Purpose: Clinical sequencing emerging in healthcare may result in secondary findings (SFs). Methods: Seventy-four of 6,240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original ACMG-recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. Results: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. Conclusion: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near term healthcare costs; additional studies are needed to confirm these findings.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

In the originally published version of this article, Table 1 unfortunately included c.542G>A instead of c.542G>T. This mutation was correctly notated as c.

In contrast to other species, localized maternal mRNAs are not believed to be prominent features of mammalian oocytes. We find by cDNA microarray analysis enrichment for maternal mRNAs encoding spindle and other proteins on the mouse oocyte metaphase II (MII) spindle. We also find that the key translational regulator, EIF4EBP1, undergoes a dynamic and complex spatially regulated pattern of phosphorylation at sites that regulate its association with EIF4E and its ability to repress translation. These phosphorylation variants appear at different positions along the spindle at different stages of meiosis. These results indicate that dynamic spatially restricted patterns of EIF4EBP1 phosphorylation may promote localized mRNA translation to support spindle formation, maintenance, function, and other nearby processes. Regulated EIF4EBP1 phosphorylation at the spindle may help coordinate spindle formation with progression through the cell cycle. The discovery that EIF4EBP1 may be part of an overall mechanism that integrates and couples cell cycle progression to mRNA translation and subsequent spindle formation and function may be relevant to understanding mechanisms leading to diminished oocyte quality, and potential means of avoiding such defects. The localization of maternal mRNAs at the spindle is evolutionarily conserved between mammals and other vertebrates and is also seen in mitotic cells, indicating that EIF4EBP1 control of localized mRNA translation is likely key to correct segregation of genetic material across cell types.T HE oocytes of many species, both invertebrate and vertebrate, contain a large collection of localized determinants in the form of proteins and translationally inactive maternal mRNAs. Similar localized determinants in mammalian oocytes have been proposed (Ciemerych et al. 2000), but this aspect of mammalian reproduction remains controversial (Hiiragi et al. 2006). Indeed, early mammalian embryogenesis is considered to be quite plastic and regulative in nature, so that localized determinants would not be expected to play essential functions. Embryo splitting can be used for twinning, and blastomere extirpation does not prevent elaboration of normal body plans and term development. Additionally, much of the volume of the mammalian oocyte eventually becomes allocated to cells that do not contribute to embryonic development, being destined instead to generate the placenta. Accordingly, prepatterning of the mammalian oocyte through localization of maternal mRNAs or proteins, if it occurs, appears to be dispensable for mammalian embryogenesis.One potential exception to this would relate to localization within the oocyte of maternal mRNAs that support a vital process that is evolutionarily conserved between mammals and other species, namely the formation and maintenance of the meiotic spindle. Recent studies in Xenopus revealed enriched localization to spindle microtubules of mRNAs encoding spindle proteins (Blower et al. 2007). The spindle is a complex structure; proteomic studies of is...

Key Points Question What genetic testing approach is most useful in maximizing diagnostic yield for children with idiopathic epilepsy? Findings In this case series study of 151 patients referred for genetic epilepsy testing from a single academic tertiary hospital, the overall diagnostic yield was 17.9%. An initial exome-based 100-gene panel contributed 10.6%, while parental testing and reflex to exome analysis added 4.7% and 2.7%, respectively, and analysis expansion to 13 recently reported genes uncovered promising findings in 6 patients. Meaning Exome-based panels may be a useful genetic testing option for children with idiopathic epilepsy, with parental testing being informative in establishing a definitive diagnosis.

PurposeHearing loss (HL) is the most common sensory disorder in children. Prompt molecular diagnosis may guide screening and management; especially in syndromic cases when HL is the single presenting feature. Exome sequencing (ES)is an appealing diagnostic tool for HL as the genetic causes are highly heterogeneous.MethodsES was performed on a prospective cohort of 43 probands with HL. Sequence data were analyzed for primary and secondary findings. Capture and coverage analysis was performed for genes and variants associated with HL.ResultsThe diagnostic rate using ES was 37.2% compared to 15.8% with clinical HL panel. Secondary findings were discovered in three patients. For 247 genes associated with HL, 94.7% of the exons were targeted for capture and 81.7% of these exons were covered at 20× or greater. Further analysis of 454 randomly selected HL-associated variants showed 89% were targeted for capture and 75% were covered at a read depth of at least 20×.ConclusionES has an improved yield to clinical testing and may capture diagnoses not initially considered due to subtle clinical phenotypes. Technical challenges were identified, including inadequate capture and coverage of HL genes. Additional considerations of ES include secondary findings, cost, and turnaround time.

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Inherited platelet disorders (IPD) are a heterogeneous group of rare disorders that affect platelet number and function and often predispose to other significant medical complications. In spite of the identification of over 50 IPD disease-associated genes, a molecular diagnosis is only identified in a minority (10%) of affected patients without a clinically suspected etiology. We studied a cohort of 21 pediatric patients with suspected IPDs by exome sequencing (ES) to: (1) examine the performance of the exome test for IPD genes, (2) determine if this exome-wide diagnostic test provided a higher diagnostic yield than has been previously reported, (3) to evaluate the frequency of variants of uncertain significance identified, and (4) to identify candidate variants for functional evaluation in patients with an uncertain or negative diagnosis. We established a high priority gene list of 53 genes, evaluated exome capture kit performance, and determined the coverage for these genes and disease-related variants. We identified likely disease causing variants in 5 of the 21 probands (23.8%) and variants of uncertain significance in 52% of patients studied. In conclusion, ES has the potential to molecularly diagnose causes of IPD, and to identify candidate genes for functional evaluation. Robust exome sequencing also requires that coverage of genes known to be associated with clinical findings of interest need to be carefully examined and supplemented if necessary. Clinicians who undertake ES should understand the limitations of the test and the full significance of results that may be returned.