Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

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

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.

Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing

Short-term costs of integrating whole-genome sequencing into primary care and cardiology settings: a pilot randomized trial.

PurposeGreat uncertainty exists about the costs associated with whole-genome sequencing (WGS).MethodsOne hundred cardiology patients with cardiomyopathy diagnoses and 100 ostensibly healthy primary care patients were randomized to receive a family-history report alone or with a WGS report. Cardiology patients also reviewed prior genetic test results. WGS costs were estimated by tracking resource use and staff time. Downstream costs were estimated by identifying services in administrative data, medical records, and patient surveys for 6 months.ResultsThe incremental cost per patient of WGS testing was $5,098 in cardiology settings and$5,073 in primary care settings compared with family history alone. Mean 6-month downstream costs did not differ statistically between the control and WGS arms in either setting (cardiology: difference = -$1,560, 95$7,558 to $3,866, p = 0.36; primary care: difference =$681, 95% confidence interval -$884 to$2,171, p = 0.70). Scenario analyses showed the cost reduction of omitting or limiting the types of secondary findings was less than $69 and$182 per patient in cardiology and primary care, respectively.ConclusionShort-term costs of WGS were driven by the costs of sequencing and interpretation rather than downstream health care. Disclosing additional types of secondary findings has a limited cost impact following disclosure

Short-term costs of integrating whole-genome sequencing into primary care and cardiology settings: a pilot randomized trial.

PurposeGreat uncertainty exists about the costs associated with whole-genome sequencing (WGS).MethodsOne hundred cardiology patients with cardiomyopathy diagnoses and 100 ostensibly healthy primary care patients were randomized to receive a family-history report alone or with a WGS report. Cardiology patients also reviewed prior genetic test results. WGS costs were estimated by tracking resource use and staff time. Downstream costs were estimated by identifying services in administrative data, medical records, and patient surveys for 6 months.ResultsThe incremental cost per patient of WGS testing was $5,098 in cardiology settings and$5,073 in primary care settings compared with family history alone. Mean 6-month downstream costs did not differ statistically between the control and WGS arms in either setting (cardiology: difference = -$1,560, 95$7,558 to $3,866, p = 0.36; primary care: difference =$681, 95% confidence interval -$884 to$2,171, p = 0.70). Scenario analyses showed the cost reduction of omitting or limiting the types of secondary findings was less than $69 and$182 per patient in cardiology and primary care, respectively.ConclusionShort-term costs of WGS were driven by the costs of sequencing and interpretation rather than downstream health care. Disclosing additional types of secondary findings has a limited cost impact following disclosure

Reconciling newborn screening and a novel splice variant in BTD

Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BTD) in homozygosity. In addition, a novel splice variant (c.44+1G>A, p.?) was identified in the invariant splice donor region of intron 1, potentially predictive of loss of function. The novel variant was predicted to impact splicing of exon 1; however, given the absence of any reported pathogenic variants in exon 1 and the presence of alternative splicing with exon 1 absent in most tissues in the GTEx database, we assigned an initial classification of uncertain significance. Follow-up medical record review of state-mandated newborn screen (NBS) results revealed an initial out-of-range biotinidase activity level. Levels from a repeat NBS sample barely passed cutoff into the normal range. To determine whether the infant was biotinidase-deficient, subsequent diagnostic enzyme activity testing was performed, confirming partial BTD, and resulted in a change of management for this patient. This led to reclassification of the novel splice variant based on these results. In conclusion, combining the genetic and NBS results together prompted clinical follow-up that confirmed partial BTD and informed this novel splice site's reclassification, emphasizing the importance of combining iterative genetic and phenotypic evaluations

Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project

Abstract Purpose Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population. Methods We compared results of NBS (including hearing screens) and ES for 159 infants in the BabySeq Project. Infants were considered "NBS positive" if any abnormal result was found indicating disease risk and "ES positive" if ES identified a monogenic disease risk or a genetic diagnosis. Results Most infants (132/159, 84%) were NBS and ES negative. Only one infant was positive for the same disorder by both modalities. Nine infants were NBS positive/ES negative, though seven of these were subsequently determined to be false positives. Fifteen infants were ES positive/NBS negative, all of which represented risk of genetic conditions that are not included in NBS programs. No genetic explanation was identified for eight infants referred on the hearing screen. Conclusion These differences highlight the complementarity of information that may be gleaned from NBS and ES in the newborn period

A curated gene list for reporting results of newborn genomic sequencing

Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately. To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project. Here, we present our curated list for 1,514 gene–disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns. Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations. Genet Med advance online publication 12 January 201

Psychosocial Effect of Newborn Genomic Sequencing on Families in the BabySeq Project: A Randomized Clinical Trial.

Importance Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on families. Objective To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of nGS on the clinical care of newborns from well-baby nurseries and intensive care units. Design, Setting, and Participants In this randomized clinical trial conducted from May 14, 2015, to May 21, 2019, at well-baby nurseries and intensive care units at 3 Boston, Massachusetts, area hospitals, 519 parents of 325 infants completed surveys at enrollment, immediately after disclosure of nGS results, and 3 and 10 months after results disclosure. Statistical analysis was performed on a per-protocol basis from January 16, 2019, to December 1, 2019. Intervention Newborns were randomized to receive either standard newborn screening and a family history report (control group) or the same plus an nGS report of childhood-onset conditions and highly actionable adult-onset conditions (nGS group). Main Outcomes and Measures Mean responses were compared between groups and, within the nGS group, between parents of children who received a monogenic disease risk finding and those who did not in 3 domains of psychosocial impact: parent-child relationship (Mother-to-Infant Bonding Scale), parents’ relationship (Kansas Marital Satisfaction Scale), and parents’ psychological distress (Edinburgh Postnatal Depression Scale anxiety subscale). Results A total of 519 parents (275 women [53.0%]; mean [SD] age, 35.1 [4.5] years) were included in this study. Although mean scores differed for some outcomes at singular time points, generalized estimating equations models did not show meaningful differences in parent-child relationship (between-group difference in adjusted mean [SE] Mother-to-Infant Bonding Scale scores: postdisclosure, 0.04 [0.15]; 3 months, –0.18 [0.18]; 10 months, –0.07 [0.20]; jointP = .57) or parents’ psychological distress (between-group ratio of adjusted mean [SE] Edinburgh Postnatal Depression Scale anxiety subscale scores: postdisclosure, 1.04 [0.08]; 3 months, 1.07 [0.11]; jointP = .80) response patterns between study groups over time for any measures analyzed in these 2 domains. Response patterns on one parents’ relationship measure differed between groups over time (between-group difference in adjusted mean [SE] Kansas Marital Satisfaction Scale scores: postdisclosure, –0.19 [0.07]; 3 months, –0.04 [0.07]; and 10 months, –0.01 [0.08]; jointP = .02), but the effect decreased over time and no difference was observed on the conflict measure responses over time. We found no evidence of persistent negative psychosocial effect in any domain. Conclusions and Relevance In this randomized clinical trial of nGS, there was no persistent negative psychosocial effect on families among those who received nGS nor among those who received a monogenic disease risk finding for their infant. Trial Registration ClinicalTrials.gov Identifier:NCT0242251