Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases.

BACKGROUND: Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. METHODS: Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem "molecular autopsy" cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. RESULTS: Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. CONCLUSIONS: The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key?

The Scripps molecular autopsy study seeks to incorporate genetic testing into the postmortem examination of cases of sudden death in the young (<45 years old). Here, we describe the results from the first 2 years of the study, which consisted of whole exome sequencing (WES) of a cohort of 50 cases predominantly from San Diego County. Apart from the individual description of cases, we analyzed the data at the cohort-level, which brought new perspectives on the genetic causes of sudden death. We investigated the advantages and disadvantages of using WES compared to a gene panel for cardiac disease (usually the first genetic test used by medical examiners). In an attempt to connect complex clinical phenotypes with genotypes, we classified samples by their genetic fingerprint. Finally, we studied the benefits of analyzing the mitochondrial DNA genome. In this regard, we found that half of the cases clinically diagnosed as sudden infant death syndrome had an increased ratio of heteroplasmic variants, and that the variants were also present in the mothers. We believe that community-based data aggregation and sharing will eventually lead to an improved classification of variants. Allele frequencies for the all cases can be accessed via our genomics browser at https://genomics.scripps.edu/browser.

Corrigendum: Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key?

[This corrects the article on p. 72 in vol. 4, PMID: 29181379.].

Physiology and immunology of Lepeophtheirus salmonis infections of salmonids.

'Sea lice' is a common name for a large number of species of marine ectoparasitic copepods, many of which are widespread and important disease-causing agents that infect both cultured and wild fish. Of these copepods, the salmon louse Lepeophtheirus salmonis is the most extensively studied because of its economic impact on the salmonid aquaculture industry and its possible impacts on wild salmonid populations. Different levels of infection by this parasite can affect the long-term survival and viability of its hosts. In this article, we review the nature of the interactions between L. salmonis and it hosts to identify crucial areas that warrant further research to aid understanding of the impact of infection with L. salmonis.

Sudden death in a neonate with idiopathic eosinophilic endomyocarditis.

A 26-day-old male infant who had been fussy and feeding poorly for a period of several hours died suddenly despite efforts at resuscitation. Postmortem examination revealed eosinophilic endomyocarditis unassociated with disease in other organs. The etiology remained unexplained after review of the medical and family histories and circumstances of death, extensive light and immunofluorescence microscopies, and microbiological, metabolic, and toxicologic testing. This appears to be the youngest reported case of eosinophilic endomyocarditis, a disorder that typically occurs in middle-age males and is often associated with benign or malignant hypereosinophilic conditions. The medical literature is reviewed.

Cardiac function and critical swimming speed of the winter flounder (Pleuronectes americanus) at two temperatures.

Using Transonic flow probes and a uniquely designed swimming flume, we directly measured cardiac parameters (Q, cardiac output; SV, stroke volume; and fH, heart rate) in winter flounder (Pleuronectes americanus) before and during critical swim speed (Ucrit) tests at 4 and 10 degrees C. Resting Q, SV and fH averaged 9.8 ml min(-1) kg(-1), 0.5 ml kg(-1) (1.0 ml g ventricle(-1)) and 21 beats min(-1) at 4 degrees C and 15.5 ml min(-1) kg(-1), 0.5 ml kg(-1) (0.95 ml g ventricle(-1)) and 34 beats min(-1) at 10 degrees C (Q10 values of 2.13, 0.91 and 2.35, for Q, SV and fH, respectively). Cardiac output, SV and fH increased by approx. 170%, 70% and 60% at both temperatures during the Ucrit test. However, cardiac parameters generally reached near maximal levels almost immediately upon swimming and remained at these levels until Ucrit (0.65 +/- 0.06 bl s(-1) at 4 degrees C and 0.73 +/ -0.07 bl s(-1) at 10 degrees C). This rapid rise in cardiac function to near maximal levels did not appear to be the result of stress alone, as Q only fell slightly when flounder were swum for 75 min at < 0.4 bl s(-1), speeds at which they appeared to swim comfortably. Our results suggest that both Q and Ucrit have been significantly overestimated in flatfishes, and that "lift-off"/slow swimming is energetically expensive. Furthermore, they show that maximum and resting stroke volume (per g of ventricle) are extremely high in the flounder as compared with other teleosts.