RT Journal Article
SR Electronic
T1 Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing
JF Archives of Disease in Childhood
JO Arch Dis Child
FD BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health
SP 1019
OP 1029
DO 10.1136/archdischild-2017-312738
VO 102
IS 11
A1 Arunabha Ghosh
A1 Helene Schlecht
A1 Lesley E Heptinstall
A1 John K Bassett
A1 Eleanor Cartwright
A1 Sanjeev S Bhaskar
A1 Jill Urquhart
A1 Alexander Broomfield
A1 Andrew AM Morris
A1 Elisabeth Jameson
A1 Bernd C Schwahn
A1 John H Walter
A1 Sofia Douzgou
A1 Helen Murphy
A1 Chris Hendriksz
A1 Reena Sharma
A1 Gisela Wilcox
A1 Ellen Crushell
A1 Ardeshir A Monavari
A1 Richard Martin
A1 Anne Doolan
A1 Senthil Senniappan
A1 Simon C Ramsden
A1 Simon A Jones
A1 Siddharth Banka
YR 2017
UL http://adc.bmj.com/content/102/11/1019.abstract
AB 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.