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This study was motivated by the hypothesis that the incidence of retained placenta (RP) in Friesian horses is associated with inbreeding. The objectives were to 1) calculate the inbreeding rate in the total registered Friesian horse population; 2) study the association of the inbreeding coefficient of the foal and the mare with the incidence of RP; and 3) study the heritability of RP in Friesian mares after normal foalings. Data from the total registered Friesian horse population from 1879 to 2000 (52,392 individuals) were collected from the registration files of the Friesian Horse Studbook. In 1999 and 2000, 495 parturitions in 436 mares were studied. From 1979 to 2000, the inbreeding rate of the total population was 1.9% per generation. The regression coefficients for the regression of the incidence of RP on inbreeding coefficients of the foal and the mare were 0.12 [+ or -] 0.052 and -0.016 [+ or -] 0.019, respectively. Mean heritability estimates of RP as a foal trait and as a mare trait were 0.046 [+ or -] 0.088 and 0.105 [+ or -] 0.123, respectively. It was concluded that, in order to avoid a further increase in the incidence of RP in Friesian mares, a decrease in the inbreeding rate by increasing the effective breeding population is required. Furthermore, the findings indicate that the high incidence of RP in Friesian horses is at least partly a result of inbreeding. Key Words: Friesian Horse, Heritability, Inbreeding, Retained Placenta

A correction to the article "CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy," is presented.

Whole-genome sequencing (WGS) can provide valuable health insight for research participants or patients. Opportunities to be sequenced are increasing as direct-to-consumer (DTC) testing becomes more prevalent, but it is still fairly unusual to have been sequenced. We offered WGS to fourteen professionals with pre-existing familiarity with an interest in human genetics - healthcare, science, policy and art. Participants received a hard drive containing their personal sequence data files (.BAM,.gvcf), without further explanation or obligation, to consider how experiencing WGS firsthand might influence their professional attitudes. We performed semi-structured pre- and post-sequencing interviews with each participant to identify key themes that they raised after being sequenced. To evaluate how their experience of the procedure evolved over time, we also conducted a questionnaire to gather their views 3 years after receiving their genomic data. Participants were generally satisfied with the experience (all 14 participants would choose to participate again). They mostly decided to participate out of curiosity (personal) and to learn from the experience (professional). Whereas most participants slightly developed their original perspective on genetic data, a small selection of them radically changed their views over the course of the project. We conclude that personal experience of sequencing provides an interesting alternative perspective for experts involved in leading, planning, implementing or researching genome sequencing services. Moreover, the personal experience may provide professionals with a better understanding of the challenges visitors of the Genetics Clinic of the Future may face., (© 2022. The Author(s).)

Clinical application of whole-exome and whole-genome sequencing (WES and WGS) has led to an increasing interest in how it could drive healthcare decisions. As with any healthcare innovation, implementation of next-generation sequencing in the clinic raises questions on affordability and costing impact for society as a whole. We retrospectively analyzed medical records of 370 patients with ID who had undergone WES at various stages of their diagnostic trajectory. We collected all medical interventions performed on these patients at the University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. We categorized the patients according to their WES-based preliminary diagnosis ("yes", "no", and "uncertain"), and assessed the per-patient healthcare activities and corresponding costs before (pre) and after (post) genetic diagnosis. The WES-specific diagnostic yield among the 370 patients was 35% (128 patients). Pre-WES costs were €7.225 on average. Highest average costs were observed for laboratory-based tests, including genetics, followed by consults. Compared to pre-WES costs, the post-WES costs were on average 80% lower per patient, irrespective of the WES-based diagnostic outcome. Application of WES results in a considerable reduction of healthcare costs, not just in current settings, but even more so when applied earlier in the diagnostic trajectory (genetics-first). In such context, WES may replace less cost-effective traditional technologies without compromising the diagnostic yield. Moreover, WES appears to harbor an intrinsic "end-of-trajectory" effect; regardless of the diagnosis, downstream medical interventions decrease substantially in both number and costs.

Although the benefits of next-generation sequencing (NGS) for the diagnosis of heterogeneous diseases such as intellectual disability (ID) are undisputed, there is little consensus on the relative merits of targeted enrichment, whole-exome sequencing (WES) or whole-genome sequencing (WGS). To answer this question, WES and WGS data from the same nine samples were compared, and WES was shown not to miss any variants identified by WGS in a gene panel including ∼500 genes linked to ID (500GP). Additionally, deeply sequenced WES data were shown to adequately cover ∼99% of the 500GP; thus, little additional benefit was to be expected from a targeted enrichment approach. To reduce costs, minimal sequencing criteria were determined by investigating the relation between sequenced reads and outcome parameters such as coverage and variant yield. Our analysis indicated that 60 million reads yielded a mean coverage of ∼60×: ∼97% of the 500GP sequences were sufficiently covered to exclude variants, whereas variant yield was ∼99.5% and false-positive and false-negative rates were controlled. Our findings indicate that WES is currently the optimal approach to ID diagnostics. This result depends on the capture kit and sequencing strategy used. The developed framework however is amenable to other sequencing approaches., (© 2015 WILEY PERIODICALS, INC.)

The scope of next-generation DNA sequencing (NGS) is transitioning from research to diagnostics (and beyond), but the conditions for routine clinical application have not been clearly defined. Technological limitations for sequencing a patient's DNA fast and affordably are rapidly disappearing. At the same time, more and more is known about the role of DNA variation in disease susceptibility, disease development and response to treatment. Consequently, more and more pediatricians, cardiologists and other medical specialists would like to apply NGS-based diagnostics. The standard, comprehensive and easy-to-handle genetic test these specialists are looking for, however, is not yet available. Molecular diagnostic laboratories have started to implement NGS into their routine workflows, but are also becoming increasingly aware that the context in which they operate is changing. It becomes apparent that the major challenges are not in the technology, but rather in anticipating the changing scope and scale. Developing the infrastructure to sustainably perform NGS-based diagnostics in a changing technological, clinical and societal context is therefore more relevant than defining minimal performance criteria or standard analysis pipelines. Implementing NGS-based diagnostics comes with novel applications, emerging service models and reconfiguration of professional roles, and should thus be considered in the context of future healthcare. Here, we present the key elements for transition of NGS from research to diagnostics.

ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation., ((c) 2010 Wiley-Liss, Inc.)

Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are MYT1L, CTNND2, NRXN1, and ASTN2, genes that play an important role in neuronal functioning but--except for NRXN1--have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.