Dataset Information

Genome sequencing as a first-line diagnostic test for hospitalized infants.

ABSTRACT:

Purpose

SouthSeq is a translational research study that undertook genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern United States, which are historically underrepresented in genomic medicine research.

Methods

GS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing.

Results

Definitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 30% of infants, and 14% of infants harbored an uncertain result. Only 43% of DD/LD findings were identified via concurrent clinical genetic testing, suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups.

Conclusion

We describe one of the largest-to-date GS cohorts of ill infants, enriched for African American and rural patients. Our results show the utility of GS because it provides early-in-life detection of clinically relevant genetic variations not detected by current clinical genetic testing, particularly for infants exhibiting certain phenotypic features.

SUBMITTER: Bowling KM

PROVIDER: S-EPMC8995345 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Genome sequencing as a first-line diagnostic test for hospitalized infants.

Bowling Kevin M KM Thompson Michelle L ML Finnila Candice R CR Hiatt Susan M SM Latner Donald R DR Amaral Michelle D MD Lawlor James M J JMJ East Kelly M KM Cochran Meagan E ME Greve Veronica V Kelley Whitley V WV Gray David E DE Felker Stephanie A SA Meddaugh Hannah H Cannon Ashley A Luedecke Amanda A Jackson Kelly E KE Hendon Laura G LG Janani Hillary M HM Johnston Marla M Merin Lee Ann LA Deans Sarah L SL Tuura Carly C Williams Heather H Laborde Kelly K Neu Matthew B MB Patrick-Esteve Jessica J Hurst Anna C E ACE Kandasamy Jegen J Carlo Wally W Brothers Kyle B KB Kirmse Brian M BM Savich Renate R Superneau Duane D Spedale Steven B SB Knight Sara J SJ Barsh Gregory S GS Korf Bruce R BR Cooper Gregory M GM

Genetics in medicine : official journal of the American College of Medical Genetics 20211127 4

<h4>Purpose</h4>SouthSeq is a translational research study that undertook genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern United States, which are historically underrepresented in genomic medicine research.<h4>Methods</h4>GS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing. ...[more]

PMID: 34930662

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Project description:ImportanceChildren with medical complexity (CMC) represent a growing population in the pediatric health care system, with high resource use and associated health care costs. A genetic diagnosis can inform prognosis, anticipatory care, management, and reproductive planning. Conventional genetic testing strategies for CMC are often costly, time consuming, and ultimately unsuccessful.ObjectiveTo evaluate the analytical and clinical validity of genome sequencing as a comprehensive diagnostic genetic test for CMC.Design, setting, and participantsIn this cohort study of the prospective use of genome sequencing and comparison with standard-of-care genetic testing, CMC were recruited from May 1, 2017, to November 30, 2018, from a structured complex care program based at a tertiary care pediatric hospital in Toronto, Canada. Recruited CMC had at least 1 chronic condition, technology dependence (child is dependent at least part of each day on mechanical ventilators, and/or child requires prolonged intravenous administration of nutritional substances or drugs, and/or child is expected to have prolonged dependence on other device-based support), multiple subspecialist involvement, and substantial health care use. Review of the care plans for 545 CMC identified 143 suspected of having an undiagnosed genetic condition. Fifty-four families met inclusion criteria and were interested in participating, and 49 completed the study. Probands, similarly affected siblings, and biological parents were eligible for genome sequencing.ExposuresGenome sequencing was performed using blood-derived DNA from probands and family members using established methods and a bioinformatics pipeline for clinical genome annotation.Main outcomes and measuresThe primary study outcome was the diagnostic yield of genome sequencing (proportion of CMC for whom the test result yielded a new diagnosis).ResultsGenome sequencing was performed for 138 individuals from 49 families of CMC (29 male and 20 female probands; mean [SD] age, 7.0 [4.5] years). Genome sequencing detected all genomic variation previously identified by conventional genetic testing. A total of 15 probands (30.6%; 95% CI 19.5%-44.6%) received a new primary molecular genetic diagnosis after genome sequencing. Three individuals had novel diseases and an additional 9 had either ultrarare genetic conditions or rare genetic conditions with atypical features. At least 11 families received diagnostic information that had clinical management implications beyond genetic and reproductive counseling.Conclusions and relevanceThis study suggests that genome sequencing has high analytical and clinical validity and can result in new diagnoses in CMC even in the setting of extensive prior investigations. This clinical population may be enriched for ultrarare and novel genetic disorders. Genome sequencing is a potentially first-tier genetic test for CMC.

Project description:BackgroundScreening for short tandem repeat (STR) expansions in next-generation sequencing data can enable diagnosis, optimal clinical management/treatment, and accurate genetic counseling of patients with repeat expansion disorders. We aimed to develop an efficient computational workflow for reliable detection of STR expansions in next-generation sequencing data and demonstrate its clinical utility.MethodsWe characterized the performance of eight STR analysis methods (lobSTR, HipSTR, RepeatSeq, ExpansionHunter, TREDPARSE, GangSTR, STRetch, and exSTRa) on next-generation sequencing datasets of samples with known disease-causing full-mutation STR expansions and genomes simulated to harbor repeat expansions at selected loci and optimized their sensitivity. We then used a machine learning decision tree classifier to identify an optimal combination of methods for full-mutation detection. In Burrows-Wheeler Aligner (BWA)-aligned genomes, the ensemble approach of using ExpansionHunter, STRetch, and exSTRa performed the best (precision = 82%, recall = 100%, F1-score = 90%). We applied this pipeline to screen 301 families of children with suspected genetic disorders.ResultsWe identified 10 individuals with full-mutations in the AR, ATXN1, ATXN8, DMPK, FXN, or HTT disease STR locus in the analyzed families. Additional candidates identified in our analysis include two probands with borderline ATXN2 expansions between the established repeat size range for reduced-penetrance and full-penetrance full-mutation and seven individuals with FMR1 CGG repeats in the intermediate/premutation repeat size range. In 67 probands with a prior negative clinical PCR test for the FMR1, FXN, or DMPK disease STR locus, or the spinocerebellar ataxia disease STR panel, our pipeline did not falsely identify aberrant expansion. We performed clinical PCR tests on seven (out of 10) full-mutation samples identified by our pipeline and confirmed the expansion status in all, showing absolute concordance between our bioinformatics and molecular findings.ConclusionsWe have successfully demonstrated the application of a well-optimized bioinformatics pipeline that promotes the utility of genome-wide sequencing as a first-tier screening test to detect expansions of known disease STRs. Interrogating clinical next-generation sequencing data for pathogenic STR expansions using our ensemble pipeline can improve diagnostic yield and enhance clinical outcomes for patients with repeat expansion disorders.

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Dataset Information

Genome sequencing as a first-line diagnostic test for hospitalized infants.

Purpose

Methods

Results

Conclusion

Publications

Genome sequencing as a first-line diagnostic test for hospitalized infants.

Similar Datasets

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