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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.

Advances in next-generation sequencing (NGS) techniques, including whole exome sequencing, have facilitated cost-effective sequencing of large regions of the genome, enabling the implementation of NGS in clinical practice. Chronic kidney disease (CKD) is a major contributor to global burden of disease and is associated with an increased risk of morbidity and mortality. CKD can be caused by a wide variety of primary renal disorders. In about one in five CKD patients, no primary renal disease diagnosis can be established. Moreover, recent studies indicate that the clinical diagnosis may be incorrect in a substantial number of patients. Both the absence of a diagnosis or an incorrect diagnosis can have therapeutic implications. Genetic testing might increase the diagnostic accuracy in patients with CKD, especially in patients with unknown etiology. The diagnostic utility of NGS has been shown mainly in pediatric CKD cohorts, while emerging data suggest that genetic testing can also be a valuable diagnostic tool in adults with CKD. In addition to its implications for unexplained CKD, NGS can contribute to the diagnostic process in kidney diseases with an atypical presentation, where it may lead to reclassification of the primary renal disease diagnosis. So far, only a few studies have reported on the diagnostic yield of NGS-based techniques in patients with unexplained CKD. Here, we will discuss the potential diagnostic role of gene panels and whole exome sequencing in pediatric and adult patients with unexplained and atypical CKD.

Nephronophthisis (NPH) is the most common monogenic cause of renal failure in children. Treatment options are limited to dialysis and transplantation. Therapeutics to significantly delay or prevent end-stage renal disease (ESRD) in children are currently not available. In the Dutch-Anglo KOUNCIL (Kidney-Oriented UNderstanding of correcting CILiopathies) consortium, several groups and specialties united to perform scientific groundwork with the aim to develop genetic and therapeutic personalized care for NPH patients. At the start of this consortium, a genetic diagnosis for NPH was available for only 30–40% of patients, which improved to 50–60% during the course of the 4-year KOUNCIL project. Other major accomplishments of the consortium were (1) the establishment of a Dutch renal ciliopathy patient database with genotype and phenotype data; (2) composition of a proteomics-based integrated network of protein modules disrupted in NPH; (3) the development of non-invasive, urine-based assays that allow functional assessment of genomic variants in NPH and of therapeutic efficiency of drugs; and (4) chemical screening toward the identification of compounds that delay or prevent disease progression in NPH, which resulted in four potential medical interventions for NPH. In conclusion, the KOUNCIL consortium effectively channeled complementary approaches to broaden our understanding of NPH pathogenesis, resulted in 54 publications, improvement of genome diagnostics for NPH patients, awareness in the nephrology and clinical genetics communities for NPH, and new avenues for patient management.