Primary objective of this research is to assess and quantify the total costs of a genetic diagnosis for children suspected for intellectual disability (ID). Secondary objective is to identify the impact of genetic testing on medical decision-making and costs in the future. We retrospectively analyzed medical records of 371 young patients who have undergone WES at various stages of their diagnostic odyssey. Complete resource use data were collected at the University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. We categorized the young patients according to their WES-based diagnosis (yes, no, and uncertain), and assessed the per-patient healthcare activities and corresponding costs before (PRE) and after (POST) the diagnosis was obtained. In the cohort of 371 patients, 129 patients received a genetic diagnosis (35%). In 89 (24%) patients no mutation was identified and 153 patients (41%) had an uncertain (variant-of-unknown-significance) diagnosis. We estimated implementation of WES-first would result in mean savings of €5122 euro per patient resulting from replacement of all other genetic technologies and 50% of non-genetic diagnostic tools and consults. A decrease in costs was observed in the majority of categories POST-WES, only the costs of consults in all categories and the costs of genetic tests after not having a diagnosis (+300%) increased. Our study confirms that WES is a cost-effective replacement of traditional diagnostic technologies for patients with ID. Looking at the high, although similar in all WES-based diagnostic groups, costs WES could be a cost-efficient and unique option when implemented early in patient care: it could reduce health care costs and induce the amount of distinct diagnoses. On the other hand, our data demonstrate that for patients not having a diagnosis the diagnostic costs have increased after WES. This indicates a change in mindset is needed when implementing WES on a broad scale.

Objective Nephronophthisis is an autosomal recessive renal ciliopathy that constitutes the leading monogenic cause of end-stage renal disease in children. The KOUNCIL consortium is a collaboration between the UMC Utrecht, the Radboud UMC Nijmegen and UC London aimed at elucidating the genetic etiology and pathophysiological mechanisms underlying nephronophthisis and identifying drugs that prevent or delay renal insufficiency. Our goal is to improve genome diagnostics, genetic counselling and therapeutic options for nephronophthisis patients. Methods We employ next-generation sequencing to identify novel disease genes in 100 nephronophthisis patients included within the AGORA biobank project. The functional effect of novel mutations is assessed using in vitro and in vivo models. Genotypic and phenotypic patient characteristics are registered in a nephronophthisis database, facilitating correlation analyses and identification of early phenotypic markers. Newly identified nephronophthisis-genes are incorporated into diagnostic next-generation sequencing panels of ciliary genes. We use a systems-biology approach to identify and functionally characterize nephronophthisis-associated protein modules. Finally, we use high-throughput repurposing screens in zebrafish embryos to identify FDA-approved drugs that halt renal failure. Results With this approach, we expect to uncover the causal mutation in 60-90% of nephronophthisis patients. KOUNCIL members were involved in the recent identification of three novel genes (IFT172, WDR34 and WDR60) for nephronophthisis-related disorders. Clinical guidelines and new diagnostic tools for nephronophthisis are developed and implemented in diagnostics. We expect to identify drugs that can lead to novel therapies for nephronophthisis. Conclusion The KOUNCIL study is designed to advance understanding of renal ciliopathies and improve clinical care for nephronophthisis patients.

In the last decade, an overwhelming number of genetic aberrations have been discovered and linked to the development of treatment for cancer. With the rapid advancement of next-generation sequencing (NGS) techniques, it is expected that large-scale DNA analyses will increasingly be used to select patients for treatment with specific anticancer agents. Personalizing cancer treatment has many advantages, but sequencing germline DNA as reference material for interpreting cancer genetics may have consequences that extend beyond providing cancer care for an individual patient. In sequencing germline DNA, mutations may be encountered that are associated with increased susceptibility not only to hereditary cancer syndromes but also to other diseases; in those cases, disclosing germline data could be clinically relevant and even lifesaving. In the context of personal autonomy, it is necessary to develop an ethical and legal framework for how to deal with identified hereditary disease susceptibilities and how to return the data to patients and their families. Because clear legislation is lacking, we need to establish guidelines on disclosure of genetic information and, in the process, we need to balance privacy issues with the potential advantages and drawbacks of sharing genetic data with patients and their relatives. Importantly, a strong partnership with patients is critical for understanding how to maximize the translation of genetic information for the benefit of patients with cancer. This review discusses the ethical, legal, and counseling issues surrounding disclosure of genetic information generated by NGS to patients with cancer and their relatives. We also provide a framework for returning these genetic results by proposing a design for a qualified disclosure policy.

Wolf-Hirschhorn syndrome is characterized by severe growth and mental retardation, microcephaly, seizures and 'Greek helmet' facies, caused by partial deletion of the short arm of chromosome 4. Growth charts are given from 0-4 years of age, based on the study of 101 individuals. Use of these specific growth charts is recommended, because standard growth charts are inapplicable for patients with WHS.