD, SS, SAJ and SB provided clinical data and analysed the impact of NGS for patients. Sequencing was performed by HS, LH, JU and SR. Bioinformatic analysis was performed by SSB. NGS panel validation and design was performed by JU and SR. Data collection was performed by AG, EC, JKB, HS and LH. Data analysis was performed by AG, EC, JKB, SSB, HS, LH, SR and SB. The manuscript was written by AG, SB and SR. All authors reviewed and approved the final version of the manuscript.
Competing interests Arunabha Ghosh reports travel grants from Shire Plc, Biomarin Pharmaceutical, outside the submitted work. Alexander Broomfield reports consulting fees from Genzyme, Synageva, outside the submitted work. Christian Hendriksz is director of FYMCA Ltd and reports consulting fees and travel grants from Actelion, Alexion, Amicus, Biomarin, Inventiva, Sanofi Genzyme and Shire and research grants from Actelion, Amicus, Biomarin, Sanofi Genzyme and Shire, outside the submitted work. Gisela Wilcox reports travel grants from Biomarin, Genzyme, Shire, Vitaflo and Actelion, outside the submitted work. Simon Jones reports travel grants, research grants and consultancy fees from Genzyme, Shire, Biomarin, Ultragenyx, Alexion, and PTC, outside the submitted work. Helene Schlecht, Lesley Heptinstall, John Bassett, Eleanor Cartwright, Sanjeev Bhaskar, Jill Urquhart, Andrew Morris, Elisabeth Jameson, Bernd Schwahn, John Walter, Sofia Douzgou, Helen Murphy, Reena Sharma, Ellen Crushell, Ardeshir Monavari, Richard Martin, Anne Doolan, Senthil Senniappan, Simon Ramsden and Siddharth Banka have nothing to disclose.
Patient consent This work is a retrospective evaluation of a clinical diagnostic service. Informed consent for NGS panel testing was obtained for all individuals in the study.
Provenance and peer review Not commissioned; externally peer reviewed.