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Eur J Hum Genet. 2019 Jan 9. doi: 10.1038/s41431-018-0330-0. [Epub ahead of print]

Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program.

Author information

1
Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular, Universidad Autónoma de Madrid, CIBERER, IdiPAZ, Madrid, Spain.
2
Unidad de Nutrición Infantil y Enfermedades Metabólicas, Hospital Universitario La Paz, Madrid, Spain.
3
Unidad de Enfermedades Mitocondriales y Enfermedades Metabólicas Hereditarias, Hospital Universitario 12 de Octubre, Madrid, Spain.
4
Dpto. de Gastroenterología y Nutrición, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
5
Unidad de Enfermedades Metabólicas, Hospital Universitario Miguel Servet, Zaragoza, Spain.
6
Laboratorio de Metabolopatías, Hospital Regional Universitario, Instituto de Investigación Biomédica de Málaga, Málaga, Spain.
7
Sección de Gastroenterología y Nutrición, Hospital Universitario Niño Jesús, Madrid, Spain.
8
Unidad de Enfermedades Metabólicas Congénitas, Hospital Universitario Ramón y Cajal, Madrid, Spain.
9
Dpto, de Pediatría, Hospital Virgen de la Salud, Toledo, Spain.
10
Dpto. de Pediatría, Hospital Universitario Virgen del Rocío, Seville, Spain.
11
Laboratorio de Metabolopatías, Hospital Universitario Virgen del Rocío, Seville, Spain.
12
Unidad de Nutrición y Metabolopatías, Hospital Universitario La Fe, Valencia, Spain.
13
Laboratorio de Metabolopatías, Hospital Universitario La Fe, Valencia, Spain.
14
Dpto. de Pediatría, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
15
Unidad de Enfermedades Metabólicas, Hospital Clínico Universitario de Santiago, Santiago de Compostela, CIBERER, Santiago, Spain.
16
Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular, Universidad Autónoma de Madrid, CIBERER, IdiPAZ, Madrid, Spain. bperez@cbm.csic.es.

Abstract

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.

PMID:
30626930
DOI:
10.1038/s41431-018-0330-0

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