Abstract 16003: Rapid Whole Genome Sequencing for Critically Ill Children With Cardiomyopathy
Introduction: Rapid whole genome sequencing (WGS) has been explored as a novel diagnostic tool in severely ill newborns, in order to replace time consuming genetic tests. Retrospective studies showed that WGS or exome sequencing results in a molecular diagnosis in 25-73% in highly selected groups of children with possible monogenic diseases. However no prospective studies in a clinical setting have been published. We therefore initiated this prospective study to test the speed and the yield of this new approach. The results in eligible newborns and infants with severe cardiomyopathy are presented.
Methods and Results: In a period of 24 months, 30 children younger than one year were included because they were severely ill, i.e. on intensive care units, and did not have an obvious diagnosis which could be confirmed by a single genetic test. We first analyzed 2,800 known disease genes present in the Clinical Genomics Database and variants were filtered according to patient specific HPO terms. Four children (13.3%, median age at inclusion 2 months) presented with cardiomyopathy and their WGS results were available in a median turnaround time of 11 days (range 6-14 days). We identified a homozygous GLB1 mutation (c.176G>A; p.Arg59His), previously described in the infantile form of GM1-gangliosidosis, an untreatable autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes. The patient, whose parents were first cousins, presented with overt heart failure due to dilated cardiomyopathy and hepatomegaly. Two days after the diagnosis was confirmed, treatment was discontinued and the patient died. The other solved case was a girl with non-compaction cardiomyopathy and an AV-block. Both SNP-array and CNV-detection in WGS data revealed a de novo 3.6Mb deletion (del 1p36.33p36.32). WGS did not provide a conclusive diagnosis in the other two cardiomyopathy patients.
Conclusions: A substantial percentage of critically ill children present with cardiomyopathies. Rapid whole genome sequencing has an important added value in the neonatal and pediatric intensive care setting, illustrated by the diagnosis of GM1-gangliosidosis and a 1p36 deletion in two patients with severe cardiomyopathy.
Author Disclosures: P.A. van der Zwaag: None. J.C. Herkert: None. G.J. du Marchie Sarvaas: None. B. Bartelds: None. C.C. van Diemen: None. T.J. de Koning: None. J.D. Jongbloed: None. B. Sikkema-Raddatz: None. L. Franke: None. R.J. Sinke: None. I.M. van Langen: None. C. Wijmenga: None. W.S. Kerstjens-Frederikse: None.
- © 2016 by American Heart Association, Inc.