Rapid Targeted Genomics in Critically Ill Newborns

Author:

van Diemen Cleo C.1,Kerstjens-Frederikse Wilhelmina S.1,Bergman Klasien A.2,de Koning Tom J.12,Sikkema-Raddatz Birgit1,van der Velde Joeri K.1,Abbott Kristin M.1,Herkert Johanna C.1,Löhner Katharina1,Rump Patrick1,Meems-Veldhuis Martine T.1,Neerincx Pieter B.T.1,Jongbloed Jan D.H.1,van Ravenswaaij-Arts Conny M.1,Swertz Morris A.1,Sinke Richard J.1,van Langen Irene M.1,Wijmenga Cisca1

Affiliation:

1. Department of Genetics, University of Groningen; and

2. Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, Netherlands

Abstract

BACKGROUND: Rapid diagnostic whole-genome sequencing has been explored in critically ill newborns, hoping to improve their clinical care and replace time-consuming and/or invasive diagnostic testing. A previous retrospective study in a research setting showed promising results with diagnoses in 57%, but patients were highly selected for known and likely Mendelian disorders. The aim of our prospective study was to assess the speed and yield of rapid targeted genomic diagnostics for clinical application. METHODS: We included 23 critically ill children younger than 12 months in ICUs over a period of 2 years. A quick diagnosis could not be made after routine clinical evaluation and diagnostics. Targeted analysis of 3426 known disease genes was performed by using whole-genome sequencing data. We measured diagnostic yield, turnaround times, and clinical consequences. RESULTS: A genetic diagnosis was obtained in 7 patients (30%), with a median turnaround time of 12 days (ranging from 5 to 23 days). We identified compound heterozygous mutations in the EPG5 gene (Vici syndrome), the RMND1 gene (combined oxidative phosphorylation deficiency-11), and the EIF2B5 gene (vanishing white matter), and homozygous mutations in the KLHL41 gene (nemaline myopathy), the GFER gene (progressive mitochondrial myopathy), and the GLB1 gene (GM1-gangliosidosis). In addition, a 1p36.33p36.32 microdeletion was detected in a child with cardiomyopathy. CONCLUSIONS: Rapid targeted genomics combined with copy number variant detection adds important value in the neonatal and pediatric intensive care setting. It led to a fast diagnosis in 30% of critically ill children for whom the routine clinical workup was unsuccessful.

Publisher

American Academy of Pediatrics (AAP)

Subject

Pediatrics, Perinatology and Child Health

Reference37 articles.

1. Online Mendelian Inheritance in Man (OMIM). OMIM Entry Statistics. Available at: www.omim.org/statistics/entry. Accessed July 22, 2016

2. Clinical genomic database.;Solomon;Proc Natl Acad Sci USA,2013

3. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units.;Saunders;Sci Transl Med,2012

4. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings.;Willig;Lancet Respir Med,2015

5. Fast and accurate short read alignment with Burrows-Wheeler transform.;Li;Bioinformatics,2009

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