Abstract
Background: Genetic disorders are a substantial cause of infant morbidity and mortality and are frequently suspected in neonatal intensive care units. Non-specific clinical presentation or limitations to physical examination can result in a plethora of genetic testing techniques, without clear strategies on test ordering. Here, we review our 2-years experiences of rapid genetic testing of NICU patients in order to provide such recommendations.Methods: We retrospectively included all patients admitted to the NICU who received clinical genetic consultation and genetic testing in our University hospital. We documented reasons for referral for genetic consultation, presenting phenotypes, differential diagnoses, genetic testing requested and their outcomes, as well as the consequences of each (rapid) genetic diagnostic approach. We calculated diagnostic yield and turnaround times (TATs).Results: Of 171 included infants that received genetic consultation 140 underwent genetic testing. As a result of testing as first tier, 13/14 patients received a genetic diagnosis from QF-PCR; 14/115 from SNP-array; 12/89 from NGS testing, of whom 4/46 were diagnosed with a small gene panel and 8/43 with a large OMIM-morbid based gene panel. Subsequent secondary or tertiary analysis and/or additional testing resulted in five more diagnoses. TATs ranged from 1 day (QF-PCR) to a median of 14 for NGS and SNP-array testing, with increasing TAT in particular when many consecutive tests were performed. Incidental findings were detected in 5/140 tested patients (3.6%).Conclusion: We recommend implementing a broad NGS gene panel in combination with CNV calling as the first tier of genetic testing for NICU patients given the often unspecific phenotypes of ill infants and the high yield of this large panel.
Highlights
1 in 47 children in the Netherlands is born with one or more congenital malformations, and roughly 25% of these congenital malformations are caused by genetic aberrations [1]
On the other side of the spectrum, exome sequencing (ES) or whole genome sequencing (WGS) without stringent filtering may result in a higher diagnostic yield, but their detection of a far larger number of variants generally requires a longer stage of variant interpretation and will result in more incidental findings [5]
Patient records and clinical notes in electronic health records for each patient were accessed to document the reasons for referral for genetic consultation, presenting phenotypes, differential diagnoses, genetic testing requested by the clinical geneticist, reports with results of genetic testing, outcome of cases and post-test counseling information
Summary
1 in 47 children in the Netherlands is born with one or more congenital malformations, and roughly 25% of these congenital malformations are caused by genetic aberrations [1]. A number of these children will require admittance to the neonatal intensive care unit (NICU), where clinical diagnostics may be complicated by a non-specific clinical presentation or limitations to physical examination, especially in the setting of critical clinical conditions. When implementing rNGS, a genetic diagnostic laboratory has to choose a sequencing approach, which can range from small targeted sequencing gene panels, to exome sequencing (ES) using a “virtual” gene panel filter, to whole genome sequencing (WGS) without extensive filtering. Each of these approaches has its benefits and its limitations and a different impact on the laboratory process. We review our 2-years experiences of rapid genetic testing of NICU patients in order to provide such recommendations
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