Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program.
Rosa NavarreteFátima LealAna I VegaAna Morais-LópezMaría Teresa Garcia-SilvaElena Martín-HernándezPilar Quijada-FraileAna BerguaInmaculada VivesInmaculada García-JiménezRaquel YahyaouiConsuelo Pedrón-GinerAmaya Belanger-QuintanaSinziana StanescuElvira CañedoOscar García-CamposMaría Bueno-DelgadoCarmen Delgado-PecellínIsidro VitoriaMaría Dolores RausellElena BalmasedaMari Luz CouceLourdes Ruiz DesviatBegoña MerineroPilar Rodríguez-PomboMagdalena UgarteCelia Pérez-CerdáBelén PérezPublished in: European journal of human genetics : EJHG (2019)
The present work describes the value of genetic analysis as a confirmatory measure following the detection of suspected inborn errors of metabolism in the Spanish newborn mass spectrometry screening program. One hundred and forty-one consecutive DNA samples were analyzed by next-generation sequencing using a customized exome sequencing panel. When required, the Illumina extended clinical exome panel was used, as was Sanger sequencing or transcriptional profiling. Biochemical tests were used to confirm the results of the genetic analysis. Using the customized panel, the metabolic disease suspected in 83 newborns (59%) was confirmed. In three further cases, two monoallelic variants were detected for two genes involved in the same biochemical pathway. In the remainder, either a single variant or no variant was identified. Given the persistent absence of biochemical alterations, carrier status was assigned in 39 cases. False positives were recorded for 11. In five cases in which the biochemical pattern was persistently altered, further genetic analysis allowed the detection of two variants affecting the function of BCAT2, ACSF3, and DNAJC12, as well as a second, deep intronic variant in ETFDH or PTS. The present results suggest that genetic analysis using extended next-generation sequencing panels can be used as a confirmatory test for suspected inborn errors of metabolism detected in newborn screening programs. Biochemical tests can be very helpful when a diagnosis is unclear. In summary, simultaneous genomic and metabolomic analyses can increase the number of inborn errors of metabolism that can be confirmed following suggestive newborn screening results.
Keyphrases
- copy number
- genome wide
- patient safety
- pulmonary embolism
- mass spectrometry
- adverse drug
- single cell
- circulating tumor
- dna methylation
- quality improvement
- gene expression
- public health
- pregnant women
- loop mediated isothermal amplification
- single molecule
- liquid chromatography
- emergency department
- transcription factor
- cord blood
- low birth weight
- gestational age
- solid phase extraction
- circulating tumor cells